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We observed that false-positive results involved: a metabolite of zolpidem that might have been mistaken for lysergic acid diethylamide, benzoylecgonine mistaken for atropine, and clomipramine and 3 phenothiazines that share several common ion transitions.
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The nigrostriatal dopaminergic neurons of the substantia nigra pars compacta (SNc) and the nondopaminergic neurons of the substantia nigra pars reticulata (SNr) receive a dense synaptic input from the serotonergic neurons of the raphe nuclei. To assess whether serotonin [5-hydroxytryptamine (5-HT)] spontaneously released at the substantia nigra could modulate motor activity, the 5-HT reuptake inhibitors (SRIs), duloxetine (6-12 nmol) and clomipramine (12 nmol), were unilaterally microinjected either into the SNc or the SNr of freely moving rats, and the circling behavior was counted with an automated rotometer. In the SNc, the main effect of the SRIs was a contraversive circling behavior that was not observed when applied at distances > or = 0.2 mm above the SNc. The circling induced by clomipramine was blocked by microinjection of haloperidol (53 nmol) into the ipsilateral neostriatum, suggesting that the circling elicited by microinjection of the SRIs into the SNc depends on an intact striatal dopaminergic transmission. Microinjection of 5-HT (21 nmol) only produced a significant contraversive circling response when it was coinjected with the SRIs. Pretreatment with methysergide (1 mg/kg ip), a nonselective 5-HT(2) antagonist, did not block the circling elicited by microinjection of clomipramine into the SNc, either alone or in combination with 5-HT. However, microinjection of the 5-HT(2) antagonist mianserin (2 nmol) into the SNc partially inhibited the circling induced by duloxetine (6 nmol), alone or coinjected with 5-HT. Since current theories of circling behavior hypothesize that the animal turns away from the cerebral hemisphere where dopamine neurotransmission predominates, these results suggest that the contraversive circling induced by the unilateral microinjection of SRIs into the SNc could be mediated by a 5-HT-induced increase of firing frequency of nigrostriatal dopaminergic neurons. When applied into the SNr, clomipramine and duloxetine also elicited a contraversive circling behavior and enhanced the circling induced by 5-HT. Systemic methysergide (1 mg/kg i.p.), but not intranigral mianserin (2 nmol), blocked the circling elicited by microinjection of clomipramine into the SNr, either alone or in combination with 5-HT. These results suggest that 5-HT(2)-like receptors are involved in the contraversive circling induced by enhancement of serotonergic transmission in the SNr.
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1. The cardiovascular responses of mianserin hydrochloride and tricyclic antidepressant drugs were investigated using non-invasive methods of cardiac investigation. A study of the interaction of mianserin and antihypertensive drug therapy is reported. 2. In six normal volunteers, mianserin hydrochloride 20 mg was shown to prolong the corrected Q-T interval at 150 min (P less than 0.001). It did not affect heart rate, systolic time intervals or the peak normalized derivative of the apexcardiogram. Amitriptyline 50 mg increased the corrected pre-ejection period interval (PEPI) and the PEP/left ventricular ejection time (LVET) ratio of the systolic time intervals at 150 min (P less than 0.001). Q-T interval was shortened at 90 minutes. 3. In a double-blind patient study, clomipramine increased heart rate, P-R interval, QRS and corrected Q-T interval in one patient at 2 weeks. Mianserin prolonged corrected Q-T interval at 1 week but this returned to the pretreatment time by 2 weeks in two patients. 4. In an open study, mianserin 20 mg three times daily did not antagonize the hypotensive action of propranolol or propranolol and hydrallazine in three patients. 5. In a double-blind study in three patients with desmethylimipramine 25 mg three times daily, mianserin 20 mg three times daily did not antagonize the hypotensive action of either guanethidine or bethanidine.
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We have previously found that tricyclic antidepressants (TCAs) induce apoptosis in quiescent human lymphocytes. The aim of the present study was to evaluate if TCAs induce apoptosis in proliferating human lymphocytes and in established blastoid lymphocytes also. The development of conA-induced lymphoblast populations was followed by measuring the CD25 membrane expression. Three TCA compounds were run with the following concentrations: imipramine (10, 20, 30, 40, 60 microM), clomipramine (1, 10, 20, 30, 40 microM) and citalopram (40, 60, 80, 100, 180 microM). They all induced a dose-dependent apoptosis both in continuously transformed, as well as in established lymphoblasts. Preincubation of the TCA up to 48 h did not significantly increase induction of apoptosis. The three drugs tested were found to be potent inducers of apoptosis in proliferating lymphocytes. Furthermore, we found that the apoptotic populations in proliferating and in established blastoid lymphocytes were of fairly the same magnitude than in the corresponding population in TCA-incubated resting lymphocytes. In conclusion, we demonstrate that TCAs induce apoptosis in proliferating lymphocytes, as they do in quiescent lymphocytes. Furthermore, the extent of apoptosis was even more pronounced in TCA-incubated lymphoblasts compared to TCA-treated resting lymphocytes.
The onset of disease of case one was started with epilepsy with myoclonic seizure. After half a year, catalepsy induced by emotion especially laughing and excessive daytime sleepiness appeared. MSLT was positive and hypocretin 1 level decreased. Narcolepsy-cataplexy was definitely diagnosed in this case. Valproate was given and seizure was controlled completely, but the excessive daytime sleepiness was aggravated. Combination of valproate, methylphenidate and clomipramine treatment improved the symptoms of narcolepsy and the patient was still free of epileptic seizures. The onset symptoms of case 2 were catalepsy and excessive daytime sleepiness. MSLT was positive. The treatment was ineffective because of bad compliance. After 2 years, episodes of impairment of consciousness with automatism occurred. VEEG showed slow waves and spikes in right temporal area. Complex partial seizure was determined. Oxcarbazepine was used and then the patients became seizures free, but the symptoms of narcolepsy were still obvious.
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Clinical and preclinical research suggests a major role of mesocortical dopamine (DA) in psychopathology through regulation of subcortical, especially mesoaccumbens, DA functioning. In these experiments we demonstrate that the high vulnerability to stress-induced 'despair' and mesoaccumbens DA inhibition, exhibited by mice of the inbred strain C57BL/6 (C57) in a common animal model of depression, depends on their being highly susceptible to stress-induced mesocortical DA activation. Thus, C57 mice but not mice of the DBA/2 strain showed an extremely high level of immobility on their first experience with the forced swimming test (FST) as well as immediate and strong activation of mesocortical DA metabolism and inhibition of mesoaccumbens DA metabolism and release. In addition, the behavioral and the mesoaccumbens DA responses to FST in C57 mice were reduced and reversed, respectively, by bilateral mesocortical DA depletion. Finally, chronic treatment with the antidepressant clomipramine reduced immobility and eliminated both mesocortical DA activation and mesoaccumbens DA inhibition in response to FST. These results suggest that a genetically determined susceptibility to stress by the mesocortical DA system may favor the development of pathological behavioral responses through inhibition of subcortical DA transmission.
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The authors sought to determine the efficacy of antidepressants in dysthymic disorder and to compare antidepressant and placebo response rates between major depressive disorder (MDD) and dysthymic disorder.
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Debrisoquine hydroxylation phenotype was determined in 22 psychiatric patients who had previously developed exceptionally high serum antidepressant (AD) concentrations, and in 22 sex-, age-, and dose-matched counterparts who had low to normal serum AD levels. The patients were recruited from 641 subjects in whom serum AD levels were monitored. In each AD level group, 16 patients had been treated with tricyclic antidepressants (amitriptyline, doxepin, trimipramine, imipramine, clomipramine) and 6 with mianserin. Eight poor metabolizer (PM) phenotypes (debrisoquine/hydroxydebrisoquine ratio in 6-hour urine greater than or equal to 41.5) were identified in the high AD level group, but only two in the group with low to normal AD level (p = 0.03, Fisher's test). Comedications in the two study groups did not differ markedly from ach other and could not, therefore, explain the greater frequency of PMs among the patients with high serum AD levels. Three of 6 mianserin patients, who had developed high serum AD levels, were PMs. This high proportion of PMs raises the question of a possible involvement of the same metabolic pathway (cytochrome P-450IID6 isoenzyme) also in mianserin hydroxylation. The results suggest further that during AD therapy with standard dosage, PM phenotypes are at special risk for high serum AD concentrations and, consequently, for clinical symptoms of toxicity.
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Although data extraction from reviews was optimised when more than one review reported data for the same RCT, the reliability of the data extraction within these reviews cannot be guaranteed by this assessment report.
In a series of 74 experiments in a double blind study, 25 healthy test persons were medicated with a single dose of Clomipramin, Desipramin, Imipramin, Diazepam, Carbamazepin, Haloperidol, and a placebo. At the end of one hour, and again at the end of three hours, an EEG was made whose frequency analysis revealed significant changes in about half the test persons. The antidepressives induced an increase in the theta waves, the slow alpha waves, and the slow beta waves, and a decrease in the fast alpha waves. The factors influencing the EEG are discussed.
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Dose equivalence of antidepressants is critically important for clinical practice and for research. There are several methods to define and calculate dose equivalence but for antidepressants, only daily defined dose and consensus methods have been applied to date. The purpose of the present study is to examine dose equivalence of antidepressants by a less arbitrary and more systematic method.
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Studying 12 women and 13 pregnancies, we found no changes in mean clomipramine concentrations, a statistically significant decrease in mean desmethylclomipramine concentrations (p = 0.014) and a significant decrease in the ratio of desmethylclomipramine/clomipramine mean concentrations during pregnancy (p = 0.014) compared to the post-partum period. Sub-therapeutic concentrations of clomipramine and desmethylclomipramine were found in three patients during whole pregnancy.
Two forms of drug administration, i.e., systemic subcutaneous administration and microinjection into the medial amygdala were employed to examine the effect of chronic administration of psychotropic drugs on muricide in olfactory bulbectomized rats. Muricide inhibition induced by the systemic doses of chlorpromazine (CPZ) 10 mg/kg and diazepam 10 mg/kg was reduced with chronic administration, while that by desipramine (DMI) 10 mg/kg and amitriptyline 30 mg/kg was augmented with chronic administration. Muricide inhibition induced by microinjection of CPZ was also reduced, while that by DMI was augmented. These results indicate that muricide by olfactory bulbectomized rats is a useful animal model for evaluating antidepressants and that a potential site of action of antidepressants is located in the medial amygdala.
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To assess the efficacy of clomipramine for treatment of canine compulsive disorder (CCD).
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Mianserin (60 mg daily) was compared with chlorimipramine (150 mg daily) in the treatment of 145 depressed in- and outpatients in four centres. The trial was double-blind and fully randomized. Both drugs were effective antidepressants. No significant differences in efficacy could be demonstrated by means of the Hamilton rating scale for depression, the Beck self-rating scale or the clinical global impression, for both in- and outpatients. Hypotension, dry mouth and tremor increased significantly more in inpatients with chlorimipramine than with mianserin. At the end of treatment weight gain was increased significantly more in outpatients after treatment with mianserin. No differences could be demonstrated between the drugs for other side-effects.
9 male and 9 female Beagles.
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Possible involvement of prostaglandins (PG) in the antimyoclonic action of clonazepam was examined in the p,p'-DDT-animal model of myoclonus. PG synthesis inhibitors and the PG antagonist polyphloretin phosphate (PPP) counteracted the antimyoclonic action of clonazepam in mice. PGE2 reduced DDT-induced myoclonus; this effect was blocked by PPP. Another antimyoclonic drug combination, L-5-hydroxytryptophan plus chlorimipramine, was not blocked by PPP or indomethacin. The antimyoclonic action of clonazepam may be mediated by enhancement of PG synthesis.
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Two pharmacotherapy and three psychotherapy trials were eligible for inclusion in the review, with data from four short-term RCTs (169 participants) available for analysis. Response data from a single placebo-controlled trial of fluoxetine suggested overall superiority of medication relative to placebo (relative risk (RR) 3.07, 95% CI 1.4 to 6.72, n = 67). Symptom severity was also significantly reduced in the RCTs of fluoxetine and clomipramine (relative to desipramine), as well as in the two CBT trials (WMD -44.96, 95% CI -54.43 to -35.49, n = 73). A low relapse rate (4/22) was demonstrated in one trial of CBT.
Intrahepatic flow disturbance may have important pharmacological and toxicological significance. However, apart from pathological conditions, flow disturbance by drugs has received little attention. In the isolated perfused rat liver (IPRL), we found that infusion of tricyclic antidepressants increased portal perfusion pressure (PP) with a coincidental decrease in oxygen uptake at concentrations of 3-30 microM; the order of potency was clomipramine > amitriptyline > imipramine approximately nortriptyline > desipramine. The characteristics of clomipramine action were as follows: (1) The extrahepatic portal vein was much less sensitive to clomipramine than the IPRL. (2) Changes in PP and oxygen uptake required Ca(2+) in the perfusate and were inhibited by papaverine, staurosporine, sodium nitroprusside and indomethacin. (3) Compared with endothelin-1, clomipramine produced a greater decrease in the ratio of oxygen uptake/PP together with a greater overflow of loaded indocyanine green for an increase in PP by about 2 cm H(2)O. (4) Vital staining with trypan blue and rhodamine 6G and histological examinations revealed that 3-10 microM clomipramine produced marked flow redistribution due to the constriction of portal vein branches. Portal flow was short-circuited to the hepatic vein at a deeper and hilar portion of the liver, with minimal perfusion of the periphery. These results demonstrate an example of drug-induced intrahepatic flow disturbance in vitro. Its contribution to the development of toxicity in vivo remains to be studied.
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Triage Plus was found to be an accurate device for the detection of tricyclic antidepressants in urine at the stated cut-off value of 1000 ng/mL tricyclic antidepressant. With the exception of cyclobenzaprine, significant cross-reactivity was not observed with other drugs commonly encountered in emergency department admissions.
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Caffeine undergoes 3-N-demethylation via CYP1A2, as well as 1-N-demethylation, 7-N-demethylation and 8-hydroxylation, which may involve other CYP isoenzymes. The aim of the present study was to investigate the influence of clomipramine, desipramine, sertraline, nefazodone and mirtazapine on cytochrome P-450 activity measured by caffeine oxidation in rat liver microsomes. The obtained results showed that all the investigated antidepressants, with an exception of mirtazapine, added in vitro to liver microsomes had an inhibitory effect on caffeine metabolism (via competitive or mixed mechanism), though their potency towards particular metabolic pathways was different. Dixon analysis of caffeine metabolism carried out in the control liver microsomes, in the absence and presence of the antidepressant drugs showed that desipramine and clomipramine exerted the most potent inhibitory effect on caffeine metabolism. Desipramine decreased the rates of 1-N-, 3-N- and 7-N-demethylations, and 8-hydroxylation of caffeine (Ki = 23.3, 36.6, 23.3 and 63.3 microM, respectively), the effect on 1-N- and 7-N-demethylation being the most pronounced. Clomipramine showed distinct inibition of 1-N- and 3-N-demethylation and 8-hydroxylation of caffeine, the effects on N-demethylations being the most pronounced (Ki = 38.6, 34.8, 45.6 microM, respectively). Its effect on 7-N-demethylation was rather weak (Ki = 97.8 microM). Sertraline decreased significantly the rate of 1-N- and 3-N-demethylation and 8-hydroxylation (Ki = 37.3, 69.3 and 64 microM, respectively), while its effect on 7-N-demethylation of caffeine was less pronounced (Ki = 92.1 microM). Nefazodone displayed clear effect on 3-N- and 7-N-demethylation (Ki = 68.8 and 66.4 microM, respectively), but was weak in inhibiting 1-N-demethylation and 8-hydroxylation of caffeine (Ki = 110 and 186 microM, respectively). In contrast to the above-tested antidepressants, mirtazapine did not decrease significantly the oxidation rates of 3-N-demethylation or 8-hydroxylation (Ki = 264 and 455 microM, respectively) and had no effect on other oxidation pathways of caffeine. In summary, we have observed intra- and inter-drug differences in the inhibitory effects of the antidepressants on the four oxidation pathways of caffeine in rat liver microsomes. The tested antidepressants (with an exception of mirtazapine) may lead to drug-drug metabolic interactions at a level of a few CYP isoforms. The obtained results provide further indirect evidence that apart from CYP1A2, other CYP isoforms are also important for the metabolism of caffeine.
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The effects of 5-hydroxytryptamine (5-HT) and 5-HT uptake inhibitors on the dissociation of [3H]paroxetine from rat brain membrane binding sites have been investigated. The dissociation induced by 5-HT (100 microM), paroxetine (0.15 microM), clomipramine (1 microM), citalopram (1 microM), imipramine (1 microM), or norzimeldine (1 microM) was consistent with first-order dissociation kinetics with half-life values of dissociation (t1/2) between 130 and 140 min. The dissociation induced by the combination of 5-HT (100 microM) with either citalopram (1 microM) or imipramine (1 microM) was not different from that initiated by either agent alone. These dissociation data, which are at variance with previous data on the 5-HT transporter labeled with [3H]imipramine, support a single-site model of the antidepressant binding/5-HT uptake site.
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A total of 97 patients, who participated in two studies on the relationship between the clinical effect and plasma levels of imipramine and clomipramine, were examined for improvement curves by use of weekly ratings on the Hamilton Depression Scale (HDS). Although we confirmed that our six-item HDS subscale, in contrast to the total 17-item HDS, was a one-dimensional measure of depression, the Rasch analysis showed that the weekly improvement in subscale scores only applied to the individual patient, i.e. an average improvement curve for a group of depressed patients is an abstraction to which the individual curves cannot be transferred. Our results indicate, however, that when the subscale scores are transformed into three clinical categories of depression: no, mild (minor), moderate/-severe (major) they could be described by a common improvement curve for all patients. This is illustrated by the percentage of patients who, week to week, changed from major to minor or no depression, or from minor to no depression. We found no specific improvement pattern for imipramine or clomipramine which could be used diagnostically. There is reason to assume that patients completing a controlled trial necessarily will follow a monotonic improvement curve, and the improvement pattern of all patients fulfilling the entry criteria should, therefore, always be reported. The present study thus indicates that calculation of average improvement curves is neither clinically nor statistically meaningful, and should be replaced by measures of changes in number of patients in different main severity categories, or by the final rating score. No difference in outcome between imipramine and clomipramine was shown neither on the subscale nor on the 17-item HDS.
Tianeptine, an antidepressant drug enhancing 5-HT uptake, was given to pregnant rats in the last 15 days of gestation and different neurotransmitter receptors as well as 5-HT2 receptor-linked inositol phosphate formation were measured in the brains of the offspring. Prenatal exposure to tianeptine significantly decreased the density of 3H-imipramine binding sites in the cerebral cortex of the pups without affecting beta-adrenoceptors, serotonin 5-HT2 and 5-HT1B receptors or inositol phosphate formation after a 5-HT challenge. Striatal dopamine D2 receptors labelled with 3H-spiroperidol were not changed but an apparent increase in the affinity of dopamine was noticed in the pups prenatally exposed to the drug. The results show that the neurochemical profile of tianeptine markedly differs from that of most antidepressants.
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Chronic treatment of young rodents with drugs altering monoamine metabolism has been reported to produce lasting effects on behavior that resemble human affective disorders. To test the generality of this finding, scopolamine, imipramine, or clomipramine was injected daily between the ages of 8 and 21 days in golden hamsters. Wheel-running rhythms were monitored continuously from the age of 4 to 20 weeks of age to test the hypothesis that neonatal treatments would lower the amplitude of biological activity rhythms in adults. Of these three neonatal treatments only scopolamine altered running rhythms, significantly increasing the amplitude of running rhythms in adult hamsters under both entrained and free-running conditions. Hamsters treated neonatally with scopolamine were also more sensitive to the hypothermic effects of the muscarinic agonist, oxotremorine, as adults. These data indicate that neonatal exposure to cholinergic receptor blockade may produce long-lasting changes in biological rhythm characteristics related to upregulation of muscarinic receptors.
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Consecutive patients with pathologically confirmed, stage 4 SCLC were analyzed in this retrospective study. Patients that were prescribed statins, aspirin, clomipramine (tricyclic antidepressant; TCA), selective serotonin reuptake inhibitors (SSRIs), doxazosin or prazosin (α1-adrenergic receptor antagonists; ADRA1) were identified.
Challenge with intravenous clomipramine (CMI) is serotonin selective and has been reported to transiently exacerbate symptoms in obsessive-compulsive disorder (OCD) patients, and to predict subsequent response to oral CMI therapy.
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Chagas infection is a major endemic disease affecting Latin American countries. The persistence of Trypanosoma cruzi generates a chronic inflammatory reactivity that induces an immune response directed to the host's tissues. The effectiveness of the treatment in the chronic phase is still unsatisfactory due, amongst other reasons, to the collateral effects of the drugs used. We investigated the effect of clomipramine, a tricyclic antidepressant that, when used as a treatment of T. cruzi-chronically infected mice, inhibits trypanothione reductase, an exclusive and vital enzyme of T. cruzi. Clomipramine improved survival (P<0.05) by diminishing the parasite intensity as demonstrated by PCR studies in the heart and skeletal muscle, and significantly prevented the evolution to fibrosis of the inflammatory infiltrates. Clomipramine could be a good candidate for the treatment of chronic Chagas disease.
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In clinical studies of antidepressants, the Hamilton Depression Rating Scale (HAMD) total score has been the gold standard instrument for establishing and comparing the efficacy of new treatments. However, the HAMD is a multidimensional measure, which may reduce its ability to detect differences between treatments, in particular, changes in core symptoms of depression. Two meta-analyses were conducted to compare the responsiveness of the HAMD total score with several published unidimensional subscale scores based upon core symptoms of depression. The first compared the above instrument's ability to detect differences between fluoxetine and placebo across eight studies involving over 1600 patients. The second analysis involved four studies and over 1200 patients randomized to tricyclic antidepressants and placebo. In both meta-analyses, the unidimensional core subscales outperformed the HAMD total score at detecting treatment differences. The implications of this on sample sizes and power for clinical studies will be discussed. In fact, studies based on the observed effect sizes from the core subscales would require approximately one-third less patients than studies based on the HAMD total score. Effect sizes from each individual HAMD item will also be presented to help explain the differences in responsiveness between the scales.
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In this study, we describe a simple and rapid method for the determination of the antipsychotic drug clozapine and five commonly co-administered antidepressants - bupropion, mirtazapine, sertraline, clomipramine and citalopram - in serum, plasma and whole blood. Sample preparation includes solid phase extraction of analytes and determination of drug concentrations by gas chromatography-mass spectrometry without any derivatization steps. The method was fully validated according to international criteria and can be successfully applied for routine analyses. Correlation coefficients of calibration curves for the tested drugs in the three specimens were in the range 0.9977-0.9999. Intra-day and inter-day precisions ranged from 0.81-7.85% and 3.60-12.91% respectively for the studied analytes and matrices. Recoveries were satisfactory for different concentrations of each drug in each specimen allowing accurate determinations in the range from sub-therapeutic to toxic levels. The presented method shows acceptable sensitivity, linearity in wide concentration ranges (sub-therapeutic, therapeutic, supra-therapeutic/toxic levels), it is simple and rapid and it is applicable for qualitative and quantitative routine toxicological analyses of clinical and postmortem cases.