Exudative erythema multiforme due to cyclobenzaprine

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Anticonvulsant hypersensitivity syndrome: cross-reactivity with tricyclic antidepressant agents.

BACKGROUND: Aromatic anticonvulsant agents such as carbamazepine and phenytoin can induce anticonvulsant hypersensitivity syndrome (AHS) at a frequency of 1 in 10,000 to 1 in 1,000 treated patients. The hypersensitivity syndrome is a potentially life-threatening adverse drug reaction with multiorgan involvement, and incidental reexposure must be strictly avoided. Patients and treating physicians must be informed and educated about the causal drug and its potential immunologic or toxicologic cross-reactivity with other compounds. It has been well established that for future antiepileptic drug therapy, carboxamides (carbamazepine and oxcarbazepine), phenytoin, and barbiturates (phenobarbital and primidone) have to be avoided owing to their high degree of cross-reactivity. Other anticonvulsant agents, such as valproic acid, benzodiazepines, and gabapentin, may be prescribed. OBJECTIVES: To present the clinical data for and to describe the potential cross-reactivity between aromatic anticonvulsant and tricyclic antidepressant agents in patients with carbamazepine- and phenytoin-induced AHS. METHODS: The knowledge of cross-reactivity among aromatic anticonvulsant agents mainly emerged from clinical experience and observations because diagnostic challenge tests are not advisable. Thirty-six patients with the diagnosis of AHS were instructed to contact our unit if the symptoms relapsed. RESULTS: Despite better knowledge of AHS, one third of the patients had avoidable recurrences after exposure to cross-reactive drugs. Besides the known cross-reactivity among aromatic anticonvulsant agents, we observed a recurrence of the hypersensitivity syndrome in 5 patients after the administration of tricyclic antidepressant agents. CONCLUSION: The important potential cross-reactivity between aromatic anticonvulsant and tricyclic antidepressant drugs should be brought to the attention of treating physicians.

A preliminary study of tricyclic antidepressant (TCA) ovine FAB for TCA toxicity.

BACKGROUND: Animal studies suggest that tricyclic antidepressant antibody fragments (TCA Fab) may be a useful therapy for tricyclic antidepressant poisoning. The objective of this study is to determine if TCA Fab increases total serum TCA levels without raising free serum TCA levels in human overdose patients, indicating that TCA Fab effectively binds TCA. METHODS: This was a prospective, dose escalation study of patients with mild to moderate TCA poisoning. Patients were treated with an escalating intravenous infusion totaling 7 or 14 gm of TCA Fab. The outcomes of interest were serum TCA levels (total and free), worsening of TCA toxicity, and adverse effects. RESULTS: Seven patients were treated with Fab. Infusion of TCA Fab was associated with a dramatic increase in total serum TCA levels, while free TCA levels fell in both dosing groups. There were no significant changes in QRS duration, heart rate or mean arterial pressure associated with the Fab Infusion. Worsening of TCA toxicity did not occur despite marked elevation of total serum TCA concentrations. The two patients with the greatest prolongation of QRS showed a prompt shortening in their QRS duration temporally associated with the Fab infusion. Mild wheezing was observed in one asthmatic patient. CONCLUSIONS: 1) TCA Fab raises total serum TCA levels while lowering free levels in TCA poisoned patients; 2) no toxic effects were associated with the increase in TCA levels and no severe adverse effects were observed during the hospital course following Fab infusion.

Quetiapine cross-reactivity with plasma tricyclic antidepressant immunoassays.

BACKGROUND: Toxicology screens obtained on patients who have overdosed on drugs frequently include tricyclic antidepressants (TCAs) as part of the evaluation. Quetiapine is an antipsychotic agent with structural similarity to the TCAs. OBJECTIVE: To determine whether quetiapine may cross-react with plasma TCA immunoassays in vitro using commonly available autoanalyzers. METHODS: Quetiapine stock solution was added to 9 separate samples of pooled drug-free human plasma to produce concentrations ranging from 1 to 640 ng/mL that were verified by gas chromatography. No quetiapine metabolites were present. Each spiked plasma sample was tested in a blinded fashion using the Abbott Tricyclic Antidepressant TDx Assay on the TDxFLx autoanalyzer in 2 separate laboratories, the Syva Emit tox Serum Tricyclic Antidepressant Assay on the AU400 autoanalyzer and the S TAD Serum Tricyclic Antidepressant Screen on the ACA-Star 300 autoanalyzer. The TDx assay is quantitative, while Emit and S TAD are qualitative screening assays with a threshold of 300 ng/mL for TCA positivity. The outcome of interest was a positive TCA result. RESULTS: The quantitative assay showed concentration-related TCA cross-reactivity beginning at quetiapine concentrations of 5 ng/mL. The 640-ng/mL spiked sample produced TCA results of 379 and 385 ng/mL in labs 1 and 2, respectively. The qualitative assays were screened as TCA positive at quetiapine concentrations of 160 and 320 ng/mL for the S TAD and Emit assays, respectively. CONCLUSIONS: Quetiapine cross-reacts with quantitative and qualitative plasma TCA immunoassays in a concentration-dependent fashion. Therapeutic use or overdose of quetiapine may result in a false-positive TCA immunoassay result.

The management of tricyclic antidepressant poisoning : the role of gut decontamination, extracorporeal procedures and fab antibody fragments.

Although there have been descriptive, uncontrolled clinical reports of removal of tablet debris by gastric lavage, there have been no clinical studies that have demonstrated that this has any impact on outcome in patients with tricyclic antidepressant (TCA) poisoning. There is also the possibility that lavage may increase drug absorption by pushing tablets into the small intestine. Furthermore, gastric lavage in patients with TCA poisoning may induce hypoxia and a tachycardia potentially increasing the risk of severe complications such as arrhythmias and convulsions. In view of the paucity of evidence that gastric lavage removes a significant amount of drug and the risk of complications associated with the procedure, the routine use of gastric lavage in the management of patients with TCA poisoning is not appropriate. Volunteer studies have shown generally that activated charcoal is more likely to reduce drug absorption if it is administered within 1 hour of drug ingestion. In the one volunteer study that looked at later administration of activated charcoal, there was a 37% decrease in plasma concentration associated with administration of activated charcoal at 2 hours post-ingestion. There have been no clinical studies that enable an estimate of the effect of activated charcoal administration on outcome in the management of patients with TCA poisoning. Volunteer studies have shown that multiple-dose activated charcoal increases the elimination of therapeutic doses of amitriptyline and nortriptyline, but not of doxepin or imipramine; however, these studies cannot be directly extrapolated to the management of patients with TCA poisoning. There have been no well designed controlled studies that have assessed the impact of multiple-dose activated charcoal in the management of patients with TCA poisoning. Because of the large volume of distribution of TCAs, it would not be expected that their elimination would be significantly increased by multiple-dose activated charcoal.Haemoperfusion, haemodialysis and the combination of these procedures do not result in significant removal of TCAs and are not recommended in the management of patients with TCA poisoning.

Quetiapine cross-reactivity among three tricyclic antidepressant immunoassays.

Quetiapine is an atypical antipsychotic agent with structural similarities to the tricyclic antidepressants (TCA). We report a case of quetiapine overdose that was initially clinically similar to that of a TCA overdose and caused a false-positive TCA immunoassay. We then analyzed three common TCA immunoassays [Microgenics (formerly Diagnostic Reagents, Inc.) Tricyclics Serum Tox EIA Assay, Syva RapidTest d.a.u., and Biosite Triage Panel for Drugs of Abuse] with quetiapine in solution as well as urine from both an overdose patient and a therapeutic patient. There was significant variation of the cutoff of false-positivity in all three immunoassays. Both the Syva and Microgenics immunoassays tested positive in both the overdose and therapeutic samples and were positive at urine levels of 100 microg/mL and 10 microg/mL, respectively. The Triage immunoassay was negative in solutions up to 1000 microg/mL and negative in both the therapeutic and overdose urine samples. Quetiapine may cause false-positive TCA immunoassay with both therapeutic use and in overdose. Significant variation exists between immunoassays to detect quetiapine as a false-positive test.

Phenytoin hypersensitivity syndrome with positive patch test. A possible cross-reactivity with amitriptyline.

A 34-year-old woman, after 2 weeks of treatment with phenytoin and amitriptyline, developed fever and cutaneous lesions consisting of a generalized maculopapular rash and eosinophilia. Her biochemical data showed abnormal liver functions with increased levels of SGOT, SGPT, LDH, gamma-glutamyl transpeptidase and alkaline phosphatase. The skin biopsy pattern was compatible with phenytoin drug eruption of the erythemamultiforme-like type (lymphocytic exocytosis, isolated dyskeratotic cells, vacuolation of basal cells and incontinence of pigment). The patch tests were positive with phenytoin (patch test biopsy showed a typical eczematous pattern). The patch test with amitriptyline was negative. An oral challenge with amitriptyline showed an erythematous maculopapular rash. The challenge with phenytoin was not carried out because the previously abnormal liver function tests contraindicated the challenge. Although there are a few cases reported, the patch tests could be useful for diagnosing phenytoin allergy. Cross-reactivity between phenytoin and amitriptyline is possible.

Redistribution of imipramine from regions of the brain under the influence of circulating specific antibodies.

The kinetics of brain-to-blood redistribution of imipramine (IMI) was assessed in nine brain regions of control rats and rats given anti-tricyclic antidepressant (anti-TCA) antibody. Two antibodies were given intravenously 6 min after intravenous [3H]IMI (1 nmol/kg). One was a murine monoclonal IgG1 (Ka = 3.8 x 10(7) M(-1)) at an IgG/IMI molar ratio of 1,000 (IgG1,000), and the other was a sheep polyclonal IgG (TAb; Ka = 1.3 x 10(10) M(-1)) at IgG/IMI molar ratios of 1, 10, and 100 (TAb1, TAb10, and TAb100). In the control rats, IMI was rapidly taken up by the brain (Cmax at 5 min) with no significant differences among the brain regions (4.1 +/- 0.4 to 5.4 +/- 0.6 pmol/ g), and brain IMI then declined monoexponentially with a half-life of 44.2 min (cerebellum) to 77.3 min (hippocampus). The greatest IMI content was in the frontal cortex and the lowest in the cerebellum. The antibodies (except TAb1) stimulated the extent and rate of IMI redistribution from all the brain regions depending on the immunoreactive capacity (NKa) of the antibody. The antibody with the highest NKa (TAb100) had the greatest effect. The fraction of IMI removed from the brain was 58-74%, and the redistribution half-life was 7.9-15.6 min; the mean residence time was reduced by 66-75% (11.8-23.9 min). These results demonstrate that circulating anti-TCA IgG rapidly and reliably removes IMI from the brain, indicating that immunotoxicotherapy could be an efficient procedure for accelerating the removal of TCA from the brain.

Bacterial expression and characterization of an anti-desipramine single-chain antibody fragment.

Tricyclic antidepressant toxicity is a leading cause of death from intentional drug overdose. Monoclonal antibody Fab' fragments specific for the tricyclic antidepressant, desipramine, reverse acute drug toxicity but may themselves have adverse effects at therapeutic doses. To evaluate the characteristics of smaller antibody fragments, we cloned, expressed and characterized a 26 kD single chain Fv fragment (G5-sFv). A DNA sequence encoding VH-linker-V1 was constructed from hybridoma mRNA encoding a high affinity monoclonal desipramine specific IgG1 and expressed in E. coli. G5-sFv was produced at high levels as insoluble inclusion bodies. Single chain Fv was solubilized, folded in a redox buffer and affinity purified on desipramine-Sepharose. The affinity of G5-sFv for desipramine was similar to that of the corresponding monoclonal Fab' as measured by surface plasmon resonance (Fab' 5.5 +/- 0.5 x 10(8) M-1, sFv 2.3 +/- 0.5 x 10(8) M-1). G5-sFv administered to rats after a tracer dose of 3H-desipramine produced rapid and marked redistribution of drug from tissues into serum. G5-sFv was stable at 4 C for greater than 6 months but lost activity at higher temperatures. We conclude that desipramine-specific-single chain Fv expressed in E. coli retains the affinity of the parent antibody for desipramine. The pharmacokinetic effect of G5-sFv on desipramine distribution suggests that it may be useful as an antidote for desipramine overdose.

Cerebral metabolism of imipramine and a purified flavin-containing monooxygenase from human brain.

Flavin-containing monooxygenase (FMO), previously reported both from hepatic and extrahepatic tissues, including brain, catalyze the oxidation of certain xenobiotics and drugs that contain a nucleophilic heteroatom. Psychoactive drugs, including the antidepressant imipramine, are substrates for the brain FMO. Since FMO-mediated metabolism of these drugs might contribute to local pharmacodynamic modulation within the human brain, the metabolism of imipramine by human brain FMO was studied in further detail. In the present study, the FMO activity was determined in human brain microsomes by estimating the actual amount of imipramine N-oxide formed. It was then compared with the corresponding activity measured using substrate (imipramine)-stimulated rates of nicotinamide adenine dinucleotide phosphate (NADPH) oxidation, which was significantly higher than the activity estimated as the amount of N-oxide assayed using high-pressure liquid chromatography (HPLC). The brain FMO activity was measurable only in the presence of detergents (sodium cholate or Lubrol PX) or in microsomes that were freeze-thawed several times. The activity was inhibited by an antibody to rabbit pulmonary FMO, but an antiserum to the rat liver NADPH cytochrome P-450 reductase had no effect indicating that cytochrome P-450 was not involved in the above metabolic pathway. The optimum pH for N-oxidation of imipramine was found to be 8.5; thermolability experiments indicated that the FMO activity was completely lost only after the incubation of brain microsomes at 45 degrees C for 20 minutes. An FMO purified to apparent homogeneity from a human brain had a molecular weight of 71,000 Da. The purified enzyme cross-reacted with the antibody to rabbit pulmonary FMO and efficiently catalyzed the metabolism of imipramine to its N-oxide. The human brain clearly contains an active FMO system, and it is conceivable that such enzymes are significantly involved in the local metabolism and modulation of pharmacological and/or toxic effects of certain xenobiotics, including psychoactive drugs.

Effects of recombinant drug-specific single chain antibody Fv fragment on [3H]-desipramine distribution in rats.

Tricyclic antidepressant overdose can be reversed in rats by drug-specific antibody Fab fragments, but the required Fab dose may itself by toxic. We studied the potential use of a smaller, recombinant desipramine (DMI)-specific single chain Fv fragment (B9-sFv) for this purpose. Anesthetized rats received a tracer (subtoxic) dose of [3H]-DMI followed in 15 min by B9-IgG, B9-Fab, B9-sFv (0.1 mumol of binding sites) or BSA. Each of the active treatments produced a rapid and substantial increase in the serum radiolabel concentration, whereas BSA did not (P < 0.001). The increase in serum radiolabel concentration 1 min after treatment was 13.3-fold with B9-IgG, 10.0-fold with B9-Fab and 7.3-fold with B9-sFv. Serum antibody concentrations were also highest after B9-IgG and lower with B9-Fab or B9-sFv. The 24-hr urinary excretion of radiolabel did not differ among groups, but was extensive even in the BSA group and probably represented the excretion of DMI metabolites. B9-sFv concentrations in urine or buffer at 37 degrees declined by >90% over 24 hr, but this fragment was much more stable in serum, retaining 70% of its activity after 96 hr. These data demonstrate that B9-sFv can alter markedly the distribution of [3H]-DMI in vivo. The rapidity of this effect, and its magnitude in comparison with Fab fragment or IgG, suggest that further study of B9-sFv as a treatment of DMI overdose is warranted.

Drug-specific antibodies as antidotes for tricyclic antidepressant overdose.

Drug-specific antibodies have been used clinically to treat digoxin or colchicine overdose. The lethal dose of tricyclic antidepressants (TCAs) is 100 times higher, and will require higher doses of antibodies (up to several g/kg) to reverse toxicity. Preliminary studies suggest that this is feasible. High affinity TCA-specific monoclonal Fab' or polyclonal Fab fragments rapidly reverse the cardiovascular toxicity of the TCA desipramine (DMI) in rats, and prolong survival. TCA-specific Fab' or Fab is generally well tolerated in rats, but doses several times higher than anticipated for human use may have adverse effects. Combining Fab with standard therapies for TCA overdose, such as NaHCO3, can reduce the required Fab dose. As an alternative, a recombinant single chain Fv fragment (sFv), one half the size of Fab, has been cloned which retains a high affinity for DMI and is able to alter DMI distribution in vivo. Because sFv has a shorter elimination half-life and more extensive renal excretion than Fab, it may have therapeutic advantages.

Immunoassay reagents for psychoactive drugs. II. The method for the development of antibodies specific to imipramine and desipramine.

Imipramine and desipramine were structurally modified by the attachment of spacer arms to the aromatic ring which were subsequently attached to bovine serum albumin. This approach utilized novel spacer arms and conjugation methods. This method yielded antisera with excellent selectivity and good titers. Rabbits were used to raise the antisera and the antibodies produced were characterized with respect to their cross-reactivity with imipramine, desipramine and hydroxy metabolites as well as selected structurally related compounds.

Adaptation of the Müller method to allow quantitative characterization of the affinity and cross-reactivity of antibodies by competitive radioimmunoassay.

A quantitative expression is derived for the evaluation of antigen-antibody affinity constants from radioimmunoassays for the completely general situation in which antigen and antibody are both multivalent. The theoretical analysis is then extended to encompass quantitative characterization of the competitive inhibition observed in screening tests for cross-reactivity of antibody with structural analogs of the eliciting antigen. These procedures are illustrated with a radioimmunological study of the cross-reactivity of a desipramine-elicited monoclonal antibody with other tricyclic antidepressants. An unexpected finding to emerge from this immunochemical study is the demonstration that a single affinity constant suffices to describe the interaction of desipramine with a polyclonal antibody elicited by this univalent antigen.

Redistribution of tricyclic antidepressants in rats using a drug-specific monoclonal antibody: dose-response relationship.

A monoclonal antibody was used to study the dose-response relationship for antibody-mediated redistribution of tricyclic antidepressants (TCA) in rats. The antibody (anti-TCA) was an IgG1 with Ka = 3.0 x 10(8) M-1 for desipramine (DMI) and 2.2 x 10(8) M-1 for imipramine (IMI). Anesthetized rats received 1 mg DMI (10% of the toxic dose), followed in 15 min by anti-TCA iv at doses representing anti-TCA/DMI molar ratios of 0.003, 0.013, and 0.07. Anti-TCA produced prompt, dose-related increases in the serum DMI concentration of 33, 164, and 776%. Similar results were obtained in rats treated with IMI. The highest dose of anti-TCA reduced the concentration of IMI in the heart. In a second protocol, the anti-TCA dose was kept constant and the DMI or IMI dose varied. The increase in serum drug concentration was 1750, 1260, and 150% (DMI) and 1460, 1200, and 170% (IMI) at drug doses of 0.1, 10, and 1000 micrograms. Thus, the percentage increase in serum drug concentration was diminished only 12-fold (DMI) or 9-fold (IMI) by a 10,000-fold increase in drug dose. At the highest anti-TCA/DMI ratio (lowest DMI dose), tissue DMI concentrations were significantly reduced. We conclude that 1) anti-TCA can effect substantial redistribution of a subtoxic dose of DMI or IMI, even when the antibody dose is less than equimolar to the TCA dose, and 2) the extent of TCA redistribution depends upon the doses of both antibody and drug; anti-TCA is most effective when the body burden of TCA is high. These data support the potential therapeutic use of anti-TCA for DMI or IMI toxicity, and should be useful in anticipating the dose and affinity of anti-TCA required.

Immunologic mimicry by a monoclonal antibody of the tricyclic anti-depressants' binding site on muscarinic acetylcholine receptors.

Inhibition constants of tricyclic anti-depressants and related drugs determined for a monoclonal anti-nortriptyline antibody were close to those previously calculated with the same compounds for the brain acetylcholine muscarinic receptor. A highly significant correlation was found between these two series of inhibition constants when no correlation existed between the inhibition constants for the antibody and those for other receptors. This suggests that the binding site for tricyclic anti-depressants on the antibody mimics the binding site for these ligands on muscarinic receptors. Although nortriptyline reveals a noncompetitive inhibition of N-methyl-scopolamine binding to muscarinic receptors, muscarinic ligands display weak or no binding to the antibody. These findings indicate that the binding site for tricyclic anti-depressants on the receptor is distinct from that for the muscarinic ligands.

Production and characterization of high affinity monoclonal antibodies to cyclic anti-depressant molecules.

A procedure is reported by which high levels of the tricyclic molecule desipramine was modified and conjugated at high density to the carrier molecules keyhole limpet hemocyanin and bovine serum albumin so that these could be used as immunogens in Balb/c mice. Such conjugates generated immune responses with high levels of antibody with specificity for the tricyclic. B cell hybridomas generated by fusion of immune Balb/c splenocytes to NS-1 cells which secreted monoclonal antibodies with specificity for the tricyclic were selected in a standard ELISA. In this report, we show that the binding constants of these monoclonal antibodies with various haptens can be assessed accurately by measuring fluorescence polarization, that a high degree of cross-reactivity between the monoclonals and various tricyclics exists, and that this procedure can be used to generate monoclonal antibodies of high binding constants.

Metalloimmunoassay of tricyclic antidepressant drugs: production and characterization of antiserum.

Metalloimmunoassay is a new immunoassay using an organometallic complex as the label. For the development of this assay, antibodies were produced in rabbits immunized with N-succinyldesipramine-bovine serum albumin conjugate. Antisera thus obtained were shown to be specific for the tricyclic antidepressant group of drugs and are tested as regard as desipramine or nortriptyline labelled by an organometallic moiety (designated metallohaptens). The evaluation of the affinity constants shows that antisera cross-react almost equally well with both imipramine labelled with tritium (radiotracer) and metallohaptens using either ferrocene or cymantrene as labels (metallotracers). Detection of metallohaptens is performed by a ZEEMAN atomic absorption spectrophotometer (ZAAS).