RESUMEN
A simple, rapid, sensitive and specific LC-MS/MS method was developed and validated for the quantitative determination of doxylamine in human plasma, using isotope doxylamine-d5 as internal standard (IS). The detection was conducted on a QTRAP 5500 tandem mass spectrometer coupled with electrospray ionization (ESI) source in positive ion mode. Quantification was achieved by positive electrospray ionization containing multiple reaction monitoring (MRM) transitions of m/z 271.0â182.0 for doxylamine and m/z 276.2â187.3 for IS. The mobile phase A was methanol, and mobile phase B was 20 mM ammonium acetate (0.2 % formic acid) in water, using a gradient elution procedure at a flow rate of 0.6 mL/min. The method was validated with a sensitivity of 0.500 ng/mL and a linear concentration range of 0.500-200 ng/mL. The inter-batch precision (%CV) was less than 5.4 %, and the accuracy deviation (%RE) ranged from - 10.6 % to 3.7 %; the inter-batch precision (%CV) was less than 6.6 %, and the accuracy deviation (%RE) was ranged from - 2.7 % to 0.1 %. The selectivity, sensitivity, extraction recovery, matrix effect, carryover, dilution reliability, stability and other characteristics were within the acceptable range. This validated method was successfully applied to a bioequivalence study that orally administered 25 mg of doxylamine succinate tablets in 60 healthy Chinese volunteers.
Asunto(s)
Doxilamina/sangre , Doxilamina/farmacocinética , Antagonistas de los Receptores Histamínicos H1/sangre , Antagonistas de los Receptores Histamínicos H1/farmacocinética , Espectrometría de Masas en Tándem/métodos , Administración Oral , China , Cromatografía Liquida/métodos , Doxilamina/administración & dosificación , Voluntarios Sanos , Antagonistas de los Receptores Histamínicos H1/administración & dosificación , Humanos , Metanol , Reproducibilidad de los Resultados , Espectrometría de Masa por Ionización de Electrospray , Comprimidos , Equivalencia TerapéuticaRESUMEN
INTRODUCTION: Doxylamine tablets are approved as an over-the-counter sleep aid. We developed a doxylamine succinate intranasal metered-dose delivery system with the expectation of a more rapid onset of action with reduced side-effect potential compared with the oral tablet. METHODS: This phase I study randomized 24 adults with chronic intermittent sleep impairment to receive either single doses of intranasal doxylamine succinate 3.2, 6.3, or 12.7 mg or doxylamine succinate 25-mg oral tablet. Doxylamine pharmacokinetics were assessed using noncompartmental methods; pharmacodynamics were evaluated using the Karolinska Sleepiness Scale (KSS) and numerous psychomotor tests. Adverse events (AEs) were monitored. RESULTS: None of the intranasal dose levels produced a mean maximum plasma concentration (Cmax) above the 50 ng/mL target level or a time to maximum concentration shorter than that of the oral tablet. At the highest intranasal dose, Cmax and area under the doxylamine concentration-time curve were approximately 25% of the values achieved with the oral dose. Variation in most pharmacokinetic parameters was higher with intranasal compared with oral dosing. A relationship between plasma doxylamine concentration and KSS change from baseline was evident for the 25-mg tablet and, to a lesser extent, for the 12.7-mg intranasal dose. Changes from baseline in psychomotor parameters did not show a relationship to intranasal dose, and did not distinguish between intranasal versus oral dosing. The most common AEs with intranasal dosing were nasal congestion, nasal dryness, and frontal headache. CONCLUSION: The nasal spray did not increase doxylamine absorption or systemic bioavailability compared with the oral tablet.
Asunto(s)
Doxilamina/análogos & derivados , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Administración Intranasal , Administración Oral , Adolescente , Adulto , Disponibilidad Biológica , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Doxilamina/efectos adversos , Doxilamina/sangre , Doxilamina/farmacocinética , Doxilamina/uso terapéutico , Femenino , Antagonistas de los Receptores Histamínicos H1/efectos adversos , Antagonistas de los Receptores Histamínicos H1/sangre , Antagonistas de los Receptores Histamínicos H1/farmacocinética , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Humanos , Masculino , Inhaladores de Dosis Medida , Persona de Mediana Edad , Adulto JovenRESUMEN
A multidrug fatality involving sumatriptan is reported. Sumatriptan is a tryptamine derivative that acts at 5-HT(1B/1D) receptors and is used for the treatment of migraines. The decedent was a 21-year-old white female found dead in bed by her spouse. No signs of physical trauma were observed and a large number of prescription medications were discovered at the scene. Toxicological analysis of the central blood revealed sumatriptan at a concentration of 1.03 mg/L. Following therapeutic dosing guidelines, sumatriptan concentrations do not exceed 0.095 mg/L. Sumatriptan was isolated by solid-phase extraction and analyzed using liquid chromatography-tandem mass spectrometry in multiple reaction monitoring mode. A tissue distribution study was completed with the following concentrations measured: 0.61 mg/L in femoral blood, 0.56 mg/L in iliac blood, 5.01 mg/L in urine, 0.51 mg/kg in liver, 3.66 mg/kg in kidney, 0.09 mg/kg in heart, 0.32 mg/kg in spleen, 0.01 mg/kg in brain, 15.99 mg/kg in lung and 78.54 mg/45 mL in the stomach contents. Carisoprodol, meprobamate, fluoxetine, doxylamine, orphenadrine, dextromethorphan and hydroxyzine were also present in the blood at the following concentrations: 3.35, 2.36, 0.63, 0.19, 0.06, 0.55 and 0.16 mg/L. The medical examiner ruled the cause of death as acute mixed drug toxicity and the manner of death as accident.
Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/sangre , Sumatriptán/envenenamiento , Autopsia , Carisoprodol/sangre , Cromatografía Liquida , Dextrometorfano/sangre , Doxilamina/sangre , Estudios de Evaluación como Asunto , Resultado Fatal , Femenino , Fluoxetina/sangre , Toxicología Forense , Humanos , Hidroxizina/sangre , Hígado/efectos de los fármacos , Hígado/metabolismo , Meprobamato/sangre , Orfenadrina/sangre , Reproducibilidad de los Resultados , Manejo de Especímenes , Sumatriptán/farmacocinética , Espectrometría de Masas en Tándem , Distribución Tisular , Adulto JovenRESUMEN
Vitamin B6 has been known to possess antiemetic effects since 1942. This water soluble compound has several forms in the circulation including pyridoxine, pyridoxal, and pyridoxal phosphate. The active antiemetic form of vitamin B6 is unknown. This was a pre-specified substudy of a randomized, placebo-controlled trial comparing the antiemetic effect of the doxylamine-vitamin B6 combination (Diclectin®) (n = 131) to placebo (n = 126) in women with nausea and vomiting of pregnancy. Serum concentrations of pyridoxine, pyridoxal, and pyridoxal 5' phosphate (PLP) and doxylamine were measured on Days 4, 8, and 15. With Diclectin® exhibiting a significant antiemetic effect in pregnancy, serum concentrations of pyridoxine were unmeasurable in almost all patients and those of pyridoxal were undetectable in half of patients. In contrast, PLP was measurable at sustained, stable steady-state levels in all patients. Our data suggest that there is a correlation between PLP levels and PUQE score of morning sickness symptoms when pyridoxine and pyridoxal levels are undetectable, and hence they might be prodrugs of PLP, which may be the active antiemetic form of vitamin B6.
Asunto(s)
Antieméticos/uso terapéutico , Diciclomina/uso terapéutico , Doxilamina/uso terapéutico , Náuseas Matinales/tratamiento farmacológico , Profármacos/uso terapéutico , Piridoxina/uso terapéutico , Antieméticos/sangre , Antieméticos/farmacocinética , Preparaciones de Acción Retardada , Diciclomina/sangre , Diciclomina/farmacocinética , Método Doble Ciego , Doxilamina/sangre , Doxilamina/farmacocinética , Combinación de Medicamentos , Femenino , Humanos , Náuseas Matinales/metabolismo , Embarazo , Profármacos/farmacocinética , Piridoxal/sangre , Fosfato de Piridoxal/sangre , Piridoxina/sangre , Piridoxina/farmacocinéticaRESUMEN
Most bioequivalence (BE) studies are conducted in males with the assumption that variability in pharmacokinetics is similar between the sexes. The purpose of this single-center, reference replicate study was to determine the effect of sex on the pharmacokinetics and BE of doxylamine-pyridoxine 10 mg-10 mg delayed-release tablets. Healthy males (n = 12) and non-pregnant females (n = 12) were administered two tablets, and blood sampling was conducted from 1 hour pre-dose until 72 hours post-dose. After 21 days, dose administration and blood sampling were re-conducted. All analytes were measured using liquid chromatography-tandem mass-spectrometry. Pharmacokinetic parameters were calculated for each study period using standard, non-compartmental methods, and differences were assessed using ANOVA. BE testing was conducted using the relative 90% confidence interval for the AUC0-t for each analyte. Females had significantly larger AUC0-t for doxylamine, 1,550 ng h/mL (coefficient of variance [CV = 19%]) versus 1,272 ng h/mL (CV = 21%; P ≤ .05), and pyridoxine, 35 ng h/mL, (CV = 43%) versus 25 ng h/mL (CV = 31%; P ≤ .05) compared to males. A higher Cmax for doxylamine was observed in females, 107 ng/mL (CV = 16%), compared to males, 86 ng/mL (CV = 15%) (P ≤ .05). BE testing did not demonstrate bioequivalence between males and females. Pharmacokinetic differences observed between the sexes have implications for future BE studies using doxylamine-pyridoxine.
Asunto(s)
Antieméticos/farmacocinética , Diciclomina/farmacocinética , Doxilamina/farmacocinética , Piridoxina/farmacocinética , Adulto , Antieméticos/sangre , Preparaciones de Acción Retardada/farmacocinética , Diciclomina/sangre , Doxilamina/sangre , Combinación de Medicamentos , Femenino , Humanos , Masculino , Embarazo , Piridoxina/sangre , Caracteres Sexuales , Equivalencia TerapéuticaRESUMEN
To characterize doxylamine pharmacokinetics in children. This study was conducted in 41 subjects, ages 2-17 years. Doxylamine succinate doses based on age/weight ranged from 3.125 to 12.5 mg. A single oral dose was administered with 2 to 4 oz. of water or decaffeinated beverages â¼2 hours after a light breakfast. Plasma samples were obtained before and for 72 hours after dosing and analyzed for doxylamine using HPLC MS/MS. Pharmacokinetic parameters were estimated using non-compartmental methods and relationships with age were assessed using linear regression. Over the fourfold dose range, Cmax was similar while AUC increased only 60%, although not statistically significant (P-value = 0.0517). As expected due to increasing body size, CLo and Vz /F increased with age. Due to a similar increase with age for Clo and Vz /F, no age-related differences in t1/2,z were observed (â¼16 hours). Allometric scaling indicated no maturation related changes in CLo ; although Vz /F remained age-dependent, the predicted range decreased â¼70%. Overall, the single doses were well tolerated. Somnolence was the most common reported AE with no apparent differences in incidence noted with age. An age/weight dosing nomogram utilizing a fourfold range of doses achieves similar Cmax , whereas AUC increases only 60%.
Asunto(s)
Doxilamina/análogos & derivados , Antagonistas de los Receptores Histamínicos H1/administración & dosificación , Antagonistas de los Receptores Histamínicos H1/farmacocinética , Administración Oral , Adolescente , Área Bajo la Curva , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Doxilamina/administración & dosificación , Doxilamina/sangre , Doxilamina/farmacocinética , Femenino , Antagonistas de los Receptores Histamínicos H1/sangre , Humanos , MasculinoRESUMEN
BACKGROUND: Doxylamine succinate, an ethanolamine-based antihistamine, is used in the short-term management of insomnia because of its sedative effects. No data on the dose proportionality of the pharmacokinetics of doxylamine are available, although this drug has been marketed in European countries for more than 50 years. OBJECTIVE: The objective of this study was to evaluate and compare the dose proportionality between two marketed strengths (12.5 mg and 25 mg) of doxylamine hydrogen succinate after a single oral dose administration under fasting conditions in healthy human subjects. STUDY DESIGN: This was a single-center, randomized, single dose, laboratory-blinded, two-period, two-sequence, crossover study. SETTING: The study was conducted in a phase I clinical unit. SUBJECTS AND METHODS: A single oral dose of doxylamine hydrogen succinate of 12.5 mg (equivalent to 8.7 mg of doxylamine base) or 25 mg (equivalent to 17.4 mg of doxylamine base) was administered to healthy volunteers under fasting conditions in each study period. The drug administrations were separated by a wash-out period of 7 calendar days. Blood samples were collected for up to 60 h post-dose, and plasma doxylamine levels were determined by an ultra high-performance liquid chromatography method with tandem mass spectrometry detection. Pharmacokinetic parameters were calculated using non-compartmental analysis. Dose proportionality was assessed based on the parameter area under the concentration-time curve (AUCt normalized). Safety was evaluated through assessment of adverse events, standard laboratory evaluations, vital signs and 12-lead electrocardiogram (ECG). RESULTS: In total, 12 healthy volunteers (3 male; 9 female) were included in the study. Mean maximum observed plasma concentration (Cmax) and area under the concentration-time curve from time zero to time t (AUCt ) of doxylamine hydrogen succinate 12.5 mg and 25 mg tablets increased linearly and dose-dependently [12.5 mg: mean Cmax 61.94 ng/mL, coefficient of variation (CV) 23.2%; mean AUCt 817.33 ng·h/mL, CV 27.4%; and 25 mg: mean Cmax 124.91 ng/mL, CV 18.7%; mean AUCt 1630.85 ng·h/mL, CV 22.8%]. Mean AUCt normalized was 815.43 ng·h/mL, CV 22.8% for 25 mg. The dose-normalized geometric mean ratio (%, 12.5 mg/25 mg) of AUCt was 98.92 (90% CI: 92.46, 105.83). The most common adverse event was somnolence. CONCLUSIONS: Exposure to doxylamine was proportional over the therapeutic dose range of 12.5-25 mg in healthy volunteers. Based on the results, a predictable and linear increase in systemic exposure can be expected. Doxylamine hydrogen succinate was safe and well tolerated.
Asunto(s)
Doxilamina/análogos & derivados , Antagonistas de los Receptores Histamínicos H1/farmacocinética , Adulto , Disponibilidad Biológica , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Doxilamina/administración & dosificación , Doxilamina/efectos adversos , Doxilamina/sangre , Doxilamina/farmacocinética , Ayuno/sangre , Femenino , Voluntarios Sanos , Antagonistas de los Receptores Histamínicos H1/efectos adversos , Antagonistas de los Receptores Histamínicos H1/sangre , Humanos , Masculino , Cumplimiento de la Medicación , Persona de Mediana Edad , ComprimidosRESUMEN
Although Diclectin (doxylamine/pyridoxine delayed-released combination) is widely used in Canada, its pharmacokinetics (PK) during pregnancy has never been described. The objective of this study was to compare the PK of doxylamine/pyridoxine delayed-released combination in pregnant versus nonpregnant women. The apparent clearances (CL) of doxylamine and pyridoxal 5'-phosphate (PLP; the active metabolite of vitamin B(6) ) during the first-trimester pregnancy in women who participated in a Diclectin randomized trial were compared with those of healthy, adult, nonpregnant women who participated in a voluntary PK trial. Eighteen nonpregnant women were compared with 50 pregnant women who were treated with Diclectin. There was no difference in the apparent CL of doxylamine in women in their first trimester of pregnancy when compared with nonpregnant women on day 4 (median = 196.7 vs 249.5 mL/h/kg, respectively, P = .065), day 8 (median = 248.4 vs 249.5 mL/h/kg, respectively, P = .82), and day 15 (median = 200.9 vs 249.5 mL/h/kg, respectively, P = .55). No difference was found in the apparent CL of PLP on day 15 (median = 342.3 vs 314.7 mL/h/kg, respectively, P = .92). There was no pregnancy-induced effect in the apparent CL of either doxylamine or PLP in women during the first trimester of pregnancy despite the existence of morning sickness.
Asunto(s)
Antieméticos/farmacocinética , Doxilamina/farmacocinética , Embarazo/metabolismo , Piridoxina/farmacocinética , Adolescente , Adulto , Antieméticos/administración & dosificación , Antieméticos/sangre , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/farmacocinética , Diciclomina , Método Doble Ciego , Doxilamina/administración & dosificación , Doxilamina/sangre , Combinación de Medicamentos , Femenino , Humanos , Persona de Mediana Edad , Primer Trimestre del Embarazo/metabolismo , Piridoxina/administración & dosificación , Piridoxina/sangre , Adulto JovenRESUMEN
In the present study, a fast, sensitive and robust method to quantify dextromethorphan, dextrorphan and doxylamine in human plasma using deuterated internal standards (IS) is described. The analytes and the IS were extracted from plasma by a liquid-liquid extraction (LLE) using diethyl-ether/hexane (80/20, v/v). Extracted samples were analyzed by high performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). Chromatographic separation was performed by pumping the mobile phase (acetonitrile/water/formic acid (90/9/1, v/v/v) during 4.0min at a flow-rate of 1.5 mL min⻹ into a Phenomenex Gemini® C18, 5 µm analytical column (150 × 4.6 mm i.d.). The calibration curve was linear over the range from 0.2 to 200 ng mL⻹ for dextromethorphan and doxylamine and 0.05 to 10 ng mL⻹ for dextrorphan. The intra-batch precision and accuracy (%CV) of the method ranged from 2.5 to 9.5%, and 88.9 to 105.1%, respectively. Method inter-batch precision (%CV) and accuracy ranged from 6.7 to 10.3%, and 92.2 to 107.1%, respectively. The run-time was for 4 min. The analytical procedure herein described was used to assess the pharmacokinetics of dextromethorphan, dextrorphan and doxylamine in healthy volunteers after a single oral dose of a formulation containing 30 mg of dextromethorphan hydrobromide and 12.5mg of doxylamine succinate. The method has high sensitivity, specificity and allows high throughput analysis required for a pharmacokinetic study.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Dextrometorfano/sangre , Dextrorfano/sangre , Doxilamina/sangre , Espectrometría de Masa por Ionización de Electrospray/métodos , Adolescente , Adulto , Dextrometorfano/farmacocinética , Dextrorfano/farmacocinética , Doxilamina/farmacocinética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sensibilidad y Especificidad , Espectrometría de Masas en Tándem/métodos , Adulto JovenRESUMEN
Diphenhydramine (DPH) is a common over the counter antihistamine that produces drowsiness and has the potential to cause driving under the influence of drugs-related accidents. To date there are no commercially available immunoassay screening kits for its detection in biological fluids such as urine and/or blood. We describe a newly developed enzyme-linked immunosorbent assay (ELISA) screen and report on its utility in the analysis of authentic specimens taken from volunteers. The assay is specific for detection of DPH and does not detect closely related antihistamines like brompheniramine, chlorpheniramine, and doxylamine. There is a varying amount of cross-reactivity seen with certain tricyclic compounds, due to similarities in side chain structure with DPH. Intra- and interday precision of the assay were determined to be less than 10%. The assay is highly sensitive and has a working range from 1 to 500 ng/mL for urine and 1 to 250 ng/mL for blood. The assay was further validated with authentic urine and blood specimens obtained from volunteers and coroner's laboratories.
Asunto(s)
Difenhidramina/sangre , Difenhidramina/orina , Ensayo de Inmunoadsorción Enzimática/métodos , Bromofeniramina/sangre , Clorfeniramina/sangre , Doxilamina/sangre , Antagonistas de los Receptores Histamínicos , Humanos , Reproducibilidad de los Resultados , Manejo de EspecímenesRESUMEN
Deaths caused by a methadone intoxication or overdose are becoming more frequent. We report a case involving a patient who had extremely high methadone blood concentrations but whose cause of death may have been unrelated to the drug. A 51-year-old woman was found deceased in bed by her daughter. At the scene were numerous bottles of methadone, with the chronic dosage of 240 mg 3 times a day. There was no history of prior suicide attempts, there were no reports of suicidal ideation having been voiced and there was no suicide note. At autopsy, there were no pills found in the stomach. Microscopic tissue examination revealed lobar pneumonia of the right lower lobe. Postmortem lung cultures grew out Streptococcus pneumoniae. Femoral blood contained methadone, 5.7 mg/L; EDDP, 2.1 mg/L; oxycodone, 0.017 mg/L; doxylamine, 0.022 mg/L; and ethanol, 13.0 mg/dL. The postmortem methadone concentration was consistent with her known dose, plausible pharmacokinetics and conditions of discovery. Various causes of death, such as a methadone-related arrhythmia from QTc prolongation or the contribution of methadone to the development of the pneumonia, cannot be ruled out and may well have caused or contributed to death, but the pneumonia was felt to be a competent cause of death. Ultimately, the most likely cause(s) of death, is a decision left to the individual medical examiner. This case is illustrative of the growing number of similar cases facing forensic pathologists. The cause of death cannot be solely based on drug concentrations and it may not be possible to come to a conclusion as to "the" cause of death and the forensic pathologist must be content with "a" cause of death.
Asunto(s)
Metadona/sangre , Narcóticos/sangre , Neumonía Neumocócica/patología , Doxilamina/sangre , Etanol/sangre , Femenino , Patologia Forense , Toxicología Forense , Cromatografía de Gases y Espectrometría de Masas , Humanos , Pulmón/patología , Persona de Mediana Edad , Oxicodona/sangreRESUMEN
BACKGROUND: Diclectin, composed of 10 mg doxylamine succinate (DOX) and 10 mg pyridoxine hydrochloride, is the drug combination of choice for the management of nausea and vomiting during pregnancy in Canada. However, there is large variability in its onset and duration of action among women. To understand and improve its effectiveness, the variability in the pharmacokinetics of the ingredients in this doxylamine succinate/pyridoxine hydrochloride combination must be studied. OBJECTIVES: To determine the pharmacokinetics of DOX and pyridoxine after oral administration of two tablets of this drug combination in the form of Diclectin and to calculate their respective relative bioavailability by comparison with intravenous administration in another population. METHODS: Eighteen nonpregnant, nonlactating, healthy females between 18 and 45 years of age were administered two tablets of Diclectin with 240 mL of water under empty stomach conditions. Blood samples were analyzed for DOX and pyridoxine along with its four active metabolites: pyridoxal, pyridoxal-5'-phosphate (PLP), pyridoxamine, and pyridoxamine-5'-phosphate using tandem mass spectrometry. For the purpose of this study, pharmacokinetic values for DOX and PLP were adjusted for body weight. RESULTS: The mean DOX-AUC0â∞ was calculated to be 3137.22 ± 633.57 ng·hr/mL (range, 2056.59-4376.06 ng·hr/mL). The mean PLP-AUC0â∞ was calculated to be 5513.10 ± 2362.35 ng·hr/mL (range, 1572.56-10,153.77 ng·hr/mL). Based on literature values of the PLP-AUC0â∞ after intravenous administration and data from the current study, the relative bioavailability of pyridoxine in Diclectin was calculated at 100%. CONCLUSION: There was a 2.1-fold variability in the DOX-AUC0â∞ and 6.5-fold variability in the PLP-AUC0â∞ after oral administration of 20 mg Diclectin. Using literature values and data from the current study, we estimated the oral bioavailability of pyridoxine to be 100%. Therefore, interindividual differences in metabolism, and not in bioavailability, may be important sources of variability that need to be addressed in dosing guidelines.
Asunto(s)
Antieméticos/farmacocinética , Doxilamina/farmacocinética , Fosfato de Piridoxal/sangre , Piridoxina/farmacocinética , Adulto , Antieméticos/sangre , Antieméticos/uso terapéutico , Disponibilidad Biológica , Canadá , Preparaciones de Acción Retardada , Diciclomina , Doxilamina/sangre , Doxilamina/economía , Doxilamina/uso terapéutico , Combinación de Medicamentos , Femenino , Humanos , Náusea/tratamiento farmacológico , Embarazo , Complicaciones del Embarazo/tratamiento farmacológico , Fosfato de Piridoxal/farmacocinética , Piridoxina/sangre , Piridoxina/economía , Piridoxina/uso terapéutico , Comprimidos , Vómitos/tratamiento farmacológico , Adulto JovenRESUMEN
Deaths involving sensory deprivation tanks are very rare. We describe a unique case in which a previously healthy 50-year-old woman apparently died while floating in a sensory deprivation tank at her residence. Autopsy failed to reveal definitive anatomical abnormalities pointing to the cause of death. A thorough scene investigation, full medicolegal autopsy to include toxicological analyses, and a complete investigation into the equipment at the scene, were conducted. Blood toxicologic studies were significant for the presence of ethanol (0.27%) and a mixture of over-the-counter sedating medications and prescription drugs. The cause of death was ruled as acute mixed drug and ethanol toxicity combined with probable environmental hyperthermia; manner was accident. This case report will help the forensic community understand the intended use of flotation tanks, as well as possible risks associated with improper use.
Asunto(s)
Baños , Espacios Confinados , Calor/efectos adversos , Privación Sensorial , Depresores del Sistema Nervioso Central/sangre , Creatinina/análisis , Difenhidramina/sangre , Doxilamina/sangre , Etanol/sangre , Femenino , Patologia Forense , Toxicología Forense , Antagonistas de los Receptores Histamínicos H1/sangre , Humanos , Pulmón/patología , Persona de Mediana Edad , Miocardio/patología , Tamaño de los Órganos , Edema Pulmonar/patología , Púrpura/patología , Inhibidores Selectivos de la Recaptación de Serotonina/sangre , Sertralina/sangre , Cuerpo Vítreo/químicaRESUMEN
Suicides with stud guns are uncommon, but are well documented in the literature. On rare occasions, stud guns are also used as a homicide weapon. This case report describes an extended suicide in which a husband killed his wife and their two dogs, which lived on the property. The husband then committed suicide with a shot from the stud gun into his skull. He was a 70-year-old pensioner, a retired butcher, who was found by his son. He was lying in a supine position on a carpet in the living room, with the stud gun stuck in his skull. During autopsy, high concentrations of an antihistamine were found in the blood of each corpse; this drug is used as a soporific. In contrast to the literature, which mainly describes powder deposits due to the use of conventional stud guns, in this case a stud gun was used in which the expanding gases and powder escaped together with the central bolt at the front of the device; powder drains were not involved. Detailed findings of the autopsy are given with reference to this type of stud gun.
Asunto(s)
Mataderos/instrumentación , Homicidio , Suicidio , Anciano , Animales , Encéfalo/patología , Perros , Doxilamina/sangre , Femenino , Patologia Forense , Traumatismos Penetrantes de la Cabeza/etiología , Traumatismos Penetrantes de la Cabeza/patología , Antagonistas de los Receptores Histamínicos/sangre , Humanos , MasculinoRESUMEN
The conditions of doxilamine isolation from biological fluids are studied. The method of its extraction with a mixture of organic solvents in pH 9 is proposed. Identification of doxilamine with techniques of thin layer chromatography, UV-, IR-spectroscopy, chromato-mass-spectrometry, densitometry, gas-liquid chromatography is described. UV-spectrometry, gas chromatography and densitometry can be used for quantitation of doxilamine.
Asunto(s)
Doxilamina/análisis , Toxicología Forense/métodos , Hipnóticos y Sedantes/análisis , Detección de Abuso de Sustancias/métodos , Animales , Doxilamina/sangre , Doxilamina/orina , Humanos , Hipnóticos y Sedantes/sangre , Hipnóticos y Sedantes/orina , Ratones , Preparaciones Farmacéuticas/química , Preparaciones Farmacéuticas/normas , Ratas , Solventes/química , ComprimidosRESUMEN
A method was suggested for identifying reladorm and donormil in pharmaceutical drugs and biological objects. The above substances are isolated by 96% ethanol or by mixture of chloroform and isopropanol. 7 color reactions, 3 microcrystalloscopic reactions and chromatography in thin sorbent layer are suggested for identification.
Asunto(s)
Barbitúricos/análisis , Diazepam/análisis , Doxilamina/análisis , Medicina Legal/métodos , Hipnóticos y Sedantes/análisis , Barbitúricos/sangre , Barbitúricos/orina , Cadáver , Cromatografía en Capa Delgada , Diazepam/sangre , Diazepam/orina , Doxilamina/sangre , Doxilamina/orina , Combinación de Medicamentos , Humanos , Hipnóticos y Sedantes/sangre , Hipnóticos y Sedantes/orina , Indicadores y Reactivos , Hígado/química , ComprimidosRESUMEN
The intranasal route of administration provides a potential useful way of administering a range of systemic drugs. In order to assess the feasibility of this approach for the treatment of nausea and vomiting, doxylamine succinate was studied in rats for the pharmacokinetics (AUC, C(max), t(max)) following intranasal, oral and intravenous administrations. Subjects (six male Sprague-Dawley rats per time interval for each route of administration) received 2-mg doses of doxylamine succinate orally and I-mg doses intranasally and intravenously, respectively. The various formulations were formulated in isotonic saline (0.9% w/v) at 25 +/- 1 degrees C. Doxylamine succinate concentrations in plasma were determined with a high-performance liquid chromatographic assay and a liquid-liquid extraction procedure. Intranasal and oral bioavailabilities were determined from AUC values relative to those after intravenous dosing. Intranasal bioavailability was greater than that of oral doxylamine succinate (70.8 vs 24.7%). The intranasal and oral routes of administration differed significantly from the intravenous route of administration. Peak plasma concentration (C(max)) was 887.6 ng/ml (S.D. 74.4), 281.4 ng/ml (S.D. 24.6) and 1296.4 ng/ml (S.D. 388.9) for the intranasal, oral and intravenous routes, respectively. The time to achieve C(max) for the intranasal route (t(max)=0.5 h) was faster than for the oral route (t(max)=1.5 h), but no statistically significant differences between the C(max) values were found using 95% confidence intervals. The results of this study show that doxylamine succinate is rapidly and effectively absorbed from the nasal mucosa.
Asunto(s)
Doxilamina/análogos & derivados , Doxilamina/administración & dosificación , Doxilamina/farmacocinética , Antagonistas de los Receptores Histamínicos H1/administración & dosificación , Antagonistas de los Receptores Histamínicos H1/farmacocinética , Administración Intranasal , Administración Oral , Animales , Área Bajo la Curva , Disponibilidad Biológica , Cromatografía Líquida de Alta Presión , Doxilamina/sangre , Antagonistas de los Receptores Histamínicos H1/sangre , Inyecciones Intravenosas , Masculino , Mucosa Nasal/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Clinicians should be aware of the complications of rhabdomyolysis in patients who ingest doxylamine succinate and other over-the-counter antihistamines. The easy availability of these substances increases the potential not only for intentional overdose by adults but also for inadvertent ingestion by children. Prompt intervention and careful assessment of renal function, urinary output, and serum creatine kinase levels may represent the difference between an uncomplicated course and acute renal failure.
Asunto(s)
Doxilamina/análogos & derivados , Antagonistas de los Receptores Histamínicos H1/envenenamiento , Rabdomiólisis/diagnóstico , Adulto , Bicarbonatos/uso terapéutico , Creatina Quinasa/sangre , Doxilamina/sangre , Doxilamina/envenenamiento , Sobredosis de Droga/sangre , Sobredosis de Droga/complicaciones , Epilepsia Tónico-Clónica/etiología , Antagonistas de los Receptores Histamínicos H1/sangre , Humanos , Intubación Intratraqueal , Masculino , Rabdomiólisis/etiología , Rabdomiólisis/terapia , Esquizofrenia Paranoide/complicaciones , Sodio/uso terapéutico , Bicarbonato de Sodio , Intento de SuicidioRESUMEN
To answer the question, "Is this death due to a drug overdose?" requires at least that the drug be unequivocally identified and a blood concentration reliably determined. The approach taken in this case as standard addition technique and use of three different chromatographic techniques-high performance liquid chromatography (HPLC), high performance thin-layer chromatography (HP-TLC) and gas chromatography/mass spectrometry (GC/MS). Each of the chromatographies was carried out on the same extract by splitting the residue three ways. HPLC provided a quantitative result which was 1.2 mg/L in blood and HP-TLC and GC/MS confirmed this result with additional quantitative data, information about two metabolites (nordoxylamine and dinordoxylamine) and conclusive identification. Blood nordoxylamine was 0.52 mg/L and doxylamine plus metabolites in urine was 25 mg/L.