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The tricyclic antidepressant drugs: imipramine, opipramol, amitryptiline and nortryptiline inhibit development of experimental arterial hypertension in rats.
Somatoform disorders are common conditions. Provided that the diagnostic criteria are known, however, they are not difficult to diagnose. In this connection, the family doctor has it within his power, by initiating empathic client-centred (conversation) therapy with the patient, to create a basis for a confidence-building and a long-lasting physician-patient relationship. In addition to a psychotherapeutic intervention or psychodynamic treatment or behavioral treatment, we now have the first positive results of a psychopharmacological treatment regimen with opipramol and the St. John's Wort extract LI 160.
Charged carboxymethyl-beta-cyclodextrin was successful in the capillary electrophoretic separation of a series of tricyclic antidepressants. The cyclodextrin alone was successful in the separation of carbamazepine, protriptyline, desipramine, clomipramine, and opipramol using a 3-(trimethoxysilyl)propyl methacrylate capillary coating to reduce the electroosmotic flow. The ideal buffer pH was found to be in the range of 6-7 and the ideal cyclodextrin concentration to be 10 mM. All nine antidepressants were resolved using the charged cyclodextrin in the micellar electrokinetic chromatography (MEKC) mode with sodium dodecyl sulfate as the surfactant. Neither the cyclodextrin nor the surfactant alone were successful in resolving the whole series of compounds under investigation but a combination of both produced the separation. Separations were performed on a linear polyacrylamide coated capillary. The ideal pH of the buffer was in the range of 5-7.
We studied neuroprotective properties of 12 structurally different sigma site ligands in primary rat hippocampal cell cultures and analyzed whether they interfere with glutamate-induced activation of the nitric oxide synthase (NOS) pathway. Neurotoxicity was triggered with 1 mM glutamate on day 8 of culture. Cells were treated with various concentrations of the compounds for 7 days before glutamate exposure (prolonged pretreatment), or during glutamate exposure (acute treatment). Protection was seen after prolonged pretreatment (long-term protection) with sabeluzole, opipramole, haloperidol, ifenprodil, fenpropimorph, carbetapentane, and tiospirone, with pIC50s of 7.30, 7.15, 6.87, 6.68, 6.66, 6.39, and 6.34, respectively. There was no protection with PD 128298, 1,3-ortho-di-tolylguanidine, BMY-14802, (+)3-(3-hydroxyphenyl)-N-1(propyl) piperidine, or dextromethorphan. Upon acute treatment, only ifenprodil was protective. Interference of the drugs with glutamate activation of the NOS pathway was determined by measuring glutamate-activated cGMP formation and citrulline levels. Glutamate-activated cGMP formation was reduced by all neuroprotective sigma ligands after prolonged pretreatment but not after acute treatment. Sigma ligands added to cell culture lysate did not reduce citrulline formation, evidence that there was no direct effect on the NOS enzyme. We conclude that some but not all sigma ligands exert long-term protective properties against glutamate-induced neurotoxicity in primary hippocampal cultures, and that this protection is accompanied by attenuation of cGMP formation in the NOS pathway. However, inhibition of cGMP formation by itself appeared not sufficient for obtaining neuroprotective effects, as inhibition of glutamate-activated cGMP formation by N omega-nitro-L-arginine, haemoglobin, or PD128298 did not provide neuroprotection.
Twenty-nine cases of self-poisoning with antidepressants (amitriptyline, imipramine, clomipramine, maprotiline, doxepine, nortriptyline, opipramol) were examined by frequent observation of CNS effects, heart rate, blood pressure and standard ECG, 24h-ECG-monitoring, measurement of systolic time intervals, EEG recordings and frequent measurement of serum levels of antidepressants and primary metabolites. None of the patients died. Maximum total serum antidepressant level (parent compound + desmethyl metabolite) ranged from 20 to 2200 micrograms/l, with concentrations above 500 micrograms/l in 11 cases. The serum amitriptyline concentration remained high for 3-4 days in some of the severely intoxicated patients and the decay curves were compatible with partly saturated elimination. A degree of unconsciousness and the occurrence of excitation and hallucinations were generally seen in cases with total serum antidepressant levels above 500 micrograms/l. Grand mal seizures occurred more frequently at high antidepressant levels, but could not be predicted from the EEG recordings. Increased heart rate and prolonged QRS- and QTc-intervals were significantly correlated with the total serum antidepressant level. 24 h-ECG-monitoring revealed no serious arrhythmias or instances of heart block. Hypotension was only seen initially in few patients. Systolic time interval measurements showed changes suggesting impaired myocardial performance (elevated PEP/LVET ratio) at intermediate (60-500 micrograms/l) but not high (greater than 500 micrograms/l) total serum antidepressant levels. Measurement of serum concentration in antidepressant intoxication is important for identification of patients with high serum levels and the corresponding risk of developing toxic reactions, and to exclude patients with a low concentration who do not require intensive observation.
This study points to the controversy over the anti-depressant efficacy of tricyclic antidepressant drugs (TAD) and emphasize their cardiotoxicity. The number of lethal poisoning cases--from the Swiss federal statistics on the cause of death--amounted to 54 for the period from 1967 to 1976. Ten of these 54 cases occurred in children who had ingested the drug accidentally; the remaining cases concerned adults who took an overdose of the drug intentionally. In addition, the authors reviewed the forensic medical examinations performed on 11 cases of unexpected death due to lethal poisoning with TAD. Our data indicated that fatality can follow drug intake quite rapidly. Autoptical and histological findings were not specific. To confirm a poisoning diagnosis, levels of TAD and their metabolites were therefore determined in nine cases in various organ tissues and body fluids. Poisoning was due to imipramine (3 cases), opipramol (2 cases), dibenzepine (3 cases), and amitriptyline (3 cases).
The interation of imipramine with human polymorphonuclear leukocytes (PMNs) results in a chemiluminescence (CL) response which has been attributed to the electronic excitation of the imipramine molecule resulting from a reaction of the drug with reactive oxygen species. In order to determine what portion of the tricyclic molecule is involved in this reaction, the interaction of other tricyclics with PMNs was monitored by chemiluminescence. It was observed that tricyclic antidepressants having a carbon atom at position 5 of the ring moiety (amitriptyline, for example) did not yield CL with either resting or zymosan-activated PMNs. In fact this group of compounds inhibited the zymosan-induced CL response. However, CL was observed, with both resting and metabolically-activated PMNs, from several tricyclics having a heterocyclic nitrogen at position 5. These included imipramine, desipramine, opipramol and iprindole. Chlorimipramine, which has a chlorine atom at position 3 of the ring system, failed to yield CL with resting or stimulated cells. Similarly, imipramine N-oxide failed to yield CL with resting cells, but enhanced CL was observed with zymosan-activated PMNs. On the basis of these observations it appears that some aspect of the ring moiety, other than just a heterocyclic nitrogen, facilitates a reaction between these molecules and reactive oxygen which culminates in the generation of CL.
The formation of nitroso compounds and mutagens by drug/nitrite interaction was screened for 14 tranquilizers. The drug (0.05 M) was reacted with nitrite (0.5 M) at pH 3-3.5. After 4 h at 37 degrees C, nitroso compound formation was observed for flupentixol, chlordiazepoxide, spiperone, thiothixene, and chlorprothixene in more than 40% yield. Mutagenicity was found in the reaction products of opipramol, chlordiazepoxide, bromazepam, thiothixene, and carpipramine by the Ames assay using Salmonella typhimurium TA98 and TA100 as tester strains.
2,2'-bipyridine is proposed as new and sensitive spectrophotometric reagent for the determination of certain dibenzazepine class of tricyclic antidepressants. The spectrophotometric method is based on the reaction of imipramine hydrochloride (IPH), desipramine hydrochloride (DPH), clomipramine hydrochloride (CPH), trimipramine maleate (TPM) and opipramol (OPP) with iron (III) and subsequent reaction with 2,2'-bipyridine in an acetic acid medium to yield a pink color with maximum absorption at 530 nm. The color developed was stable over 3-4 h at room temperature (approximately 27 degrees C). The commonly encountered excipients and additives did not interfere with the determination. Results from the analysis of pure drugs and commercial tablets agreed well with those of the official method (United States Pharmacopoeia, 24, USP Convention, Rockville 2000, pp. 505-506, 865-867.).
This method describes the simultaneous determination of amisulpride, amitriptyline, aripiprazole, benperidol, chlorpromazine, chlorprothixene, citalopram, clomipramine, clozapine, desipramine, doxepin, fluoxetine, flupentixol, fluphenazine, fluvoxamine, haloperidol, hydroxyrisperidone, imipramine, levomepromazine, maprotiline, mianserine, mirtazapine, moclobemide, norclomipramine, nordoxepin, norfluoxetine, nortriptyline, O-desmethylvenlafaxine, olanzapine, opipramol, paroxetine, perazine, perphenazine, pimozide, pipamperone, quetiapine, reboxetine, risperidone, sertraline, sulpiride, thioridazine, trazodone, trimipramine, venlafaxine, viloxazine, ziprasidone, zotepine and zuclopenthixol with a single sample/triple injection approach. Drugs were assigned to subgroups covering low, medium and high concentrations (overall range of therapeutic levels to be considered: 0.5-2000 ng/mL) by further dilution of the supernatant obtained after the first protein precipitation. Chromatographic separation was necessary for isobaric mass fragments and performed on a monolithic C18 column (50mmx4.6mm) with methanol gradient and 5mM acetate buffer at pH 3.9. The injection interval was 8 min. A set of three internal standards was used for quantification of drugs with widely varying hydrophobicity. After electrospray ionization positive ion fragments were detected in the multiple reaction monitoring (MRM) mode with an API 4000 tandem mass spectrometer. Regression parameters of calibration curves and limits of quantification showed good covering of therapeutic and subtherapeutic ranges with an average correlation coefficient of 0.9988. Imprecision and inaccuracy measures were prepared for intra- and inter-assay comparisons at three concentration ranges in all subgroups. Average coefficients of variation were 6.1% for intra-assay and 7.4% for inter-assay comparisons, while average deviations from spiked concentrations were 4.8% for intra-assay and 4.2% for inter-assay comparisons, respectively. Recovery rates, measured as the percent recoveries of spiked serum samples against standard solutions without serum matrix, varied between 92 and 111%, with an average of 101%. As the only exception, the olanzapine response was much higher (185%) in serum matrix than in matrix-free controls.
A combined pH/organic solvent linear gradient mode in high performance liquid chromatography (HPLC) is presented as a new approach to determination of low concentrations of ionogenic analytes in biological material. The approach consists in simultaneous development of linear gradients of pH and organic modifier in the mobile phase. Advantages of the method are illustrated in postmortem analysis of opipramol in material from suicide victims. Very narrow peaks without tailing were obtained and several times lower limits of analyte quantitation were achieved using ultraviolet detection as compared to a standard isocratic method. The double gradient HPLC method seems to be especially valuable in case of ionogenic analytes dispersed in complex biological matrices. That is due to a high selectivity of the double gradient method and the lack of peak tailing, which is commonly observed for basic analytes chromatographed at isocratic conditions.
Trimetazidine, an antiischaemic drug, has been shown to restore impaired mitochondrial functions. Specific binding sites for [(3)H]-trimetazidine have been previously detected in liver mitochondria. In the present study we confirm this observation and provide additional evidence for the involvement of these sites in the pharmacological effects of the drug. Inhibition experiments using a series of trimetazidine derivatives revealed the presence of three classes of binding sites. An N-benzyl substituted analogue of trimetazidine exhibited a very high affinity (K(i)=7 nM) for one of these classes of sites. Compounds from different pharmacological classes were evaluated for their ability to inhibit [(3)H]-trimetazidine binding. Among the drugs tested pentazocine, ifenprodil, opipramol, perphenazine, haloperidol, and to a lower extent prenylamine, carbetapentane and dextromethorphan competed with high affinity, suggesting a similarity of high affinity [(3)H]-trimetazidine sites with sigma receptors. [(3)H]-Trimetazidine binding was modulated by pH. Neutral trimetazidine had about 10 fold higher affinity than protonated trimetazidine for its mitochondrial binding sites. Various cations also affected [(3)H]-trimetazidine binding. Ca(2+) was the most potent inhibitor and totally suppressed the binding of [(3)H]-trimetazidine to the sites of medium affinity. An endogenous cytosolic ligand was able to displace [(3)H]-trimetazidine from its binding sites. Its activity was not affected by boiling for 15 min, suggesting a non-protein compound. These data suggest that mitochondrial [(3)H]-trimetazidine binding sites could have a physiological relevance and be involved in the antiischaemic effects of the drug.
Sigma receptors have been identified in many brain areas and are especially abundant in those regions known to be involved in control of movement. Sigma receptors have been located autoradiographically in the granule cell layer of cerebellum in adult rat brain. In the current study, we identified sigma receptors in rat neonatal granule cells in culture using radioligand binding. The tritium labeled form of the putative sigma antagonist haloperidol bound with high affinity to membranes prepared from these cells, and ligands selective for sigma receptors competed well against [3H]haloperidol binding. The excitatory amino acid N-methyl-D-aspartate and the direct phospholipase A2 activator melittin stimulated the release of [3H]arachidonic acid from cerebellar granule cells. The N-methyl-D-aspartate-stimulated, but not the melittin-stimulated, release was inhibited in a concentration-dependent manner by the sigma-selective agonist (+)-pentazocine. In addition, the novel sigma 1 agonist BD737 inhibited N-methyl-D-aspartate-stimulated release. Pentazocine inhibition was almost completely reversed by the sigma antagonists NPC-16377 and opipramol. A 1 microM concentration of the phencyclidine receptor-selective ligand MK-801 inhibited approximately 65% of N-methyl-D-aspartate-stimulated release. These results suggest that sigma receptors may play a role in modulating arachidonic acid release in cerebellar granule cells.
Additional specificity data of the fluorescent polarization immunoassay (FPIA) for tricyclic antidepressants (TCA) in serum were evaluated. The TDx TCA assay exhibits cross-reactivities for a variety of the tricyclic antidepressants, tetracyclic antidepressants, phenothiazines, and several metabolites from these compounds. Significant cross-reactivities were found for dixyrazine (20-40%), alimemazine (20-47%), perazine (23-33%), Iofepramine (27-30%), desmethyltrimipramine (40-57%), opipramol (60-77%), amitriptylinoxide (73-85%), and dothiepin (97-113%).
A sensitive and specific direct-injection high-performance liquid chromatography-atmospheric pressure chemical ionization tandem mass-spectrometry (HPLC-APCI-MS-MS) method has been developed for the rapid identification and quantitation of seven tricyclic antidepressants-amitriptyline, nortriptyline, doxepin, dosulepin, dibenzepin, opipramol, and melitracen-in human plasma. After the addition of the internal standard lofepramine and dilution with 0.1% formic acid, plasma samples were injected into the LC-MS-MS system. Proteins and other large biomolecules were removed during an on-line sample cleanup using an Oasis extraction column (1 x 50 mm, ID, 30 microm) with a 100% aqueous mobile phase at a flow rate of 4 mL/min. The extraction column was subsequently brought in-line with the analytical column by automatic valve switching. Analytes were separated on a 5-microm Symmetry C18 (Waters) analytical column (3.0 x 150 mm, ID) using a step gradient of acetonitrile-0.1% formic acid at a flow rate of 0.6 mL/min. The total analysis time was only 12 minutes per sample. The interday and intraday coefficients of variation for all compounds were </=11%. The assay was sufficiently sensitive to monitor all seven compounds within their therapeutic ranges. The proposed method has been in routine use for more than 1 year and permits direct analysis of plasma samples without time-consuming sample preparation, which may be especially advantageous for clinical laboratories.
1 The effect of a series of antidepressant drugs on noradrenaline accumulation was studied in the isolated anococcygeus muscle of the rat. 2 The most potent inhibitors of noradrenaline accumulation were nortriptyline, desipramine and protriptyline. Opipramol, trimipramine and iprindole were active only in high concentrations. 3 Contractions of the anococcygeus muscle produced by noradrenaline were strongly potentiated by nortriptyline, desipramine and protriptyline. Other uptake inhibitors were less active in potentiating the noradrenaline response. 4 Nortriptyline, in concentrations that potentiated the action of noradrenaline, reduced or abolished the response to tyramine.
1. The effects of a range of structurally-dissimilar compounds which possess affinity for sigma binding sites were examined on the responses of cultured hippocampal pyramidal neurones to the excitatory amino acid analogues N-methyl-D-aspartate (NMDA), kainate and (RS)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA). 2. In mouse hippocampal neurones under whole-cell voltage-clamp, the compounds tested reversibly attenuated NMDA-, but not kainate- or AMPA-, evoked currents with a rank order potency (IC50 values in microM): ifenprodil (0.8) > (+)-N-allylnormetazocine (1.1) > dextromethorphan (1.8) = haloperidol (1.9) > (+)-pentazocine (7.2) > 1S,2R-(-)-cis-N-methyl-N-[2-(3, 4-dichlorophenyl) ethyl]-2-(1-pyrrolidinyl)cyclohexylamine (17) = rimcazole (18) > 1,3-di(2-tolyl)guanidine (37) > opipramol (96) > caramiphen (110) = carbetapentane (112) > > (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine (485). 3. The attenuation of NMDA-evoked responses was not mediated through interactions with the agonist, glycine (except haloperidol) or polyamine (except ifenprodil) binding sites on the NMDA receptor-channel complex but, in the light of the voltage- and, in some cases, use-dependent nature of their antagonism, an interaction with the ion channel appears to be a likely mechanism of action for many of the compounds. 4. Micromolar concentrations of selected sigma site ligands also reduced NMDA-evoked rises in intracellular free calcium concentration in Fura-2-loaded cultured hippocampal neurones of the rat with the same rank order potency as observed in the electrophysiological studies. 5. The data indicate that, at micromolar concentrations, the sigma site ligands tested act as NMDA receptor antagonists, an action which does not appear to be mediated by high-affinity sigma binding site(s). The functional effects of micromolar concentrations of sigma site ligands cannot, therefore, be attributed exclusively to interactions with high-affinity sigma binding sites.
1. The effects of a series of structurally-dissimilar sigma site ligands were examined on high voltage-activated Ca2+ channel activity in two preparations of cultured hippocampal pyramidal neurones. 2. In mouse hippocampal neurones under whole-cell voltage-clamp, voltage-activated Ca2+ channel currents carried by barium ions (IBa) were reduced with the rank order (IC50 values in microM): 1S,2R-(-)-cis-N-methyl-N-[2-(3,4-dichlorophenyl)ethyl]- 2-(1-pyrrolidinyl)cyclohexylamine (7.8) > rimcazole (13) > haloperidol (16) > ifenprodil (18) > opipramol (32) > carbetapentane (40) = 1-benzylspiro[1,2,3,4-tetrahydronaphthalene-1,4-piperidine] (42) > caramiphen (47) > dextromethorphan (73). At the highest concentrations tested, the compounds almost abolished IBa in the absence of any other pharmacological agent. 3. The current-voltage characteristics of the whole-cell IBa were unaffected by the test compounds. The drug-induced block was rapid in onset and offset, with the exceptions of carbetapentane and caramiphen where full block was achieved only after two to three voltage-activated currents and was associated with an apparent increase in the rate of inactivation of IBa. 4. In rat hippocampal neurones loaded with the Ca(2+)-sensitive dye Fura-2, rises in intracellular free Ca2+ concentration evoked by transient exposure to 50 mM K(+)-containing medium, either in the absence or in the presence of 10 microM nifedipine (to block L-type high voltage-activated Ca2+ channels), were also reversibly attenuated by the sigma ligands. The rank order potencies for the compounds in these experimental paradigms were similar to that observed for blockade of IBa in the electrophysiological studies. 5. These results indicate that, at micromolar concentrations, the compounds tested block multiple subtypes of high voltage-activated Ca2+ channels. These actions, which do not appear to be mediated by high-affinity sigma binding sites, may play a role in some of the functional effects previously described for the compounds.