Highly sensitive LC-MS/MS-ESI method for determination of phenelzine in human plasma and its application to a human pharmacokinetic study.

A selective, sensitive and rapid LC-MS/MS method has been developed and validated for quantification of the phenelzine (PZ) in 200µL of human plasma using hydroxyzine (HZ) as an internal standard (IS) as per regulatory guidelines. The sample preparation involved the derivatization of PZ using pentaflurobenzaldehyde followed by solid phase extraction process to extract PZ and HZ from human plasma. LC-MS/MS was operated under the multiple reaction-monitoring mode (MRM) using the electro spray ionization technique in positive ion mode and the transitions of m/z 305.1→105.1 and m/z 375.3→201.1 were used to measure the derivative of PZ and IS, respectively. The total run time was 3.5min and the elution of PZ and HZ occurred at 2.53, and 1.92min, respectively; this was achieved with a mobile phase consisting of 10mM ammonium acetate: acetonitrile (20:80, v/v) at a flow rate of 1.0mL/min on an Ace C18 column with a split ratio of 70:30. The developed method was validated in human plasma with a lower limit of quantitation 0.51ng/mL. A linear response function was established for the range of concentrations 0.51-25.2ng/mL (r>0.995) for PZ. The intra- and inter-day precision values met the acceptance criteria. PZ was stable in the battery of stability studies viz., stock solution, bench-top, auto-sampler, long-term and freeze/thaw cycles. The developed assay method was applied to an oral bioequivalence study in humans.

Acute myocarditis after massive phenelzine overdose.

BACKGROUND: Monoamine oxidase inhibitors (MAOIs) are uncommonly used due to their high frequency of adverse effects, including tachycardia and hypertension. Recently, there has been renewed interest in the role of this class of drugs in treating a variety of psychiatric disorders. The clinical features of MAOI overdose are poorly characterised. This paper describes a novel cardiac complication of phenelzine toxicity in a previously healthy young adult with no history of cardiovascular disease. METHODS: A 23-year-old woman presented to hospital after massive phenelzine overdose, and the clinical features and pathological findings are discussed in light of existing literature. RESULTS: Clinical features of phenelzine toxicity included reduced consciousness level, seizures, and tachycardia, in keeping with previous reports. Unexpectedly, the patient developed severe and unexplained hypotension and impaired left ventricular function, and died 3 days after initial presentation. Post-mortem examination confirmed high serum phenelzine concentrations (4.1 mg/L) and histopathological features that were consistent with drug-induced acute myocarditis. CONCLUSION: Acute myocarditis was attributed to phenelzine in the absence of any plausible alternative explanation. This possible complication should be considered in patients who develop unexplained hypotension after phenelzine overdose.

Quantitative determination of phenelzine in human fluids by gas chromatography with nitrogen specific detection.

A quantitative gas chromatographic assay for the determination of phenelzine in plasma or other fluids is presented. A stable derivative is formed by cyclization with acetylacetone, and the derivative is separated, purified, and concentrated by liquid-liquid solvent extraction. Analysis of the extracts is by capillary gas chromatography with nitrogen specific detection. Detection limits of less than 1 ng/mL and CVs of 5% at the 10-ng/mL level are attainable with a 2-mL sample and benzylhydrazine as the internal standard.

Effects of antidepressant medication on sexual function: a controlled study.

There has been little systematic study of the types of sexual dysfunction produced by antidepressant medication or of the frequency with which this type of adverse effect occurs. The authors report results of a double-blind study in which the effects of imipramine, phenelzine, and placebo on specific aspects of sexual function were assessed in depressed outpatients before and after 6 weeks of treatment. Both active treatments were associated with a high incidence of adverse changes in sexual function and produced significantly more adverse effects on sexual function than placebo. Orgasm and ejaculation were impaired to a greater extent than erection. Adverse sexual function changes secondary to antidepressant medication occurred frequently in both men and women, although men reported a higher incidence. Antidepressant-related sexual dysfunction may be of clinical importance for medication compliance in view of current recommendations that antidepressants be administered for longer periods as maintenance therapy or for prophylaxis.

Phenelzine v imipramine in atypical depression. A preliminary report.

Sixty patients meeting specific criteria for atypical depression completed six weeks of double-blind, randomly assigned treatment with phenelzine sulfate, imipramine hydrochloride, or placebo. The overall response rates were 67% with phenelzine, 43% with imipramine, and 29% with placebo. At week 6, phenelzine was superior to placebo on many measures, while the superiority of imipramine to placebo was confined to several variables. Phenelzine was superior to imipramine on the interpersonal sensitivity and paranoia factors of the 90-item Hopkins Symptom Checklist, with trends toward superiority on several other measures, while imipramine was not differentially superior on any measure. Atypical depressive patients with a history of spontaneous panic attacks and hysteroid dysphoric patients both showed extremely low rates of response to placebo and high rates of response to phenelzine. Conversely, those without panic or hysteroid dysphoric features responded equally to all three treatments. Responders to pheneizine also had greater platelet monoamine oxidase inhibition while receiving drug therapy than did nonresponders. Completion of the 120-patient sample will allow more detailed analyses.

Cardiovascular effects of phenelzine and amitriptyline in depressed outpatients.

Blood pressure and ECG changes were monitored in depressed outpatients treated for 6 weeks with amitriptyline, 150 mg/day, or phenelzine, 60 mg/day, as part of an ongoing double-blind study. Phenelzine produced significant decreases in blood pressure and a significant increase in orthostatic fall in pressure. Amitriptyline produced little overall change in blood pressure. The degree of MAO inhibition in phenelzine-treated patients was significantly correlated with blood pressure. Tricyclic plasma concentrations were also related to some blood pressure measures. Reported dizziness/faintness did not correlate with blood pressure changes in either group. Amitriptyline significantly increased heart rate, while phenelzine produced slowing. Amitriptyline was associated with significant prolongation of QRS and QTc but not PR intervals. Phenelzine produced significant shortening of the QTc interval.

Determination of phenelzine in human plasma with gas chromatography-mass spectrometry using an isotope labeled internal standard.

A quantitative gas chromatographic-mass spectrometric assay was developed for the determination of phenelzine in human plasma. Phenelzine, in aqueous solution or in plasma reacts at room temperature with pentafluorobenzaldehyde to form quantitatively a hydrazone derivative. The derivative has good gas chromatographic characteristics. The assay utilizes selected ion monitoring in a gas chromatographic effluent, the molecular ion generated by electron impact ionization of phenelzine derivative. Phenelzine-d, was synthesized and used as an internal standard. The assay can measure 2 ng/ml of the drug with about 10% precision. The method was used for the determination of steady state levels of phenelzine in the plasma of patients taking a therapeutic dose of the drug.

A comparison of electroconvulsive therapy and combined phenelzine-amitriptyline in refractory depression.

Combined monoamine oxidase (MAO) inhibitor-tricyclic antidepressant therapy and electroconvulsive therapy (ECT) were compared in a population of refractory depressive patients. Seventeen patients were randomly assigned to either of the treatment groups, and an independent observer was used to rate overall progress. Between four and ten ECTs or a combination of phenelzine and amitriptyline were administered. Assays for MAO activity and plasma levels of amitriptyline and nortriptyline were performed. In both psychotic and neurotic depression, ECT was superior. When depression was accompanied by character disorder, the response was generally poor. Adequate levels of MAO inhibition were obtained, but tricyclic antidepressant levels were low. Electroconvulsive therapy is still considered to be the treatment of choice for severe depression, whereas the combination of low doses of phenelzine and amitriptyline are ineffective. This treatment modality needs further investigation.