The role of QT-prolonging medications in a forensic autopsy study from Western Denmark.

Medication-induced prolongation of the QT-interval (miQTP) can lead to cardiac arrhythmia. Our aim was to investigate the prevalence of forensic autopsy cases where fatal cardiac arrhythmia related to treatment with QT-prolonging medications (QT-PMs) could be suspected. We performed a cross-sectional study of 741 forensic autopsies undertaken at our institution in non-drug addicts aged 15 years or above from 2017 to 2019. We defined a high risk of miQTP by one detected QT-PM in a concentration above therapeutic level, or two or more detected QT-PMs in post mortem blood. We reviewed the autopsy reports from cases with a high miQTP-risk to identify cases with no other apparent cause of death. We discarded suicides and cases with lethal levels of QT-PMs. We identified 167 cases (22.5%) with high risk of miQTP, and discarded 36 suicides (4.9%) and 7 (0.9%) with lethal levels of QT-PMs. Apart from a high risk of miQTP, no other apparent explanation of the cause of death was present in seven (0.9%). In 18 cases (2.4%) with high miQTP-risk, the cause of death was primarily attributed to cardiac changes other than acute cardiovascular events. In conclusion, 22.5% had a high risk of miQTP, and fatal cardiac arrhythmia related to treatment with QT-PMs could be suspected in 0.9%. However, a genetic pro-arrhythmic background could not be excluded in our study. Furthermore, it is possible that QT-PMs could have played a role in some of the 2.4% of cases where the cause of death was mainly attributed to cardiac changes and the risk of miQTP was high.

Emedastine During Pregnancy and Lactation: Emedastine Levels in Maternal Serum, Cord Blood, Breast Milk, and Neonatal Serum.

Background: Emedastine difumarate is a second-generation antihistamine that is more effective for nasal congestion than first-generation antihistamines. The oral form of emedastine is used for the treatment of allergic rhinitis (AR). However, data characterizing emedastine transfer across the placenta and excretion into breast milk are limited. In this case report, we assessed emedastine concentrations in maternal and neonatal blood, cord blood, and breast milk. Materials and Methods: After the patient provided informed consent, emedastine concentrations in maternal serum, breast milk, cord blood, and neonatal serum were measured while the mother was taking oral emedastine 2 mg once daily. Case Report: A 39-year-old woman with AR received emedastine during pregnancy and lactation. Her female infant was born at 37 weeks of gestation with a birth weight of 2,820 g. Emedastine concentrations in maternal serum at 11.5 and 19.0 hours after maternal dosing were 0.39 and 0.22 ng/mL, respectively. The emedastine concentration in cord blood (19.6 hours after maternal dosing) was 0.18 ng/mL. At 24 hours after delivery (44 hours after maternal dosing), emedastine was under the lower limit of quantification (<0.05 ng/mL) in the infant's serum. Emedastine concentrations in breast milk ranged from 0.06 to 0.44 ng/mL. Calculated infant doses through breast milk were much lower than the clinical dose of emedastine. The infant had normal developmental progress and no detectable drug-related adverse effects. Conclusions: Rates of emedastine transfer into placenta and breast milk were low. Further study is required to assess the safety of emedastine in fetuses and breastfed infants.

Ultrasonication-aided synthesis of nanoplates-like iron molybdate: Fabricated over glassy carbon electrode as an modified electrode for the selective determination of first generation antihistamine drug promethazine hydrochloride.

The innovation of novel and proficient nanostructured materials for the precise level determination of pharmaceuticals in biological fluids is quite crucial to the researchers. With this in mind, we synthesized iron molybdate nanoplates (Fe2(MoO4)3; FeMo NPs) via simple ultrasonic-assisted technique (70 kHz with a power of 100 W). The FeMo NPs were used as the efficient electrocatalyst for electrochemical oxidation of first-generation antihistamine drug- Promethazine hydrochloride (PMH). The as-synthesized FeMo NPs were characterized and confirmed by various characterization techniques such as XRD, Raman, FT-IR, FE-SEM, EDX and Elemental mapping analysis and electron impedance spectroscopy (EIS). In addition, the electrochemical characteristic features of FeMo NPs were scrutinized by electrochemical techniques like cyclic voltammetry (CV) and differential pulse voltammetry technique (DPV). Interestingly, the developed FeMo NPs modified glassy carbon electrode (FeMo NPs/GCE) discloses higher peak current with lesser anodic potential on comparing to bare GCE including wider linear range (0.01-68.65 µM), lower detection limit (0.01 µM) and greater sensitivity (0.97 µAµM-1cm-2). Moreover, the as-synthesized FeMo NPs applied for selectivity, reproducibility, repeatability and storage ability to investigate the practical viability. In the presence of interfering species like cationic, anionic and biological samples, the oxidation peak current response doesn't cause any variation results disclose good selectivity towards the detection of PMH. Additionally, the practical feasibility of the FeMo NPs/GCE was tested by real samples like, commercial tablet (Phenergan 25 mg Tablets) and lake water samples which give satisfactory recovery results. All the above consequences made clear that the proposed sensor FeMo NPs/GCE exhibits excellent electrochemical behavior for electrochemical determination towards oxidation of antihistamine drug PMH.

Cetirizine per os: exposure and antihistamine effect in the dog.

BACKGROUND: Cetirizine is an antihistamine used in dogs, but plasma concentrations in relation to effect after oral administration are not well studied. This study investigated cetirizine exposure and the plasma cetirizine concentration-antihistamine response relation in the dog following oral administration of cetirizine. RESULTS: Eight Beagle dogs were included in a cross-over study consisting of two treatments. In treatment one, cetirizine 2-4 mg/kg was administered per os once daily for 3 days. The other treatment served as a control. Wheal diameter induced by intra-dermal histamine injections served as response-biomarker. Cetirizine plasma concentration was quantified by UHPLC-MS/MS. Median (range) cetirizine plasma terminal half-life was 10 h (7.9-16.5). Cetirizine significantly inhibited wheal formation compared with the premedication baseline. Maximum inhibition of wheal formation after treatment with cetirizine per os was 100% compared with premedication wheal diameter. The median (range) IC50-value for reduction in wheal area was 0.33 µg/mL (0.07-0.45). The median (range) value for the sigmoidicity factor was 1.8 (0.8-3.5). A behavioral study was also conducted and revealed no adverse effects, such as sedation. CONCLUSION: The results indicate that a once-daily dosing regimen of 2-4 mg/kg cetirizine per os clearly provides a sufficient antihistamine effect. Based on this experimental protocol, cetirizine may be an option to treat histamine-mediated inflammation in the dog based on this experimental protocol but additional clinical studies are required.

Liquid chromatography-tandem mass spectrometry method for the quantification of a potent H3 receptor antagonist conessine in serum and its application to pharmacokinetic studies.

Conessine, a steroidal alkaloid obtained from the bark and seeds of the plant species of Apocynaceae family, elicits a histamine antagonistic action, selectively for the H3 histaminergic receptors. This alkaloid is used mainly for the treatment of dysentery and helminthic disorders. For the quantification of conessine in serum, a liquid chromatography-tandem mass spectrometry method was developed. Chromatographic separation was achieved on a Zorbax SB-CN column (100 × 4.6 mm, 3.5 µm), and a mobile phase consisting of 90% methanol in aqueous ammonium acetate buffer (pH 3.5) with 0.1% (v/v) formic acid at an isocratic flow rate of 0.6 ml/min at 40℃ provides efficiency in separation. A volume of 40 µl was injected each time and the run time for each sample was 5 min. Phenacetin (internal standard) was added to 50 µl of serum sample prior to liquid-liquid extraction using 3% isopropanol in n-hexane. The detection was performed on a 5500 QTRAP mass spectrometer by multiple reaction monitoring mode via electrospray ionization source. The multiple reaction monitoring of conessine and IS was m/ z 357.4 to m/ z 312.1 and m/ z 180.1 to m/ z 138.1, respectively. The method that showed selectivity and linearity in the range of 1-200 ng/ml was validated in terms of sensitivity, accuracy, precision and stability. The detection and quantitation limits were recognized at 0.1 and 1 ng/ml, respectively. The intra- and inter-day precision and accuracy fulfils the acceptance criteria. Applying the method to the pharmacokinetic studies in rats, conessine showed a peak serum concentration at 2 h post oral dose with a good bioavailability of 71.28 ± 4.65%.

Pilots using selective serotonin reuptake inhibitors compared to other fatally injured pilots.

Selective Serotonin Reuptake Inhibitors (SSRI) were a disqualifying medication for U.S. civil pilots before April 5, 2010. After this date, a Federal Aviation Administration policy was created that allowed airmen, on select SSRIs, a pathway to hold a valid medical certificate. The purpose of this study was to provide a detailed look at SSRIs in the U.S. pilot population since the inception of this new policy. We examined the toxicology results from fatally injured airmen in addition to outcomes concerning pilots who are participating in the program. This study examined data from the Civil Aerospace Medical Institute's Bioaeronautical Sciences Research Laboratory in conjunction with the Medical Analysis Tracking Registry and the Document Imaging and Workflow System. A count-based regression model quantified the relationships between positive SSRI findings with additional factors of interest. These factors included pilot rating, ethanol, and first generation antihistamines. There were 1484 fatally injured airmen over the six year study period, of which 44-tested positive for an SSRI. First-generation antihistamines were statistically associated with positive findings of SSRIs.

Bioanalysis of antihistamines for clinical or forensic purposes.

Antihistamines are a class of drugs that inhibit the action of histamine and are used to alleviate symptoms associated with allergic reactions, but some of them can cause side effects, the most unpleasant and dangerous of which are the sedative effects that may hinder important psychological functions and impair skilled performance. These side effects could decrease safety in certain common and critical tasks, such as driving or operating machinery, leading to accidents. Antihistamines can also cause intoxications, sometimes lethal, especially when co-administered with alcohol or other sedative drugs. Thus, the development of analytical methods for their determination in biological fluids is considered to be useful for the investigation of clinical and forensic cases. These methodologies could also be used for pharmacokinetic studies. Several liquid and a few gas chromatographic methods have been developed for the determination of antihistamines in biological matrices after proper pretreatment procedures. This article reviews the published analytical methodologies that were gathered through the search in PubMed database and the recent developments on isolation or determination of antihistamines in biological materials. Current trends and future perspectives on bioanalysis of antihistamines are also discussed. Copyright © 2016 John Wiley & Sons, Ltd.

Elimination of cetirizine following administration of multiple doses to exercised thoroughbred horses.

Cetirizine is an antihistamine used in performance horses for the treatment of hypersensitivity reactions and as such a withdrawal time is necessary prior to competition. The objective of the current study was to describe the disposition and elimination of cetirizine following oral administration in order to provide additional serum concentration data upon which appropriate regulatory recommendations can be established. Nine exercised thoroughbred horses were administered 0.4 mg/kg of cetirizine orally BID for a total of five doses. Blood samples were collected immediately prior to drug administration and at various times postadministration. Serum cetirizine concentrations were determined and selected pharmacokinetic parameters determined. The serum elimination half-life was 5.83 ± 0.841 h. Average serum cetirizine concentrations were still above the LOQ of the assay (0.05 ng/mL) at 48 h (final sample collected) postadministration of the final dose.

Unexpectedly high affinity of a novel histamine H(3) receptor antagonist, GSK239512, in vivo in human brain, determined using PET.

BACKGROUND AND PURPOSE: This study aimed to investigate the relationship between the plasma concentration (PK) of the novel histamine H3 receptor antagonist, GSK239512, and the brain occupancy of H(3) receptors (RO) in healthy human volunteers. EXPERIMENTAL APPROACH: PET scans were obtained after i.v. administration of the H(3) -specific radioligand [(11) C]GSK189254. Each subject was scanned before and after single oral doses of GSK239512, at 4 and 24 h after dose. PET data were analysed by compartmental analysis, and regional RO estimates were obtained by graphical analysis of changes in the total volumes of distribution of the radioligand, followed by a correction for occupancy by the high affinity radioligand. The PK/RO relationship was analysed by a population-modelling approach, using the average PK of GSK239512 during each scan. KEY RESULTS: Following administration of GSK239512, there was a reduction in the brain uptake of [(11) C]GSK189254 in all regions, including cerebellum. RO at 4 h was higher than at 24 h, and the PK/RO model estimated a PK associated with 50% of RO of 0.0068 ng·mL(-1) . This corresponds to a free concentration of 4.50 × 10(-12 ) M (pK = 11.3). CONCLUSIONS AND IMPLICATIONS: The affinity of GSK239512 for brain H3 receptors in humans in vivo is much higher than that expected from studies in vitro, and higher than that observed in PET studies in pigs. The study illustrates the utility of carrying out PET studies in humans early in drug development, providing accurate quantification of GSK239512 RO in vivo as a function of time and dose.

Integration of preclinical and clinical knowledge to predict intravenous PK in human: bilastine case study.

Modern pharmacometrics can integrate and leverage all prior proprietary and public knowledge. Such methods can be used to scale across species or comparators, perform clinical trial simulation across alternative designs, confirm hypothesis and potentially reduce development burden, time and costs. Crucial yet typically lacking in integration is the pre-clinical stage. Prediction of PK in man, using in vitro and in vivo studies in different animal species, is increasingly well theorized but could still find wider application in drug development. The aim of the present work was to explore methods for bridging pharmacokinetic knowledge from animal species (i.v. and p.o.) and man (p.o.) into i.v. in man using the antihistamine drug bilastine as example. A model, predictive of i.v. PK in man, was developed on data from two pre-clinical species (rat and dog) and p.o. in man bilastine trials performed earlier. In the knowledge application stage, two different approaches were used to predict human plasma concentration after i.v. of bilastine: allometry (several scaling methods) and a semi-physiological method. Both approaches led to successful predictions of key i.v. PK parameters of bilastine in man. The predictive i.v. PK model was validated using later data from a clinical study of i.v. bilastine. Introduction of such knowledge in development permits proper leveraging of all emergent knowledge as well as quantification-based exploration of PK scenario, e.g. in special populations (pediatrics, renal insufficiency, comedication). In addition, the methods permit reduction or elimination and certainly optimization of learning trials, particularly those concerning alternative off-label administration routes.

LC-MS/MS method for the determination of pitolisant: application to rat pharmacokinetic and brain penetration studies.

A simple and sensitive LC-MS/MS method was developed and validated for the quantitation of pitolisant, an H3 receptor antagonist/inverse agonist. Acetonitrile protein precipitation technique was used to prepare rat blood and brain tissue homogenate samples by using aripiprazole as internal standard (IS). Chromatographic separation was performed by using Xbridge column (2.1 × 50 mm, 3.5 µm) with a gradient elution program. The mobile phase consists of ammonium formate (10 mm) with 0.2% formic acid and acetonitrile. Multiple reaction monitoring mode was used in positive polarity with a transition of m/z 296.3 → 98.2 for the pitolisant and m/z 448.2 → 285.3 for the IS. The calibration curves were linear in the range of 0.1-100 ng/mL in both the blood and brain homogenate samples. This method was applied to quantify samples obtained from the pharmacokinetic and brain penetration studies in male wistar rats. Mean maximum concentration, area under the curve from zero to infinity and half-life of the pitolisant were found to be 3.4 ± 1.7 ng/mL, 5 ± 4 ng h/mL and 1.9 ± 0.3 h, respectively, after a 3 mg/kg oral dose. The mean calculated concentrations in the brain were found to be 38, 60 and 52 ng/g at 0.5, 1 and 2 h, respectively.

Should postmortem subclavian blood be considered a peripheral or central sample?

The phenomenon of postmortem redistribution has long been described, but the processes driving it have not, as yet, been fully elucidated. Peripheral blood samples are currently used, when available, in an effort to minimize the effects of postmortem redistribution on drug concentrations, but what sources of blood are peripheral sources? A study was undertaken to determine if postmortem subclavian (SC) blood should be considered a peripheral or central blood sample. Twenty-eight cases were identified in which drugs were quantified in at least 2 of the following blood sources: femoral (F), SC, and heart (H); the concentrations found in each source were compared. Twenty different drugs were analyzed including 6 antidepressants, 6 opioid medications and metabolites, 3 benzodiazepines, 2 antihistamines, 2 sedative hypnotics, and 1 muscle relaxant. Analysis found that SC blood concentrations reflect neither F nor H blood concentrations, with the exception of the benzodiazepines where SC blood concentrations closely mirrored H blood concentrations. Overall, SC blood drug concentrations tended to be 1.3 times greater than F blood and 0.77 times less than H blood. Therefore, it is recommended that the exact source of the blood, rather than simply "peripheral" or "central," be notated on toxicology results to ensure appropriate interpretation.

Validation of LC-TOF-MS screening for drugs, metabolites, and collateral compounds in forensic toxicology specimens.

Liquid chromatography time-of-flight mass spectrometry (LC-TOF-MS) analysis provides an expansive technique for identifying many known and unknown analytes. This study developed a screening method that utilizes automated solid-phase extraction to purify a wide array of analytes involving stimulants, benzodiazepines, opiates, muscle relaxants, hypnotics, antihistamines, antidepressants and newer synthetic "Spice/K2" cannabinoids and cathinone "bath salt" designer drugs. The extract was applied to LC-TOF-MS analysis, implementing a 13 min chromatography gradient with mobile phases of ammonium formate and methanol using positive mode electrospray. Several common drugs and metabolites can share the same mass and chemical formula among unrelated compounds, but they are structurally different. In this method, the LC-TOF-MS was able to resolve many isobaric compounds by accurate mass correlation within 15 ppm mass units and a narrow retention time interval of less than 10 s of separation. Drug recovery yields varied among spiked compounds, but resulted in overall robust area counts to deliver an average match score of 86 when compared to the retention time and mass of authentic standards. In summary, this method represents a rapid, enhanced screen for blood and urine specimens in postmortem, driving under the influence, and drug facilitated sexual assault forensic toxicology casework.

Brain pharmacokinetics of non-imidazole biphenyl H3 receptor antagonists: a liquid chromatography/electrospray-mass spectrometry and ex vivo binding study in rats.

In the present article, we report on the kinetics of brain penetration in rats of the H3R antagonist 1,1'-[1,1'-biphenyl-4,4'-diylbis(methylene)]bis-[piperidine] (1), which had shown a favorable in vitro pharmacological profile and in vivo potency in preventing scopolamine-induced amnesia. Two different approaches were employed: high-performance liquid chromatography/electrospray-mass spectrometry (HPLC/ESI-MS) and ex vivo binding against the labeled agonist [(3)H]-(R)-α-methylhistamine ([(3)H]RAMHA). Starting from the structure of 1, the rigid piperidine ring was replaced by a flexible dipropylamino group (see 2) or by a morpholino ring (see 3), endowed with lower basicity. The effect of replacement on rat plasma and brain disposition in the 24 h after administration was analyzed. High (µM) and persistent concentrations of 1 were found in rat plasma, while plasma levels were significantly lower (range: 0-200 nM) for the other two derivatives. This could be explained, among other factors, by the higher stability, observed for 1, to liver metabolic cleavage. The applied chemical modulation had an important effect on in vivo brain disposition, as, despite the comparable physico-chemical properties, 2 did not show the tendency to accumulate within the brain, as stated by its brain vs. plasma concentration ratios, if compared to 1. These structureproperty relationships should be taken into account in the pharmacokinetic optimization of new series of H3 receptor antagonists.

Simultaneous determination of 25 common pharmaceuticals in whole blood using ultra-performance liquid chromatography-tandem mass spectrometry.

An ultra-performance liquid chromatography-tandem mass spectrometry method was developed and validated for the quantification of 25 common pharmaceuticals in whole blood. The selected pharmaceuticals represent the most frequently detected drugs in our forensic laboratory with basic properties such as analgesics, antidepressants, antihistamines, antihypertensives, antipsychotics and ß-blockers. Whole blood samples were extracted with butyl acetate after adjusting pH with 2M NaOH. The target analytes were separated on a 100 × 2.1 mm ACQUITY BEH 1.7 µm C18 column by a formic acid/acetonitrile gradient elution using a Waters ACQUITY Ultra-Performance Liquid Chromatography system. Quantification was performed on a Waters tandem quadrupole ACQUITY TQD using multiple reaction monitoring in positive mode. The analytes were eluted within 11 min. The limit of quantification (LOQ) ranged from 0.002 to 0.01 mg/kg depending on the analyte. A good linear behavior was achieved for all analytes in the range from LOQ to 1.0 or 2.0 mg/kg blood. The absolute recoveries were between 55-87% for all compounds except norfluoxetine (44%). The method showed acceptable precision and accuracy for almost all analytes. Only unstable compounds like levomepromazine, methylphenidate, mirtazapine, norfluoxetine and zuclopenthixol deviated more. The method was successfully applied to more than 200 authentic blood samples within a year from forensic investigations.

INCB38579, a novel and potent histamine H4 receptor small molecule antagonist with anti-inflammatory pain and anti-pruritic functions.

The histamine H4 receptor mediates several histamine-induced cellular functions of leukocytes, including cell migration and cytokine production. Recent studies suggest that histamine signaling through the histamine H4 receptor can also have anti-pruritic and anti-nociceptive functions. 1-(7-(2-amino-6-(4-methylpiperazin-1-yl) pyrimidin-4-yl)-3, 4-dihdroisoquinolin-2(1H)-yl)-2-cyclopentylethanone (INCB38579) is a novel small molecule antagonist of the human and rodent histamine H4 receptors with at least 80-fold selectivity over the human histamine H1, H2 and H3 receptors, and has good pharmacokinetic properties in rats and mice. The compound is potent in inhibiting histamine binding to and signaling through the recombinant human, mouse and rat histamine H4 receptors and blocks the histamine-induced migration of human and mouse dendritic cells, as well as the cell shape change and migration of human eosinophils. INCB38579 and histamine may have separate but overlapping binding sites on the human histamine H4 receptor. This novel inhibitor is efficacious when evaluated in two previously established in vivo models for histamine H4 receptor activity (histamine-induced itch in mice and carrageenan-induced acute inflammatory pain in rats). When examined in formalin-induced pain models, INCB38579 significantly reduces the sustained inflammatory pain experienced by rats and mice. A good correlation between the protein binding adjusted potency from in vitro studies and its analgesic effect in vivo was observed. These results suggest that INCB38579 can serve as a useful tool for pharmacologic characterization of the histamine H4 receptor and further support the hypothesis that targeting the histamine H4 receptor may provide new therapeutic agents for various chronic inflammatory diseases, including inflammatory pain.

Determination of azatadine in human plasma by liquid chromatography/tandem mass spectrometry.

A sensitive method using liquid chromatography with tandem mass spectrometric detection (LC-MS/MS) was developed and validated for the analysis of antihistamine drug azatadine in human plasma. Loratadine was used as internal standard (IS). Analytes were extracted from human plasma by liquid/liquid extraction using ethyl acetate. The organic phase was reduced to dryness under a stream of nitrogen at 30 °C and the residue was reconstituted with the mobile phase. 5 µL of the resulting solution was injected onto the LC-MS/MS system. A 4.6 mm × 150 mm, I.D. 5 µm, Agilent TC-C(18) column was used to perform the chromatographic analysis. The mobile phase consisted of ammonium formate buffer 0.010 M (adjusted to pH 4.3 with 1M formic acid)/acetonitrile (20:80, v/v) The chromatographic run time was 5 min per injection and flow rate was 0.6 mL/min. The retention time was 2.4 and 4.4 min for azatadine and IS, respectively. The tandem mass spectrometric detection mode was achieved with electrospray ionization (ESI) iron source and the multiple reaction monitoring (MRM) (291.3 → 248.2m/z for azatadine, 383.3 → 337.3m/z for IS) was operated in positive ion modes. The low limit of quantitation (LLOQ) was 0.05 ng/mL. The intra-day and inter-day precision of the quality control (QC) samples was 8.93-11.57% relative standard deviation (RSD). The inter-day accuracy of the QC samples was 96.83-105.07% of the nominal values.

Liquid chromatography-mass spectrometric method for determination of the non-imidazole H3-receptor antagonist UPR1056 in rat plasma.

The non-imidazole H3 receptor antagonist UPR1056 was dosed in plasma samples from rats individually administered with a single i.p. dose of 1.25 mg/kg by means of a newly validated HPLC-MS method. UPR1056 was extracted from rat plasma by protein precipitation with acetonitrile and was separated by linear gradient elution, employing water and methanol both additioned with 0.05% trifluoroacetic acid as mobile phases. UPR1056 was detected in MS using an electrospray ion source operating in positive ion mode. Acquisition was performed in single ion monitoring mode at m/z=349.3. The method was validated over the concentration range of 17.43-1743 ng/mL (50-5000 pmol/mL). Within- and between-run precision for the low, mid and high quality controls (QC) levels were 6.75% or less and accuracy ranged from 95.8 to 107.6%. The lower limit of quantification was 17.43 ng/mL. The analysis of the time course of UPR1056 concentrations over the 24-h period revealed a C(max) of 1147 ng/mL after 2 h from peripheral administration of the non-imidazole H(3)-receptor antagonist, with a prolonged elimination half-life of over 9 h.

Capillary electrophoresis determination of antihistamines in serum and pharmaceuticals.

A capillary electrophoresis (CE) procedure combined with UV detection has proved useful for the quantification of the most frequently prescribed antihistamines corresponding to the ethylendiamine, ethanolamine, propylamine, piperazine and other derivative groups in serum samples and pharmaceuticals. Discussions have focused primarily on the optimisation of the separation conditions by considering the following experimental parameters: pH, pressure injection and voltage; under the criteria of maximum resolution and minimum analysis time. The optimised parameters for the determination of antihistamines were a 24 cm capillary (effective length), UV detection at 214 nm, 20 mM phosphate running buffer at pH 2.0, 2 psi s(-1) injection pressure and 5 kV applied voltage. Under these conditions, the analysis time was below 10 min. The proposed method was validated according to the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines. The limits of detection and quantification were in the ranges of 4-28 and 40-250 ng L(-1), respectively. Intra- and inter-day precision were tested at three different concentrations of the drugs, obtaining RSD values lower than 3% in most cases. The method was robust (RSD<5.6%), simple, specific and suitable for the practical determination of antihistamines in serum samples and pharmaceuticals with high recoveries (95.7-102.9%) without interferences.

Extended suicide using an atypical stud gun.

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.