Development and characterization of a non-enzymatic electrochemical biosensor for rapid determination of sorbent-based extracted trazodone and doxepin in complicated samples.

BACKGROUND: Given the importance of achieving optimal therapeutical concentration in patients treated with antidepressants, this study investigates a novel technique for the simultaneous determination of trazodone (TRZ) and doxepin (DOX) in human plasma and serum samples for the first time. RESULTS: To achieve simultaneous determination of two antidepressants, TRZ and DOX, a novel detection system was designed: a non-enzymatic voltammetric biosensor based on boron-reduced graphene oxide/manganese oxide nanoparticles (GCE/B-rGO/MnO NPs). The detection was accomplished after pre-concentration and extraction trace amounts of the analytes using the thin film-solid phase microextraction (TF-SPME) technique, which employed polyvinyl alcohol/polyvinyl acetate/copper oxide nanoparticles (PVA/PVAc/CuO NPs) electrospun nanofibers. The successful preparation of composite nanofibers and modified electrodes was confirmed using the evaluation of field emission-scanning electron microscopy (FE-SEM) and energy-dispersive X-ray spectroscopy (EDX). Also, the composite nanofibers were characterized with attenuated total reflectance-Fourier transform-infrared (ATR-FT-IR) and X-ray diffraction (XRD). In the solution of TRZ and DOX, under optimum experimental conditions, the linear dynamic ranges (LDRs) were 0.1-20.0 µmol L-1 and 0.5-27.0 µmol L-1, respectively. Also, the limit of detection (LOD) values of TRZ and DOX were 0.032 and 0.150 µmol L-1. SIGNIFICANCE: PVAc acts as a cross-linking agent for PVA, and their mixture is effective for sample preparation and pre-concentration of analytes in complex matrices. Also, adding CuO NPs to this polymeric mixture enhanced the adsorption efficiency. Taking advantage of the high surface area of MnO NPs and the high electrical conductivity of B-rGO, and considering the superiority of their simultaneous utilization, the constructed electrochemical biosensor is both cost-effective and rapid. It demonstrates excellent stability, repeatability, and sensitivity for the simultaneous determination of TRZ and DOX under optimal conditions. This biosensor, the first of its kind, is specifically designed for the simultaneous determination of TRZ and DOX in human plasma and serum samples, representing a significant advancement in biosensing technology.

Development and validation of a simultaneous analytical method for non-steroidal therapeutic compounds in cosmetics using liquid chromatography-tandem mass spectrometry.

Atopic dermatitis is a typical chronic inflammatory skin disease that affects all age groups and requires basic skin care for treatment. Anti-inflammatory and antiallergy steroids are the most frequently used treatments but they are limited due to their side effects caused by a weakening of the immune system. Many consumers focus on performance as a criterion for selecting cosmetics. However, steroids have been illegally used to improve the performance of cosmetics, and consumers have been adversely affected by the corresponding side effects. In this paper, we propose a simple and rapid method using liquid chromatography-tandem mass spectrometry to simultaneously analyze ten non-permitted atopic therapeutic compounds in cosmetic products: chlorpheniramine maleate, ketotifen fumarate, doxepin hydrochloride, azelastine hydrochloride, bufexamac, clotrimazole, tranilast, fusidic acid, tacrolimus, and pimecrolimus. Additionally, the major characteristic fragment ions for tacrolimus, pimecrolimus, and clotrimazole were identified by time-of-flight mass spectrometry. The specificity, linearity, limit of detection, limit of quantification, recovery, precision, accuracy, and stability of the proposed method were validated. The limit of detection and quantification were in the ranges of 5.05-203.30 pg/mL and 15.15-609.90 pg/mL, respectively. The proposed analysis method could help improve the safety management of cosmetics.

Suitability of 1-hexyl-3-methylimidazolium ionic liquids for the analysis of pharmaceutical formulations containing tricyclic antidepressants.

The reversed-phase chromatographic behaviour of six tricyclic antidepressants (amitryptiline, clomipramine, doxepin, imipramine, nortryptiline and maprotiline) was examined in this work with acetonitrile-water mobile phases, in the absence and presence of the ionic liquids 1-hexyl-3-methylimidazolium chloride and 1-hexyl-3-methylimidazolium tetrafluoroborate, which have interesting features for the separation of basic compounds, in terms of peak shape combined with reduced retention. Tricyclic antidepressants are low polarity drugs that strongly associate to the alkyl chains of conventional stationary phases. They are also positively charged in the usual working pH range (2-8) in reversed-phase liquid chromatography, due to their strong basic character. In consequence, they may interact with the residual ionised silanols present in conventional silica-based stationary phases, which is translated in stronger retention, and tailed and broad peaks. A simple chromatographic procedure for the control of tricyclic antidepressants in pharmaceutical formulations was developed using a C8 column and a mobile phase containing 30% acetonitrile/10 mM 1-hexyl-3-methylimidazolium chloride at pH 3, with UV detection. Intra- and inter-day precisions were usually below +1.0%, and intra- and inter-day bias (trueness) ranged between ‒2.1% and +2.4%, and between ‒3.0% and +2.3%, respectively. Sample preparation was simple and only required solubilisation and filtration previous to injection.

Suicidal overdose with relapsing clomipramine concentrations due to a large gastric pharmacobezoar.

The paper presents a case of fatal intoxication after massive sustained-release clomipramine overdosage with prolonged toxicity related to a large gastric pharmacobezoar. 42-year-old female was admitted to the toxicology unit 14 h after drugs ingestion. At admission patient was deeply unconscious, required controlled mechanical ventilation. Serum total level of TCAs was 1955 ng/mL. Gastric lavage revealed no pills. Within the next 12h the patient's clinical condition improved. TCAs level decreased to 999 ng/mL. However, after another 10h the clinical condition started deteriorating again and the patient went into a deep coma requiring controlled mechanical ventilation. TCAs level increased to 2011 ng/mL. X-ray and computed tomography revealed large pharmacobezoar consisted from radio-opaque pills. In the 28th h of hospitalization gastrotomy was performed, confirming presence of pharmacobezoar formed from Anafranil SR tablets. After surgery TCAs level was gradually decreasing. However, the patient's condition did not improve, she died 32 h after gastrotomy. Post-mortem analyses revealed drug and its metabolite toxic levels in blood (clomipramine - 1729 ng/mL, norclomipramine - 431 ng/mL) and toxic levels in internal organs: myocardium (clomipramine - 14,420 ng/g, norclomipramine - 35,930 ng/g), vitreous humor (clomipramine - 1000 ng/mL, norclomipramine - 3110 ng/mL). Described case report indicates that sustained release clomipramine tablets may form pharmacobezoar. X-ray and computed tomography examinations should be considered in cases of massive abuse of sustained release clomipramine, particularly if symptoms of intoxication are recurrent or persistent.

Stability studies of clonazepam, diazepam, haloperidol, and doxepin with diverse polarities in an acidic environment.

Stability of clonazepam, diazepam, haloperidol, and doxepin was determined in acidic solutions. In addition, determination of the kinetic and thermodynamic properties of this stability was carried out. Reaction rate constants (k), half-life times (t(0.1) and t(0.5)), and activation energy (Ea) were estimated for the drugs, which differed in polarity expressed with log P values. It was observed that estimated Ea values increased from 42.13 to 125.03 kJ/mol with an increase of lipophilicity (log P) beginning from the most hydrophilic drug (clonazepam, 2.70 log P) to the most lipophilic drug (doxepin, 4.10 log P). All degradation products were studied using an HPLC/electrospray ionization-MS technique in the positive ionization mode.

Quantification of rimonabant (SR 141716A) in monkey plasma using HPLC with UV detection.

Using an isocratic high-performance liquid chromatography (HPLC) system and UV detection, a simple and precise analytical procedure was developed to quantify levels of the CB(1) receptor antagonist rimonabant in the plasma of rhesus monkeys. Rimonabant was extracted from plasma samples into 5% isopropanol in hexane. After separation, the isopropanol-hexane fractions were dried to residue, redissolved in mobile phase, and then injected into the HPLC. The HPLC system included an acetonitrile-phosphate buffer (62:38, v/v) mobile phase (pH 6.7), flow rate of 1.5 mL/min, C(18) column (4.6 mm i.d. x 150 mm length, 5 microm), and UV detection at 280 nm. Retention times for rimonabant and doxepin (internal standard) were 9.9 and 2.4 min, respectively. The regression of the spiked calibrator curve was linear from 60 to 4000 ng/mL (r(2) = 0.996). The lower limit of quantification was 60 ng/mL, and recovery was 83.6%. Rimonabant was stable in stock solutions and monkey plasma across a range of temperatures and concentrations. To demonstrate utility, plasma rimonabant was measured in six rhesus monkeys at 60 and 240 min after intramuscular administration of 1 mg/kg rimonabant. Rimonabant levels ranged from 175 to 1290 ng/mL. The analytical assay described here provides a simple and accurate procedure for multiple within-subject measurements of the CB(1) antagonist rimonabant.

A novel electrochemical sensor for probing doxepin created on a glassy carbon electrode modified with poly(4-amino- benzoic acid)/multi-walled carbon nanotubes composite film.

A novel electrochemical sensor for sensitive detection of doxepin was prepared, which was based on a glassy carbon electrode modified with poly(4-aminobenzoic acid)/multi-walled carbon nanotubes composite film [poly(4-ABA)/MWNTs/GCE]. The sensor was characterized by scanning electron microscopy and electrochemical methods. It was observed that poly(4-ABA)/MWNTs/GCE showed excellent preconcentration function and electrocatalytic activities towards doxepin. Under the selected conditions, the anodic peak current was linear to the logarithm of doxepin concentration in the range from 1.0 × 10(-9) to 1.0 × 10(-6) M, and the detection limit obtained was 1.0 × 10(-10) M. The poly(4-ABA)/MWNTs/GCE was successfully applied in the measurement of doxepin in commercial pharmaceutical formulations, and the analytical accuracy was confirmed by comparison with a conventional ultraviolet spectrophotometry assay.

Spectrofluorimetric method for the determination of doxepin hydrochloride in commercial dosage forms.

A novel spectrofluorimetric method has been developed for the determination of doxepin hydrochloride in commercial dosage forms. The method is based on the fluorescent ion pair complex formation of the drug with eosin Y in the presence of sodium acetate-acetic acid buffer solution of pH 4.52 which is extractable in dichloromethane. The extracted complex showed fluorescence intensity at lambdaem=567 nm after excitation at 464 nm. The calibration curve was linear over the working range of 0.1-0.8 microg ml(-1). Under the optimized experimental conditions, present method is validated as per International Conference on Harmonization guidelines. The limit of detection for the developed method is 2.95 ng ml(-1). The method has been successfully applied to the determination of doxepin hydrochloride in commercial dosage forms. The results are compared with the reference spectrofluorimetric method.

Doxepin and nordoxepin concentrations in body fluids and tissues in doxepin associated deaths.

Body fluids and tissues in eight doxepin (Dox)-related deaths were investigated in order to prove whether the individual concentration of Dox, the concentration sum of parent drug and its active metabolite N-desmethyldoxepin (NDox) or the concentration ratio Dox/Ndox valuably contribute to making a cause of death determination. Individual case histories were shortly described. Dox and NDox concentrations were determined by LC-MS/MS. Dox concentration measured from two cases was well within a concentration range considered therapeutic, whereas subtherapeutic dosing may have occurred in another two cases. There were two cases of fatal Dox ingestion, as well as a case of high dosage and advanced putrefaction, respectively. The liver concentration sum may be more useful if a fatal ingestion cannot be clearly separated from a person's medication usage. High concentrations could be observed in lung tissue, and combined concentrations of Dox and NDox may also be helpful in making a cause of death determination. There was a trend to a higher concentration sum in the brain with increasing combined levels in blood. Overall, the sum of the absolute figures allows a more accurate interpretation in Dox-related deaths as compared to the molar concentration ratio which may be helpful in acute ingestion. Determination of the N-desmethyl metabolite along with its parent is recommended and analysis should include more than a single specimen.

Supported liquid membranes in hollow fiber liquid-phase microextraction (LPME)--practical considerations in the three-phase mode.

In this work, three-phase liquid-phase microextraction (LPME) based on a supported liquid membrane (SLM) sustained in the wall of a hollow fiber was investigated with special focus on optimization of the experimental procedures in terms of recovery and repeatability. Recovery data for doxepin, amitriptyline, clomipramine, and mianserin were in the range of 67.8-79.8%. Within-day repeatability data for the four basic drugs were in the range of 4.1-7.7%. No single factor was found to be responsible for these variations, and the variability was caused by several factors related to the LPME extractions as well as to the final HPLC determination. Although the volume of the SLM varied within 0.4-3.1% RSD depending on the preparation procedure, and the volume of the acceptor solution varied within 4.8% RSD, both recoveries and repeatability were found to be relative insensitive to these variations. Thus, the handling of microliters of liquid in LPME was not a very critical factor, and the preparation of the SLM was accomplished in several different ways with comparable performance. Reuse of hollow fibers was found to suffer from matrix effects due to built-up of analytes in the SLM, whereas washing of the hollow fibers in acetone was beneficial in terms of recovery, especially for the extraction of the most hydrophobic substances. Several of the organic solvents used in the literature as SLM suffered from poor long-term stability, but silicone oil AR 20 (polyphenylmethylsiloxane), 2-nitrophenyl octyl ether (NPOE), and dodecyl acetate (DDA) all extracted with unaltered performance even after 60 days of storage at room temperature.

Development of an HPLC method for the monitoring of tricyclic antidepressants in biofluids.

A simple, rapid and sensitive HPLC method was developed and validated for the determination of four tricyclic antidepressants (TCAs): amitriptyline, doxepin, clomipramine (CLO) and imipramine, in pharmaceutical formulations and biological fluids. A Kromasil C(8 )analytical column (250 x 4 mm, 5 microm) was used for the separation, with a mobile phase consisting of 0.05 M CH(3)COONH(4) and CH(3)CN (45:55 v/v) delivered at 1.5 mL/min isocratically. Quantification was performed at 238 nm, with bromazepam (1.5 ng/microL) as the internal standard. The determination of TCAs in blood plasma was performed after protein precipitation. Urine analysis was performed by means of SPE using Lichrolut RP-18 Merck cartridges providing high absolute recoveries (> 94%). Direct analysis of urine was also performed after two-fold dilution. The developed method was fully validated in terms of selectivity, linearity, accuracy, precision, stability and sensitivity. Repeatability (n = 5) and between-day precision (n = 5) revealed RSD <13%. Recoveries from biological samples ranged from 91.0 to 114.0%. The absolute detection limit of the method was calculated as 0.1-0.6 ng in blood plasma and 0.2-0.5 ng in extracted urine or 0.4-0.7 in diluted urine. The method was applied to real samples of plasma from a patient under CLO treatment.

Densitometric high performance thin-layer chromatography identification and quantitative analysis of psychotropic drugs.

A thin-layer chromatography (TLC)-densitometry method has been developed to identify and quantify haloperidol, amitriptyline, sulpiride, promazine, fluphenazine, doxepin, diazepam, trifluoperazine, clonazepam, and chlorpromazine in selected psychotropic drugs. Separation was performed on precoated silica gel 60 F254 TLC plates. Chromatograms were developed in various mobile phases, and 8 of 30 tested phases were selected based on spot location and developing time. The identification and quantification were carried out based on ultraviolet densitometric measurements at chosen wavelengths. In addition to retention coefficients, the absorption spectra recorded directly from chromatograms were also used in qualitative analysis. Under established experimental conditions, high sensitivity of the method was achieved. The limit of detection ranged from 0.009 to 0.260 microg, depending on the wavelength selected for measuring. A satisfactory recovery, ranging from 92.99 to 104.70%, was achieved for individual constituents.

Extractive spectrophotometric methods for the determination of doxepin hydrochloride in pharmaceutical preparations using titanium (IV) and iron (III) thiocyanate complexes.

Two simple, precise, and accurate extractive spectrophotometric methods have been developed for the determination of doxepin hydrochloride in pharmaceutical preparations. The methods are based on the formation of ion association complexes of doxepin with titanium (IV) and iron (III) thiocyanate complexes in acidic medium. The produced compounds are insoluble in water but well soluble in some organic solvents. They are extracted with mixtures of butyl alcohol-chloroform (2:3, v/v) and (1:4, v/v) and measured spectrophotometrically at 400 and 490 nm for DOX-Ti-SCN and DOX-Fe(III)-SCN methods, respectively. Beer's law was obeyed in the concentration ranges of 5-50 and 3-30 microg/ml with molar absorptivity of 7.12 x 10(3) and 1.36 x 10(4) l mol(-1) cm(-1) for DOX-Ti-SCN and DOX-Fe-SCN systems, respectively. The proposed methods have been successfully applied for the analysis of the drug in dosage forms. No interference was observed from common pharmaceutical adjuvants. The methods have been also used for the determination of the drug in the presence of its degradation product. Statistical comparison of the obtained results with the reference methods shows excellent agreement and indicates no significant difference in accuracy and precision.

Interfacing the orbitrap mass analyzer to an electrospray ion source.

The orbitrap mass analyzer employs the trapping of pulsed ion beams in an electrostatic quadro-logarithmic field. This field is created between an axial central electrode and a coaxial outer electrode. Stable ion trajectories combine rotation around the central electrode with harmonic oscillations along it. The frequencies of axial oscillations and hence mass-to-charge ratios of ions are obtained using fast Fourier transform of the image current detected on the two split halves of the outer electrode. This work proves that such a trap could be coupled to a continuous, electrospray, ion source. Such a coupling necessitated the development of an rf-only quadrupole for external accumulation of ions and their injection in very short (< 1 micros) ion bunches. Along with good sensitivity, this mass spectrometer provides mass resolving power up to 150,000 fwhm, mass accuracies within a few parts per million, and relative mass range up to 8-fold. The maximum number of ions available for analysis is limited by the space-charge capacity of the accumulation quadrupole.

Spectrophotometric determination of some antidepressant drugs using 3-methylbenzothiazolin-2-one hydrazone.

A sensitive spectrophotometric method for the determination of amitriptyline hydrochloride, nortriptyline hydrochloride and doxepin hydrochloride in pure and dosage forms, is described. The method is based on the oxidative coupling of the drugs with 3-methylbenzothiazolin-2-one hydrazone in the presence of iron(III) chloride in 1 M hydrochloric acid. The commonly encountered excipients and additives do not interfere with the determinations. Results of the present method are comparable with those of official methods. The new method offers the advantage of simplicity and rapidity.

Stereoselective measurement of E- and Z-doxepin and its N-desmethyl and hydroxylated metabolites by gas chromatography-mass spectrometry.

A stereoselective method of analysis of the antidepressant drug doxepin (DOX, an 85:15% mixture of E-Z stereoisomers), its principal metabolites E- and Z-N-desmethyldoxepin (desDOX) and ring-hydroxylated metabolites in microsomal incubation mixtures is described. DOX and its metabolites were extracted from alkalinised incubation mixtures by either: 9:1 hexane-propan-2-ol (method 1) or 1:1 hexane-dichloromethane (method 2), derivatised with trifluoroacetic anhydride and analysed by GC-MS with selected ion monitoring. Both methods were suitable for the analysis of individual desDOX isomers as indicated by correlation coefficients of > or = 0.999 for calibration curves constructed between 50 and 2500 nM, and good within-day precision at 125 nM (C.V. < or = 14%) and 1000 nM (C.V. < or = 8%). Method 1, however, was unsuitable for the analysis of ring-hydroxylated metabolites of DOX, whereas the hydroxylated metabolites of E-DOX and E-desDOX (generated in situ) were extracted by method 2 with a C.V. of ca. 13%. This is the first assay method that permits the simultaneous measurement of desDOX and hydroxylated metabolites of DOX in microsomal mixtures.

On-line capillary electrophoresis-electrospray ionization mass spectrometry using a polymerized anionic surfactant.

On-line capillary electrophoresis-electrospray ionization-mass spectrometry (CE-ESI-MS) has been used to determine the tricyclic antidepressant drugs (imipramine, doxepin, and amitriptyline) as well as the beta-adrenergic blocker drugs (propranolol and alprenolol). A CE-ESI-MS interface linking a manually operated CE system and a Finnigan MAT-900 sector mass spectrometer (with an Analytica electrospray ionization source) has been constructed in-house and employed for this study. Although a water/methanol based capillary zone electrophoresis (CZE) buffer was initially used to determine these analytes, enhanced resolution was obtained by addition of a polymerized surfactant, i.e., poly-sodium undecylenic sulfate (poly-SUS), into the electrokinetic chromatography (EKC) buffer. When a low concentration of this poly-SUS surfactant was added to a volatile EKC buffer, these structurally similar cationic drugs were EKC separated and on-line detected by ESI-MS.

Detection of doxepin and its major metabolite desmethyldoxepin in hair following drug therapy.

Doxepin is a tricyclic antidepressant that is widely prescribed for the treatment of mild depression. In this study, hair samples collected from a patient receiving 25 mg of doxepin daily were analyzed. Doxepin was administered to the patient for 4 months (June 15 to October 15, 1996). Five hair samples were collected: 1 and 3 months after doxepin therapy began and 1, 3, and 5 months after drug therapy ended. Solid-phase extraction was employed to isolate doxepin and its major metabolite desmethyldoxepin from the hair matrix, and gas chromatography-mass spectrometry (GC-MS) was used for quantitation of both drugs. Six-point standard curves (0.25-20 ng/mg) were prepared for both compounds with an internal standard (doxepin-d3). The standard curves for doxepin and desmethyldoxepin were linear over the range reported and had correlation coefficients of 0.984 and 0.985, respectively. The limit of quantitation for both analytes was 0.25 ng/mg of hair. In addition, the replicate analysis of control hair preparations was performed at two levels (2 ng/mg and 15 ng/mg) to determine intra- and interday variability. Doxepin and desmethyldoxepin were not detected in the patient's sample collected 1 month after doxepin therapy began. The samples collected 3 months after doxepin therapy began and 5 months after drug therapy was terminated had detectable amounts of doxepin and desmethyldoxepin. The highest concentrations of doxepin (mean, 0.59 ng/mg) and desmethyldoxepin (mean, 0.40 ng/mg) were found 5 months after doxepin therapy began, which was also 1 month after the patient had stopped using the drug. Five months after doxepin therapy was terminated, the drug and its metabolite were still present in the patient's hair. The concentration of doxepin in hair was always significantly higher than the concentration of desmethyldoxepin.

[A systematic screening and identification method for 29 central nervous system drugs in body fluid by high performance capillary electrophoresis].

A systematic screening method has been developed for the detection of 29 central nervous system (CNS) drugs in human plasma, urine and gastric juice by high performance capillary electrophoresis (HPCE). The first step is sample preparation. The patient's or normal human plasma (0.5 ml) spiked with CNS drugs was extracted with 2 x 4 ml dichloromethane, while 2 ml of patient's or spiked urine was extracted with 2 x 6 ml chloroform. The combined extract from plasma or urine was evaporated to dryness in a rotation evaporator at 35 degrees C. The residue was dissolved in 100 microliters methanol and subsequently 400 microliters of redistilled water was added. The patient gastric juice (3 ml) was centrifuged at 2,000 r.min-1 for 5 min. The supernatant was filtered through 0.45 micron microporous membrane for injection onto capillary columns. The second step was to perform CZE separation in acidic buffer composed of 30 mmol.L-1(NH4)3PO4(pH 2.50) and 10% acetonitrile (condition A). Most of the benzodiazepines (diazepam, nitrazepam, chlordiazepoxide, flurazepam, extazolam, alprazolam) and methaqualone were baseline separated and detected at 5-13 min, while thiodiphenylamines showed group peaks at 3-5 min and barbiturates migrate with electroosmotic fluid (EOF) together. The third step is to separate the drugs in basic buffer constituted of 70 mmol.L-1 Na2HPO4(pH 8.60) and 30% acetonitrile (condition B). The thiodiphenylamines and some other basic drugs could be well separated, which include thihexyphenidyl, imipramine, amitriptyline, diphenhydramine, chlorpromazine, doxepin, chlorprothixene, promethazine and flurazepam, while the rest of the CNS drugs did not interfere with the separation. The last step was to separate the drugs by micellar electrokinetic chromatography (MEKC) in such a buffer as 70 mmol.L-1 SDS plus 15 mmol.L-1 Na2HPO4 (pH 7.55) and 5% methanol (condition C). Barbiturates (barbital, phenobarbital, methylphenobarbital, amobarbital, thiopental, pentobarbital, secobarbital) and some hydrophobic drugs (glutethimide, alprazolam, clonazepam, carbamazepine, trifluoperazine, oxazepam) could be well separated. These drugs might be identified by both the relative migration time (rtm = tdrug/tEOF) and the ratios of peak heights (rh) monitored at different wavelength, since the ratios are characteristic of the spectrum of a drug. This method has been used in several real clinical samples of intoxication. For example, perphenazine and doxepin were detected in the gastric juice and phenobarbital in blood and gastric juice of an intoxicated patient.

A report of a suicide involving digoxin and doxepin.

In this report we give details on an overdose fatality involving both digoxin and doxepin. There have been numerous reported fatalities, both accidental and suicidal, involving digoxin and many more reports of fatalities involving doxepin. We believe that this is the first time a fatality from this drug combination has been reported in the literature.