Acute hypertensive crisis and severe headache after concurrent use of armodafinil and tranylcypromine: Case report and review of the literature.

Concurrent use of modafinil or armodafinil with monoamine oxidase inhibitors (MAOIs) is contraindicated due to a theoretical risk of drug synergism and acute hypertensive episodes. However, few data are available to substantiate that risk, and several case studies have suggested that the combination is safe. To our knowledge, we present the first case of a patient treated concurrently with armodafinil and tranylcypromine. The patient developed an acute hypertensive crisis with severe headache, nausea, blurry vision, and neck stiffness. Her symptoms corresponded with the predicted pharmacokinetic and pharmacodynamic response. She was also taking brexpiprazole, which could have contributed to her underlying symptoms. However, limited data suggest that the single combination of brexpiprazole with armodafinil or MAOIs would be safe. Upon review of the literature, two out of seven patients, including our own, treated concurrently with modafinil or armodafinil and an MAOI developed an adverse reaction. Physicians should exercise caution if using these classes of drugs together.

Novel potent inhibitors of the histone demethylase KDM1A (LSD1), orally active in a murine promyelocitic leukemia model.

BACKGROUND: Histone lysine demethylases (KDMs) are well-recognized targets in oncology drug discovery. They function at the post-translation level controlling chromatin conformation and gene transcription. KDM1A is a flavin adenine dinucleotide-dependent amine oxidase, overexpressed in several tumor types, including acute myeloid leukemia, neuroblastoma and non-small-cell lung cancer. Among the many known monoamine oxidase inhibitors screened for KDM1A inhibition, tranylcypromine emerged as a moderately active hit, which irreversibly binds to the flavin adenine dinucleotide cofactor. MATERIAL & METHODS: The KDM1A inhibitors 5a-w were synthesized and tested in vitro and in vivo. The biochemical potency was determined, modulation of target in cells was demonstrated on KDM1A-dependent genes and the anti-clonogenic activity was performed in murine acute promyelocytic Leukemia (APL) blasts. An in vivo efficacy experiment was conducted using an established murine promyelocytic leukemia model. RESULTS: We report a new series of tranylcypromine derivatives substituted on the cyclopropyl moiety, endowed with high potency in both biochemical and cellular assays. CONCLUSION: The most interesting derivative (5a) significantly improved survival rate after oral administration in a murine model of promyelocitic leukemia.

Withdrawal and discontinuation phenomena associated with tranylcypromine: a systematic review.

Tranylcypromine (TCP) is an effective antidepressant with a complex pharmacological profile and a relevant risk of abuse and dependence. Withdrawal phenomena (WP, in the case of TCP-abuse/dependence) or discontinuation phenomena (DP, in the case of absent TCP-abuse/dependence) subsequent to abrupt termination of TCP are a potentially severe clinical syndrome. We conducted a systematic review of all previously published WP/DP cases following abrupt termination of TCP in order to identify typical clinical presentations and risk factors of WP/DP and frequency of TCP abuse or dependence within these patients. By searching the Medline and Scopus databases we identified n=25 cases (cohort WP: n=18, cohort DP: n=7). Delirium was found in n=13 patients (cohort WP: 10/55.6%; cohort DP: 3/42.9%), n=6 demonstrated WP/DP without delirium (WP: 6/33.3%; DP: 0/0%) and n=5 rapid relapse in depression (WP: 1/5.6%; DP: 4/57.1%). Mean time until development of WP/DP was 1.9 (WP) and 2.2 (DP) days. Mean duration of WP/DP was 5.7 (WP) and 11.3 (DP) days. All patients of cohort WP were described to feature TCP-abuse/dependence. Patients with delirium were on average older (41.8 years vs. 37.8 years) and featured higher mean prescribed (71.0 mg vs. 38.3 mg) and actually taken daily TCP dosages (285.8 mg vs. 187.7 mg). In conclusion, even termination of lower daily dosages of TCP may result in delirium. Thrombocytopenia features diagnostic value in patients with deliria of unknown etiology. TCP should be administered with great care, especially in dependence-prone patients.·

TCP-FA4: a derivative of tranylcypromine showing improved blood-brain permeability.

A variety of approaches have been taken to improve the brain penetration of pharmaceutical agents. The amphipathic character of a compound can improve its interaction with the lipid bilayer within cell membranes, and as a result improve permeability. Fatty acid chains or lipoamino acids of various lengths were attached to tranylcypromine (TCP), in an attempt to improve the blood-brain barrier (BBB) permeability by increasing the lipophilicity as well as the amphiphatic character of the drug. TCP-FA4, one of the derivatives containing a four carbon alkyl acid chain, showed the greatest improvement in permeability. This molecule was slightly neuroprotective in a beta-amyloid-induced neurodegeneration assay and may also be capable of upregulating brain derived neurotrophic factor (BDNF), as indicated by cell culture assays using human umbilical vein endothelial cells. Since decreased levels of BDNF are observed in many CNS disorders, and direct injection of BDNF is not a viable option due to its poor permeability across the BBB, small molecules capable of regulating BDNF that also cross the BBB may be an interesting treatment option.

Transdermal selegiline: the new generation of monoamine oxidase inhibitors.

The clinical use of monoamine oxidase inhibitors (MAOIs) has declined due to concerns about food and drug interactions and waning physician experience. Evidence indicates that MAOIs are effective in depressive disorders, in particular depression with atypical features. Efforts to address safety issues have led to the development of more selective and reversible MAOIs, such as moclobemide. Selegiline, a selective monoamine oxidase B inhibitor, has been approved for the adjunctive treatment of Parkinson's disease at low doses. At higher doses, oral selegiline is also effective in major depressive disorder (MDD) but loses its selectivity and has the potential for tyramine interactions. To overcome these problems, a transdermal formulation of selegiline, the selegiline transdermal system (STS), was developed with novel pharmacokinetic and pharmacodynamic properties. Compared with oral administration, transdermal selegiline leads to sustained plasma concentrations of the parent compound, increasing the amount of drug delivered to the brain and decreasing metabolite production. In addition, STS allows targeted inhibition of central nervous system monoamine A (MAO-A) and monoamine B isoenzymes with minimal effects on MAO-A in the gastrointestinal and hepatic systems, thereby reducing the risk of interactions with tyramine-rich foods (the "cheese-reaction"). Clinical trials have found 6 mg/24 hours of STS to be effective in MDD without the need for dietary restrictions. The efficacy and safety profile of STS supports its use in MDD. It is possible that STS may demonstrate benefit in MDD with atypical features or MDD resistant to other antidepressants. However, more research is needed. Clinicians should familiarize themselves with the properties and indications for the new generation of MAOIs.

Failure to detect amphetamine or 1-amino-3-phenylpropane in humans or rats receiving the MAO inhibitor tranylcypromine.

BACKGROUND: There have been conflicting reports in the literature about whether or not tranylcypromine is metabolized to amphetamine. In the current report, we investigated this possible route of metabolism in both rats and humans. Body fluid samples from patients and rats and brain, liver and heart samples from rats were analyzed for levels of amphetamine and 1-amino-3-phenylpropane, another potential product of cleavage of the cyclopropyl ring of tranylcypromine after administration of tranylcypromine. Extracted samples were reacted with pentofluorobenzenesulfonyl chloride and analyzed using electron-capture gas chromatography. RESULTS: Amphetamine or 1-amino-3-phenylpropane were not found in any of the samples, indicating that opening of the cyclopropyl ring of tranylcypromine is not a significant route of metabolism for this drug at usual doses. LIMITATIONS: The assay procedure did not permit analysis of 1-amino-2-phenylpropane (another possible product of cleavage of the cyclopropyl ring of tranylcypromine) or of N-methylamphetamine. CONCLUSIONS: These studies support the growing body of evidence indicating that opening of the cyclopropyl ring of tranylcypromine to form amphetamine, a drug of abuse, is not significant at usual doses of tranylcypromine.

Serotonin syndrome from venlafaxine-tranylcypromine interaction.

Excessive stimulation of serotonin 5HT1A receptors causes a syndrome of serotonin excess that consists of shivering, muscle rigidity, salivation, confusion, agitation and hyperthermia. The most common cause of this syndrome is an interaction between a monoamine oxidase inhibitor (MAOI) and a specific serotonin reuptake inhibitor. Venlafaxine is a new antidepressant agent that inhibits the reuptake of serotonin and norepinephrine. We report a venlafaxine-MAOI interaction that resulted in the serotonin syndrome in a 23-y-old male who was taking tranylcypromine for depression. He had been well until the morning of presentation when he took 1/2 tab of venlafaxine. Within 2 h he became confused with jerking movements of his extremities, tremors and rigidity. He was brought directly to a hospital where he was found to be agitated and confused with shivering, myoclonic jerks, rigidity, salivation and diaphoresis. His pupils were 7 mm and sluggishly reactive to light. Vital signs were: blood pressure 120/67 mm Hg, heart rate 127/min, respiratory rate 28/min, and temperature 97 F. After 180 mg of diazepam i.v. he remained tremulous with muscle rigidity and clenched jaws. He was intubated for airway protection and because of hypoventilation, and was paralyzed to control muscle rigidity. His subsequent course was remarkable for non-immune thrombocytopenia which resolved. The patient's maximal temperature was 101.2 F and his CPK remained < 500 units/L with no other evidence of rhabdomyolysis. His mental status normalized and he was transferred to a psychiatry ward. This patient survived without sequelae due to the aggressive sedation and neuromuscular paralysis.

[Monoamine oxidase inhibitors in psychiatry. Status of current knowledge]. / Monoaminoxidasehemmer in der Psychiatrie. Aktueller Kenntnisstand.

With the introduction of moclobemide as the first reversible and selective inhibitor of monoamine oxidase (type A), the therapeutic principle of monoamine oxidase inhibition gained new importance. In this paper the clinical pharmacology, efficacy and side effects of traditional monoamine oxidase inhibitors and specifically of tranylcypromine as an example) are compared with those of the reversible and selective monoamine oxidase inhibitors (as exemplified by moclobemide).

Dopamine D2 receptors: a potential pharmacological target for nomifensine and tranylcypromine but not other antidepressant treatments.

Treatment for 1 or 14 days by IP injection with the antidepressants, amitriptyline (10 mg/kg), bupropion (30 mg/kg), desipramine (10 mg/kg), GBR 12909 (10 mg/kg), sibutramine HCl (3 mg/kg), mianserin (5 mg/kg), and zimeldine (10 mg/kg), did not affect the number or affinity of dopamine D2 receptors determined by [3H]raclopride binding to rat striatal membranes. Similarly, neither did a single, nor repeated (five times over 10 days), electroconvulsive shock, given under halothane anaesthesia, have any effect on [3H]raclopride binding parameters. By contrast, the noradrenaline and dopamine reuptake inhibitor, nomifensine (5 mg/kg), and the monoamine oxidase inhibitor, tranylcypromine (5 mg/kg), decreased the number of dopamine D2 receptors by 12% and 11%, respectively, when given for 14 days. Administration of the D2 receptor antagonist, haloperidol (1 mg/kg), for 14 days increased the number of [3H]raclopride binding sites by 17%. Thus, the data demonstrate that although nomifensine and tranylcypromine decrease D2 receptor number after 14 days administration, this adaptive change is not observed with other antidepressant treatments. However, the findings do not preclude a contribution of altered dopamine D2 receptor function to the efficacy of those drugs with potent effects on dopaminergic neuronal function.

The pharmacokinetics of tranylcypromine enantiomers in healthy subjects after oral administration of racemic drug and the single enantiomers.

The pharmacokinetics of the two enantiomers of tranylcypromine were evaluated in six healthy subjects after oral dosage of the racemate (20 mg of the sulphate) and the single enantiomers (10 mg of the sulphate) using an enantiospecific assay. Significant differences in AUC, Cmax, lambda(z), and CLR of the two enantiomers were observed both on administration of the racemate and of the individual enantiomers. The plasma concentrations and urinary excretion rates of (-)-tranylcypromine exceeded those of (+)-tranylcypromine. AUCs of the (-)-enantiomer [arithmetical means 197 ng ml(-1) h after the racemate, 130 ng ml(-1) h after the enantiomer] were greater than those of the (+)-enantiomer [26 ng ml(-1) h after the racemate, 28 ng ml(-1) h after the enantiomer] (P = 0.0001). No in vivo racemisation was detected. The power of the study was insufficient to establish any enantiomer-enantiomer interaction except for a possible interaction at the level of renal clearance (P = 0.013 for both enantiomers).

Possible monoamine oxidase inhibitor-serotonin uptake inhibitor interaction: fluoxetine clinical data and preclinical findings.

The primary objective of this article is to review information pertinent to and emphasize the seriousness of a potential adverse monoamine oxidase inhibitor (MAOI)-serotonin uptake inhibitor interaction by considering, within the context of preclinical data, clinical cases in which an MAOI and fluoxetine hydrochloride, a specific serotonin uptake inhibitor, were administered in close temporal proximity. Clinical cases were identified by a review of spontaneous adverse event reports submitted voluntarily to Eli Lilly and Company through its drug surveillance program and by a review of reports of MAOI interactions published in the scientific literature. A discussion of eight selected clinical cases of acute adverse reactions (seven with fatal outcomes; one with a favorable response after cyproheptadine therapy) reported to Eli Lilly and Company in which an MAOI was initiated concurrently or shortly after the discontinuation of fluoxetine and a review of preclinical data suggest a possible role of serotonin and/or serotonin-dopamine interactions in the hypermetabolic state that may occur when a serotonin uptake inhibitor and an MAOI are coadministered, although alternative etiologic processes are possible as well. Data reviewed reinforce the idea that the administration of an MAOI in close temporal proximity to fluoxetine is contraindicated.

Postmortem changes in blood tranylcypromine concentration: competing redistribution and degradation effects.

Site and temporal changes in tranylcypromine (TCP) and lithium concentrations in blood were studied in a human poisoning case. Blood samples from peripheral vessels and six central vessels were obtained at 0, 6, 24, 48 and 72 h after starting the autopsy. Nine tissue samples were obtained on completion. TCP showed preferential concentration in liver (2.21 micrograms/g) and brainstem (2.46 micrograms/g). There was a moderate post mortem redistribution phenomenon with TCP concentrations lowest in peripheral blood (0.17 micrograms/ml) at 0 h and highest in central vessels at 24 h (0.52 micrograms/ml). At 72 h blood TCP concentrations fell below those at 0 time but the samples showed marked putrefactive changes. Control blood samples spiked with TCP and incubated for 48 h at 37 degrees C showed a 58% fall in drug concentration. By contrast with TCP, lithium, which has a small Vd (0.8 l/kg) and is chemically stable, did not show this pattern of change in blood concentration. The site and temporal differences in TCP concentration in blood can be explained by the competing effects of post mortem redistribution and drug degradation. Redistribution is an early post mortem phenomenon characterised by diffusion, along a concentration gradient, from drug reservoirs in solid organs into adjacent blood vessels. Drug degradation is a later phenomenon associated with putrefactive change.

Enantiospecific high-performance liquid chromatographic assay with fluorescence detection for the monoamine oxidase inhibitor tranylcypromine and its applicability in pharmacokinetic studies.

In order to be able to measure low concentrations of tranylcypromine enantiomers in biological material, chiral fluorescent derivatization and high-performance liquid chromatography (HPLC) were employed. The internal standard S-(+)-amphetamine and borate-sodium hydroxide buffer pH 11 were added to plasma or urine sample aliquots. o-Phthaldialdehyde was used for precolumn derivatization in combination with the chiral mercaptan N-acetylcysteine. HPLC resolution of the diastereoisomeric derivatives was possible on an octadecylsilane column. The mobile phase consisted of sodium phosphate buffer solution pH 6.5, methanol and tetrahydrofuran. The fluorescence of the eluate was monitored at 344/442 nm. The intra-day coefficients of variation were below 10%, the limit of determination was 0.5 ng/ml. The assay was found to be applicable for routine analyses in a preliminary pharmacokinetic study, in which an oral dose of 20 mg racemic tranylcypromine sulfate was administered to three healthy volunteers. The plasma concentrations were generally low, and those of S-(-)-tranylcypromine significantly exceeded those of the R-(+)-enantiomer. Average maximum concentrations were 57.5 and 6.3 ng/ml for S- and R-tranylcypromine, respectively. While S-tranylcypromine was well detectable within the whole study period (8 h), R-tranylcypromine concentrations fell below the detection limit after 4 h in two out of the three studied volunteers.

Plasma tranylcypromine: relationship to pharmacokinetic variables and clinical antidepressant actions.

Because the clinical actions of psychotherapeutic agents can be influenced by their pharmacokinetics, we investigated plasma tranylcypromine in relation to treatment outcome in 26 patients with bipolar depression. After oral administration of a tranylcypromine dose, plasma drug levels were measured hourly from 5-8 hours (N = 16) or 0-8 hours (N = 10) postdose, and pharmacokinetic parameters were calculated. Depressive symptoms were rated using the Hamilton Rating Scale for Depression (HAM-D), and subjects were categorized as responders, partial responders, or nonresponders, based on end-pair ratings. Twelve subjects were responders, seven were partial responders, and seven were nonresponders (mean scores = 3.2, 13.1, and 24.9, respectively); pretreatment HAM-D scores did not differ among the three groups. Tranylcypromine elimination (t1/2) was unrelated to clinical outcome. However, plasma tranylcypromine measured 5 hours postdose (5hTCP) was correlated with the end-pair HAM-D scores (r = 0.48, p less than 0.015) and was significantly higher in nonresponders than in responders (ANOVA, F = 4.7, p less than 0.02; Newman-Keuls test, p less than 0.05). For subjects who were studied from 0-8 hours postdose, the time to peak absorption (Tpeak), the area under the plasma tranylcypromine-versus-time curve, and the volume of distribution (Vd) were determined. Two subjects having delayed (3-4 hours) Tpeak also manifested elevated mean 5hTCP (63.9 vs. 34.1 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Adverse consequences of fluoxetine-MAOI combination therapy.

The authors describe two series of patients: 12 treated simultaneously with fluoxetine and a monoamine oxidase inhibitor and 6 patients started on treatment with an MAOI 10 days or more after stopping fluoxetine treatment. All patients had extremely refractory depression and were treated in open fashion before general knowledge was obtained of the side effects that may accompany the fluoxetine-MAOI combination. During the fluoxetine-MAOI trial, most patients continued to receive other psychotropic combinations that had been partially helpful. The use of fluoxetine and an MAOI, either together or in close succession, was accompanied by a very high incidence of adverse effects, especially the "serotonergic syndrome." This syndrome was characterized by mental status changes, such as hypomania and confusion, and physical symptoms, such as myoclonus, hypertension, tremor, and diarrhea. Because of the high incidence of side effects and the lack of definite efficacy, the concurrent use of fluoxetine and MAOIs should generally be avoided. The long half-lives of fluoxetine and norfluoxetine, as well as the prolonged metabolic effects of MAOIs, may also dispose patients to an interaction if one of the drugs is started soon after stopping the other.

Neurochemical and neuropharmacological properties of 4-fluorotranylcypromine.

1. The 4-fluoro analogue of the monoamine oxidase-inhibiting antidepressant tranylcypromine was compared to the parent drug with regard to the following: inhibition of monoamine oxidases A and B in vitro and ex vivo; levels of both drugs in brain, liver, and blood after injection of equimolar doses; and effects on brain levels of the amines 2-phenylethylamine, tryptamine, norepinephrine, dopamine, and 5-hydroxytryptamine. 2. 4-Fluorotranylcypromine was found to be 10 times more potent than tranylcypromine at inhibiting monoamine oxidases A and B in vitro in rat brain homogenates. 3. After administration (0.1 mmol/kg, ip), 4-fluorotranylcypromine attained higher brain and liver levels and provided greater availability than did tranylcypromine after the injection of an equimolar amount. 4. At the dose employed, the ex vivo monoamine oxidases A and B inhibitory profiles in brain and liver over a 24-hr period following tranylcypromine and 4-fluorotranylcypromine treatment were not different from each other. 5. Although the drugs had similar effects on inhibition of brain MAO ex vivo, they differed from one another at several time intervals in the increases in concentrations of 2-phenylethylamine, tryptamine, norepinephrine, dopamine, and 5-hydroxytryptamine produced in brain. 6. In conclusion, fluorination of tranylcypromine in the 4 position of the phenyl ring produced a drug which was more potent than the parent drug at inhibiting MAO in vitro and attained higher levels in brain than did tranylcypromine itself after intraperitoneal injection of equimolar amounts of the drugs. 4-Fluorotranylcypromine increased the concentrations of trace amines, catecholamines, and 5-hydroxytryptamine in brain at most time intervals following intraperitoneal injection, and at some time intervals there were differences from tranylcypromine with regard to the amine concentrations produced.