L.P. Hackett

Antidepressant Toxicity and the Need for Identification and Concentration Monitoring in Overdose

SummaryAntidepressant drugs are among the most commonly encountered causes of self-poisoning. These drugs include tricyclics, tetracyclics, bicyclics and mono-cyclics, as well as monoamine oxidase (MAO) inhibitors and selective serotonin reuptake inhibitors (SSRIs). Of these, the tricyclic antidepressants (TCAs) are generally more toxic in overdose, with major toxicity usually manifesting within the first 6 hours after overdose.Various studies indicate that patients at risk of toxicity from TCA overdose may be identified by neurological, cardiovascular and electrocardiography status, together with a quantitative estimate of the plasma drug concentration. While there are various methods available for such chemical estimations, the most satisfactory appears to be fluorescence polarisation immunoassay which gives rapid quantitative results for a variety of TCAs.The selective MAO-A inhibitor antidepressants and the SSRIs are relatively nontoxic when taken alone. However, overdoses of combinations of MAO inhibitors and either SSRIs or TCAs with serotonin reuptake blocking activity may result in a serotonin syndrome with a severe or fatal outcome. Features of this syndrome include hyperpyrexia, disseminated intravascular coagulation, convulsions, coma and muscle rigidity, which may not develop until 6 to 12 hours after overdose. While qualitative chemical identification of these drugs following overdose is helpful in confirming the diagnosis, it is not mandatory. The increasing use of MAO-A inhibitors and SSRIs in the treatment of depression suggests that careful clinical observation is required when combination overdoses are suspected.

Comparison of cyclosporine measurement in whole blood by high-performance liquid chromatography, monoclonal fluorescence polarization immunoassay, and monoclonal enzyme-multiplied immunoassay

Monitoring of cyclosporine concentrations in whole blood is used routinely as a guide to adjusting dose so as to achieve optimal therapeutic benefit with minimal adverse effects. In the present study, we have compared a specific high-performance liquid chromatography (HPLC) assay with a fluorescence polarization immunoassay (TDx) and an enzyme-multiplied immunoassay (Emit). Both Emit and TDx assays employ a monoclonal antibody to cyclosporin A and therefore have the potential for a high degree of specificity. Blood specimens (EDTA as anticoagulant) were obtained from 113 patients (71 renal transplants, 17 liver transplants, and 25 other categories) taking cyclosporine and analysed by all three methods. There were significant correlations between results for HPLC and Emit (Emit = 10.54 + 1.07 x HPLC; r2 = 0.82, p less than 0.001) and between results for HPLC and TDx (TDx = 9.16 + 1.42 x HPLC; r2 = 0.82, p less than 0.001). Compared to HPLC analysis, 74% and 96%, respectively, of Emit and TDx results were to the left of the line of identity. The TDx monoclonal antibody appears to have a lesser degree of specificity than that used in the Emit assay. Mean concentrations of cyclosporine measured by Emit and TDx were 17% and 51% higher, respectively, than those measured by HPLC. Because of this overestimation, we suggest that both Emit and TDx methods may find their most appropriate use in routine therapeutic monitoring of renal transplant patients in whom metabolite concentrations are less variable over time.

A Comparison of High-performance Liquid Chromatography and Fluorescence Polarization Immunoassay for Therapeutic Drug Monitoring of Tricyclic Antidepressants

Although the manufacturer of the polyclonal fluorescence polarization immunoassay (FPIA) for tricyclic antidepressants (TCA) only recommends its use in the diagnosis of overdose, the assay is nevertheless widely used in therapeutic drug monitoring. Using plasma samples from 337 patients taking one of eight different tricyclic antidepressants, the authors investigated the performance of the TDx assay procedure for eight different TCAs by comparison to specific high-performance liquid chromatography (HPLC) assay methods. The regression correlation between the TDx assay value and that for active tricyclic measured by HPLC was poor (r2 < 0.9) for amitriptyline, clomipramine, dothiepin, and doxepin. The regression line for amitriptyline also had a significant positive y-axis intercept. Moreover, the TDx method overestimated the concentration of active drug to an extent that varied considerably between different TCAs and within the usual therapeutic range for a single TCA. The authors conclude that the TDx assay is probably satisfactory for routine TDM of desipramine, imipramine, nortriptyline, and trimipramine. However, it significantly overestimates therapeutic concentrations of amitriptyline, clomipramine, dothiepin, and doxepin. The use of TDx and HPLC assay methods by different laboratories for sequential therapeutic drug monitoring of TCAs in the same patient may confuse physicians and confound dose adjustment and patient management. Although their study shows that the TDx assay can give satisfactory therapeutic drug monitoring results for some drugs, the authors conclude that its use should be restricted to the evaluation of overdose as recommended by the manufacturer.

Estimated dose exposure of the neonate to buprenorphine and its metabolite norbuprenorphine via breastmilk during maternal buprenorphine substitution treatment

OBJECTIVE The aim of the present study was to estimate the dose of buprenorphine and its primary metabolite norbuprenorphine that a breastfed infant would receive during maternal maintenance treatment with buprenorphine. STUDY DESIGN Seven pregnant opioid-dependent women taking buprenorphine (median, 7 mg/day; range, 2.4-24 mg) and who intended to breastfeed were recruited. After lactation was established, several milk samples were collected from each subject over a 24-hour dose interval, and buprenorphine and norbuprenorphine concentrations were measured by liquid chromatography-tandem mass spectrometry. The average concentration (C(avg)) across the dose interval was estimated as for both buprenorphine and norbuprenorphine (as buprenorphine equivalents). Absolute infant dose (AID), defined as C(avg) × daily milk intake, and relative infant dose (RID), defined as 100×AID/weight-adjusted maternal daily dose, via milk were calculated, assuming a milk intake of 0.15 L/kg/day. The infants health and progress were assessed directly and by questionnaire on the study day. RESULTS Mean (95% confidence interval) norbuprenorphine concentration in milk and AID values (1.94 [0.79-3.08] μg/L and 0.29 [0.12-0.46] μg/kg/day, respectively) were approximately half those for buprenorphine (3.65[1.61-5.7] μg/L and 0.55 [0.24-0.85] μg/kg/day, respectively). Similarly, the mean RID values were 0.18% (0.11-0.25%) for norbuprenorphine and 0.38% (0.23-0.53%) for buprenorphine. The breastfed infants showed no adverse effects, were all in good health, and were progressing as expected. CONCLUSION Thus the dose of buprenorphine and norbuprenorphine received via milk is unlikely to cause any acute adverse effects in the breastfed infant.

Gabapentin and Breastfeeding: A Case Report

The aim of this study was to describe the milk-plasma ratio and relative infant dose of gabapentin in a breastfeeding mother and to determine the well-being of her exposed infant. The mother-infant pair was studied over a 24-hour dose interval at steady state. Gabapentin concentrations were quantified by high-performance liquid chromatography. Infant exposure was calculated as concentration in milk multiplied by an estimated milk production of 0.15 L/kg/d and normalized to the weight-adjusted maternal dose. The milk-plasma ratio was 0.86; the relative infant dose was 2.34%. The absolute infant dose was approximately 3% of the children’s dose for gabapentin, and the infant plasma level of 0.4 mg/L was approximately 6% of the maternal plasma drug concentration. No adverse effects attributable to gabapentin were noted in the infant. In combination with a previously published report, these limited data support the prescription of gabapentin to a breastfeeding mother after a careful individual risk-benefit analysis.

Disposition of dothiepin after overdose : effects of repeated-dose activated charcoal

Although the tricyclic antidepressant dothiepin is often encountered in deliberate self-poisonings, there are no published studies of its disposition in overdose. In the present study, we have documented the plasma disposition of dothiepin and its major metabolites in eight overdose patients. All had high initial levels of dothiepin (819-3,851 micrograms/L), dothiepin-S-oxide (655-2,162 micrograms/L), nordothiepin (88-422 micrograms/L), and nordothiepin-S-oxide (176-530 micrograms/L) that were considerably above steady-state therapeutic concentrations. In three patients who received treatment with repeated-dose activated charcoal, dothiepin half-lives were 10.6, 12.5, and 13.1 h compared with the literature range of 18.5-24 h. All patients survived and none experienced any significant cardiovascular event despite exhibiting clinical signs of tricyclic antidepressant overdose. We suggest that repeated-dose activated charcoal treatment may decrease the dothiepin half-life after overdose.

Quantification of naltrexone and 6,β-naltrexol in plasma and milk using gas chromatography-mass spectrometry. Application to studies in the lactating sheep

A selective gas chromatography-mass spectrometry method using solid-phase extraction has been developed for the detection and quantification of naltrexone and its metabolite, 6,beta-naltrexol in plasma and milk from humans and sheep at pharmacologically relevant concentrations. Di- or tri-acetyl derivatives were formed and quantified by selected-ion monitoring. Recoveries of naltrexone (30 microg/l) and 6,beta-naltrexol (250 microg/l) from both human plasma and milk were greater than 70%. Intra-assay and inter-day precision ranged from 3 to 21% for naltrexone and 2-18% for 6,beta-naltrexol for all matrices investigated, with an overall mean accuracy of 104% for naltrexone, and 99% for 6,beta-naltrexol. Human samples containing these analytes were stable for at least 3 weeks at -20 degrees C or 6 weeks at -80 degrees C. Analysis of the plasma and milk from the lactating sheep showed mean milk-to-plasma ratios of 55 for naltrexone and 3 for 6,beta-naltrexol.

High-performance liquid chromatographic method for measurement of pentamidine in plasma and its application in an immunosuppressed patient with renal dysfunction.

Summary A rapid method for the quantitation of pentamidine in plasma by high-performance liquid chromatography is described. Pentamidine was extracted from plasma using a mixed solvent of 40% acetonitrile in chloroform. Reversed-phase chromatography was then performed on a μ Bondapak C-18 column, using a mobile phase of acetonitrile containing 0.1% H3PO4 and 0.1% NaCl (20:80) and the eluting peaks detected by their UV absorbance at 262 nm. The assay had a within-day coefficient of variation of less than 3.8%, an absolute recovery of 92%, and a limit of detection of 15 nmol/L. The method was applied during pentamidine mesylate treatment (4 mg/kg/day) for Pneumocystis carinii pneumonia in an immunosuppressed patient with impaired renal function. Plasma levels rose slowly to a plateau (range 530–880 nmol/L) after 7 days of treatment, suggesting a half-life of around 1.5–2 days.

Disposition and clinical outcome after intraperitoneal meperidine and ropivacaine administration during laparoscopic surgery

BACKGROUND:Limited evidence supports the efficacy of intraperitoneal (IP) meperidine or local anesthetic for postoperative analgesia. Our study aims were to investigate analgesic efficacy and to quantify the plasma concentrations of meperidine and ropivacaine after IP administration. The null hypothesis was that there was no significant difference among groups for dynamic pain in the first 24 h after major abdominal laparoscopic surgery. METHODS:This double-blind, five parallel group, placebo-controlled, two-center trial randomized 250 women having laparoscopic surgery to receive IP meperidine 50 or 100 mg (groups M50 and M100), ropivacaine 150 mg (group R150), meperidine 50 mg and ropivacaine 150 mg (group M50R150), all with intramuscular saline, or IP saline, with intramuscular meperidine 50 mg (group C). The primary outcome was pain during recovery. A pharmacokinetic profile of the drugs was obtained. RESULTS:There were no significant differences among groups for mean (sd) dynamic pain scores in the postoperative care unit (2.2 [2.8], 2.5 [3.3], 1.6 [2.5], 2.6 [3.2], 2.7 [3.2] for groups C, M50, M100, R150, and M50R150, P = 0.50) or thereafter. There were no significant differences among groups for pain scores at rest, IV morphine use, recovery characteristics and patient satisfaction. After IP administration of meperidine 50 mg the plasma concentration (median average 55–60 &mgr;g/L) was approximately half that of an equivalent intramuscular dose (median average 113 &mgr;g/L). CONCLUSIONS:Compared with systemic opioid, IP meperidine and ropivacaine, alone or in combination, did not produce better pain relief or opioid dose-sparing after laparoscopic surgery.

Application of a multi-faceted approach for the assessment of treatment response in falciparum malaria: a study from Malaysian Borneo

Thirty-two patients reporting to the Lundu District Hospital, Sarawak, Malaysian Borneo, with uncomplicated falciparum malaria were recruited into a multifaceted study to assess treatment response. Following combined chloroquine and sulphadoxine/pyrimethamine treatment the patients were followed for 28 days according to the World Health Organisation in vivo drug response protocol. The in vivo study revealed that 13 (41%) of the patients had a sensitive response to treatment, five (16%) cleared asexual stage parasites but had persistent gametocytes, 11 (34%) had RI type resistance and three (9%) had RII type resistance requiring quinine intervention before day 7 for parasite clearance. Although clinically insignificant, patients with persistent gametocytes, surviving chloroquine and sulphadoxine/pyrimethamine treatment during maturation, were placed in the reduced response to treatment group for analysis. Allelic typing detected 100% prevalence of the pfcrt K76T marker associated with chloroquine resistance and 78% prevalence of the pfdhfr NRNL haplotype associated with sulphadoxine/pyrimethamine treatment failure. High serum chloroquine levels and pfdhfr haplotypes with <or=2 point mutations were independently associated with a sensitive response to treatment. However four patients in the sensitive response group had both low serum chloroquine levels and the pfdhfr NRNL haplotype. A degree of immunity, consistent with malaria endemicity, may account for the apparently paradoxical presence of markers of drug resistance in the sensitive group.