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Clinical testing typically relies on invasive blood draws and biopsies. Alternative methods of sample collection are continually being developed to improve patient experience; swabbing the skin is one of the least invasive sampling methods possible. To show that skin swabs in combination with untargeted mass spectrometry (metabolomics) can be used for non-invasive monitoring of an oral drug, we report the kinetics and metabolism of diphenhydramine in healthy volunteers (n = 10) over the course of 24 hours in blood and three regions of the skin. Diphenhydramine and its metabolites were observed on the skin after peak plasma levels, varying by compound and skin location, and is an illustrative example of how systemically administered molecules can be detected on the skin surface. The observation of diphenhydramine directly from the skin supports the hypothesis that both parent drug and metabolites can be qualitatively measured from a simple non-invasive swab of the skin surface. The mechanism of the drug and metabolites pathway to the skin's surface remains unknown.

Clinical testing typically relies on invasive blood draws and biopsies. Alternative methods of sample collection are continually being developed to improve patient experience; swabbing the skin is one of the least invasive sampling methods possible. To show that skin swabs in combination with untargeted mass spectrometry (metabolomics) can be used for non-invasive monitoring of an oral drug, we report the kinetics and metabolism of diphenhydramine in healthy volunteers (n = 10) over the course of 24 hours in blood and three regions of the skin. Diphenhydramine and its metabolites were observed on the skin after peak plasma levels, varying by compound and skin location, and is an illustrative example of how systemically administered molecules can be detected on the skin surface. The observation of diphenhydramine directly from the skin supports the hypothesis that both parent drug and metabolites can be qualitatively measured from a simple non-invasive swab of the skin surface. The mechanism of the drug and metabolites pathway to the skin's surface remains unknown.

People who use illicit drugs (PWUDs) have been identified as a key at-risk group for tuberculosis (TB). Examination of illicit drug use networks has potential to assess the risk of TB exposure and disease progression. Research also is needed to assess mechanisms for accelerated TB transmission in this population. This study aims to 1) assess the rate of TB exposure, risk of disease progression, and disease burden among PWUD; 2) estimate the proportion of active TB cases resulting from recent transmission within this network; and 3) evaluate whether PWUD with TB disease have physiologic characteristics associated with more efficient TB transmission. Our cross-sectional, observational study aims to assess TB transmission through illicit drug use networks, focusing on methamphetamine and Mandrax (methaqualone) use, in a high TB burden setting and identify mechanisms underlying accelerated transmission. We will recruit and enroll 750 PWUD (living with and without HIV) through respondent driven sampling in Worcester, South Africa. Drug use will be measured through self-report and biological measures, with sputum specimens collected to identify TB disease by Xpert Ultra (Cepheid) and mycobacterial culture. We will co-enroll those with microbiologic evidence of TB disease in Aim 2 for molecular and social network study. Whole genome sequencing of Mycobacteria tuberculosis (Mtb) specimens and social contact surveys will be done for those diagnosed with TB. For Aim 3, aerosolized Mtb will be compared in individuals with newly diagnosed TB who do and do not smoke illicit drug. Knowledge from this study will provide the basis for a strategy to interrupt TB transmission in PWUD and provide insight into how this fuels overall community transmission. Results have potential for informing interventions to reduce TB spread applicable to high TB and HIV burden settings.

Seafood, one of the most important food commodities consumed worldwide, is considered a high-quality, healthy, and safe food option. However, marine ecosystems are the ultimate destination for a large group of chemicals, including contaminants of emerging concern, and seafood consumption is a major pathway of human exposure. With growing awareness of food safety and food quality, and increased demand for information on the risk of contaminants of emerging concern, there is a need to assess food safety issues related to harmful contaminants in seafood and ensure the safety of marine food resources. In this study, the risks of emerging compounds (endocrine disruptors, brominated flame retardants, pharmaceuticals and personal care products, and toxic elements) in fish and seafood were analyzed according to their PBT (persistence, bioaccumulation, toxicity) properties as well as in terms of their concentration levels in seafood. A hazard index (HI) was estimated for each compound by applying an artificial neural network (ANN) approach known as Self-Organizing-Maps. Subsequently, an integrated risk rank (IRI) was developed considering the values of HI and the concentrations of emerging compounds in seafood species gathered from the scientific literature. Current results identified HHCB, MeHg, NP, AHTN and PBDE209 as the top five highest ranked compounds present in seafood, according to the 50th percentile (mean) of the IRI. However, this ranking slightly changed when taking into account the 99th percentile of the IRI, showing toxic elements, methylmercury and inorganic arsenic, as having the highest risk. The outcome of this study identified the priority contaminants and should help in regulatory decision-making and scientific panels to design screening programs as well as t

Cisplatin is widely used as an anti-tumor drug for the treatment of solid tumors. Unfortunately, it causes nephrotoxicity as a critical side effect, limiting its use, given that no preventive drug against cisplatin-induced nephrotoxicity is currently available. This study identified that a previously developed drug, diphenhydramine, may provide a novel treatment for cisplatin-induced nephrotoxicity based on the results of the analysis of medical big data. We evaluated the actual efficacy of diphenhydramine via in vitro and in vivo experiments in a mouse model. Diphenhydramine inhibited cisplatin-induced cell death in renal proximal tubular cells. Mice administered cisplatin developed kidney injury with renal dysfunction (plasma creatinine: 0.43 ± 0.04 mg/dl vs 0.15 ± 0.01 mg/dl, p<0.01) and showed augmented oxidative stress, increased apoptosis, elevated inflammatory cytokines, and mitogen-activated protein kinases activation; however, most of these symptoms were suppressed by treatment with diphenhydramine. Further, the renal concentration of cisplatin was attenuated in diphenhydramine-treated mice (platinum content: 70.0 ± 3.3 µg/g dry kidney weight vs 53.4 ± 3.6 µg/g dry kidney weight, p<0.05). Importantly, diphenhydramine did not influence or interfere with the anti-tumor effect of cisplatin in any of the in vitro or in vivo experiments. Moreover, a retrospective clinical study of 1467 cancer patients treated with cisplatin showed that patients who had used diphenhydramine exhibited less acute kidney injury than patients who had not used diphenhydramine (6.1 % vs 22.4 %, p<0.05). Thus, diphenhydramine demonstrated efficacy as a novel preventive medicine against cisplatin-induced nephrotoxicity.

Aquatic systems receive a wide range of pharmaceuticals that may have adverse impacts on aquatic wildlife. Among these pharmaceuticals, antihistamines are commonly found, and these substances have the potential to influence the physiology of aquatic invertebrates. Previous studies have focused on how antihistamines may affect behaviours of aquatic invertebrates, but these studies probably do not capture the full consequences of antihistamine exposure, as traditional recording techniques do not capture important animal movements occurring at the scale of milliseconds, such as prey escape responses. In this study, we investigated if antihistamine exposure can impact escape responses in aquatic insect, by exposing damselfly (Coenagrion hastulatum) larvae to two environmentally relevant concentrations (0.1 and 1 μg L−1) of diphenhydramine. Importantly, we used a high-speed imaging approach that with high-time resolution captures details of escape responses and, thus, potential impacts of diphenhydramine on these behaviours. Our results show overall weak effects of antihistamine exposure on the escape behaviours of damselfly larvae. However, at stage 2 of the C-escape response, we found a significant increase in turning angle, which corresponds to a reduced swimming velocity, indicating a reduced success at evading a predator attack. Thus, we show that low concentrations of an antihistamine may affect behaviours strongly related to fitness of aquatic insect prey – effects would have been overlooked using traditional recording techniques. Hence, to understand the full consequences of pharmaceutical contamination on aquatic wildlife, high-speed imaging should be incorporated into future environmental risk assessments.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenic disorder caused by AIRE mutations, presents with several autoimmune diseases. Among these, endocrine organ failure is widely recognized, but the prevalence, immunopathogenesis, and treatment of non-endocrine manifestations such as pneumonitis remain poorly characterized. We enrolled 50 patients with APECED in a prospective observational study and comprehensively examined their clinical and radiographic findings, performed pulmonary function tests, and analyzed immunological characteristics in blood, bronchoalveolar lavage fluid, and endobronchial and lung biopsies. Pneumonitis was found in >40% of our patients, presented early in life, was misdiagnosed despite chronic respiratory symptoms and accompanying radiographic and pulmonary function abnormalities, and caused hypoxemic respiratory failure and death. Autoantibodies against BPIFB1 and KCNRG and the homozygous c.967-979del13 AIRE mutation are associated with pneumonitis development. APECED pneumonitis features compartmentalized immunopathology, with accumulation of activated neutrophils in the airways and lymphocytic infiltration in intraepithelial, submucosal, peribronchiolar, and interstitial areas. Beyond APECED, we extend these observations to lung disease seen in other conditions with secondary AIRE deficiency (thymoma and RAG deficiency). Aire-deficient mice had similar compartmentalized cellular immune responses in the airways and lung tissue, which was ameliorated by deficiency of T and B lymphocytes. Accordingly, T and B lymphocyte-directed immunomodulation controlled symptoms and radiographic abnormalities and improved pulmonary function in patients with APECED pneumonitis. Collectively, our findings unveil lung autoimmunity as a common, early, and unrecognized manifestation of APECED and provide insights into the immunopathogenesis and treatment of pulmonary autoimmunity associated with impaired central immune toleran

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenic disorder caused by AIRE mutations, presents with several autoimmune diseases. Among these, endocrine organ failure is widely recognized, but the prevalence, immunopathogenesis, and treatment of non-endocrine manifestations such as pneumonitis remain poorly characterized. We enrolled 50 patients with APECED in a prospective observational study and comprehensively examined their clinical and radiographic findings, performed pulmonary function tests, and analyzed immunological characteristics in blood, bronchoalveolar lavage fluid, and endobronchial and lung biopsies. Pneumonitis was found in >40% of our patients, presented early in life, was misdiagnosed despite chronic respiratory symptoms and accompanying radiographic and pulmonary function abnormalities, and caused hypoxemic respiratory failure and death. Autoantibodies against BPIFB1 and KCNRG and the homozygous c.967-979del13 AIRE mutation are associated with pneumonitis development. APECED pneumonitis features compartmentalized immunopathology, with accumulation of activated neutrophils in the airways and lymphocytic infiltration in intraepithelial, submucosal, peribronchiolar, and interstitial areas. Beyond APECED, we extend these observations to lung disease seen in other conditions with secondary AIRE deficiency (thymoma and RAG deficiency). Aire-deficient mice had similar compartmentalized cellular immune responses in the airways and lung tissue, which was ameliorated by deficiency of T and B lymphocytes. Accordingly, T and B lymphocyte-directed immunomodulation controlled symptoms and radiographic abnormalities and improved pulmonary function in patients with APECED pneumonitis. Collectively, our findings unveil lung autoimmunity as a common, early, and unrecognized manifestation of APECED and provide insights into the immunopathogenesis and treatment of pulmonary autoimmunity associated with impaired central immune toleran

A diverse cocktail of pharmaceuticals is spreading via water treatment plants’ effluent to surface water with known and unknown consequences of individual organisms and the ecosystem. In prior research on what consequences the pharmaceutical discharge can have, the antihistamine diphenhydramine has been found in surface waters and has been linked to alteration in organisms’ behaviours. In this study, Dytiscidae larvae were filmed before and after being exposed to diphenhydramin with a concentration of 1 µg/l. The exposure was done using four different treatments: no diphenhydramine, diphenhydramine in water, in their food or in both water and food. This was done to observe whether the behaviour, specifically activity and boldness, of Dytiscidae larvae would change with the exposure of the antihistamine and therefore potentially be a problem in aquatic ecosystems exposed to effluent. The experiment showed a significant difference (P = 0.015) between larvae in the control group and larvae only exposed to diphenhydramine through water, where exposed larvae were less active than the control group. Also, a trend pointed to a potential difference in exploration between the same groups, where the group exposed to diphenhydramine explored more than the control group. No behavioural change was found when larvae was exposed via food or food and water. The changed behaviour found here could influence fitness of the larvae and potentially also other parts of the ecosystem through cascading effects. Further research is required to confirm the dangers and consequences of diphenhydramine in surface waters, but my results suggest that it can alter the organism’s behaviour in aquatic ecosystems.

Drug monitoring is crucial for providing accurate and effective care; however, current methods (e.g., blood draws) are inconvenient and unpleasant. We aim to develop a non-invasive method for the detection and monitoring of drugs via human skin. The initial development toward this aim required information about which drugs, taken orally, can be detected via the skin. Untargeted liquid chromatography-mass spectrometry (LC-MS) was used as it was unclear if drugs, known drug metabolites, or other transformation products were detectable. In accomplishing our aim, we analyzed samples obtained by swabbing the skin of 15 kidney transplant recipients in five locations (forehead, nasolabial area, axillary, backhand, and palm), bilaterally, on two different clinical visits. Untargeted LC-MS data were processed using molecular networking via the Global Natural Products Social Molecular Networking platform. Herein, we report the qualitative detection and location of drugs and drug metabolites. For example, escitalopram/citalopram and diphenhydramine, taken orally, were detected in forehead, nasolabial, and hand samples, whereas N-acetyl-sulfamethoxazole, a drug metabolite, was detected in axillary samples. In addition, chemicals associated with environmental exposure were also detected from the skin, which provides insight into the multifaceted chemical influences on our health. The proof-of-concept results presented support the finding that the LC-MS and data analysis methodology is currently capable of the qualitative assessment of the presence of drugs directly via human skin.

The blood-brain barrier (BBB) is the primary obstacle for efficient drug delivery to the central nervous system (CNS). One promising strategy to enhance brain delivery is to utilize nanocarriers (NC), e.g., liposomes, encapsulating CNS drugs. However, there is still a lack of understanding of how carrier- and payload-associated factors with liposomal brain delivery may influence brain drug uptake and ultimately therapeutic performance. In this thesis, the impact of factors including the liposomal formulation, the addition of a BBB-targeting ligand and the BBB transport properties of the payload itself on brain drug delivery were quantitatively investigated in vivo with microdialysis. Furthermore, by using a model-based approach, the benefits of NCs with different properties to increase the therapeutic index of CNS drugs were studied and key parameters influencing the therapeutic performance were identified. The formulation of PEGylated (PEG) liposomes could significantly influence brain delivery of methotrexate (MTX). Compared to free MTX, PEG liposomes based on egg-yolk phosphatidylcholine (EYPC) increased brain uptake of MTX by 3-fold, while the formulation based on hydrogenated soy phosphatidylcholine (HSPC) did not affect the uptake at all. Also, PEG liposomes could influence the BBB transport of payloads differently, depending on if the payload itself show active uptake or efflux at the BBB. For diphenhydramine (DPH), a drug with active uptake at the BBB, PEG-EYPC liposomes significantly reduced its uptake into the brain. Moreover, the brain-targeting effect of glutathione (GSH)-tagged PEG liposomal MTX was highly dependent on the liposomal formulation that is combined with GSH. Compared to the PEG control formulations, GSH-PEG-HSPC liposomes increased brain delivery of MTX 4-fold, while GSH-coating on PEG-EYPC liposomes did not further enhance the uptake. In the last simulation study, two independent processes of nanodelivery to the brain were identified. A NC

Despite the promising features of liposomes as brain drug delivery vehicles, it remains uncertain how they influence the brain uptake in vivo. In order to gain a better fundamental understanding of the interaction between liposomes and the blood–brain barrier (BBB), it is indispensable to test if liposomes affect drugs with different BBB transport properties (active influx or efflux) differently. The aim of this study was to quantitatively evaluate how PEGylated (PEG) liposomes influence brain delivery of diphenhydramine (DPH), a drug with active influx at the BBB, in rats. The brain uptake of DPH after 30 min intravenous infusion of free DPH, PEG liposomal DPH, or free DPH + empty PEG liposomes was compared by determining the unbound DPH concentrations in brain interstitial fluid and plasma with microdialysis. Regular blood samples were taken to measure total DPH concentrations in plasma. Free DPH was actively taken up into the brain time-dependently, with higher uptake at early time points followed by an unbound brain-to-plasma exposure ratio (Kp,uu) of 3.0. The encapsulation in PEG liposomes significantly decreased brain uptake of DPH, with a reduction of Kp,uu to 1.5 (p < 0.05). When empty PEG liposomes were coadministered with free drug, DPH brain uptake had a tendency to decrease (Kp,uu 2.3), and DPH was found to bind to the liposomes. This study showed that PEG liposomes decreased the brain delivery of DPH in a complex manner, contributing to the understanding of the intricate interactions between drug, liposomes, and the BBB.

The blood-brain barrier (BBB) is the primary obstacle for efficient drug delivery to the central nervous system (CNS). One promising strategy to enhance brain delivery is to utilize nanocarriers (NC), e.g., liposomes, encapsulating CNS drugs. However, there is still a lack of understanding of how carrier- and payload-associated factors with liposomal brain delivery may influence brain drug uptake and ultimately therapeutic performance. In this thesis, the impact of factors including the liposomal formulation, the addition of a BBB-targeting ligand and the BBB transport properties of the payload itself on brain drug delivery were quantitatively investigated in vivo with microdialysis. Furthermore, by using a model-based approach, the benefits of NCs with different properties to increase the therapeutic index of CNS drugs were studied and key parameters influencing the therapeutic performance were identified. The formulation of PEGylated (PEG) liposomes could significantly influence brain delivery of methotrexate (MTX). Compared to free MTX, PEG liposomes based on egg-yolk phosphatidylcholine (EYPC) increased brain uptake of MTX by 3-fold, while the formulation based on hydrogenated soy phosphatidylcholine (HSPC) did not affect the uptake at all. Also, PEG liposomes could influence the BBB transport of payloads differently, depending on if the payload itself show active uptake or efflux at the BBB. For diphenhydramine (DPH), a drug with active uptake at the BBB, PEG-EYPC liposomes significantly reduced its uptake into the brain. Moreover, the brain-targeting effect of glutathione (GSH)-tagged PEG liposomal MTX was highly dependent on the liposomal formulation that is combined with GSH. Compared to the PEG control formulations, GSH-PEG-HSPC liposomes increased brain delivery of MTX 4-fold, while GSH-coating on PEG-EYPC liposomes did not further enhance the uptake. In the last simulation study, two independent processes of nanodelivery to the brain were identified. A NC

Objective: Botulinum Neurotoxin-A (BoNT-A) injections are considered the standard of care for children with spastic equinus resulting from cerebral palsy (CP). Few studies have reported objective measures such as 3-dimensional (3D) kinematics, or examined injection effects on overall gait function, instead focusing on subjective or objective measures of ankle function. Study Design: Prospective cohort study of children who received BoNT-A injections for spastic equinus, in conjunction with injection of proximal muscles when clinically indicated. Three-dimensional kinematics were collected before and after injection. The study was IRB approved and no external funding was received. Method(s): Children with unilateral (hemiplegia) and bilateral (diplegia) spastic CP were included, GMFCS Levels I-III, if capable of completing a 3D gait analysis, with or without a gait aid (crutches or posterior walker). Using electrical stimulation for muscle localisation, a fixed 6U/Kg dose of Botox (Allergan Corporation) was injected into the gastrocnemius in children with bilateral, and gastrocsoleus in children with unilateral CP, following published guidelines. Three-dimensional kinematics were captured 1-4 weeks before and 4-8 weeks after injection, with the aim of detecting peak injection effects. Gait Profile Scores (GPS), Gait Variable Scores (GVS) and selected ankle and knee kinematic parameters were calculated from 3D kinematics. Results were expressed as medians with confidence intervals (CIs). Kruskal-Wallis testing was used to compare pre-post injection differences. Usual orthoses and physiotherapy were continued and serial casting was not permitted. Result(s): There were 20 boys and 17 girls, mean age 5y7m (range 4y1m - 8y2m). Nineteen had unilateral and 18 had bilateral CP, with 16 children functioning at GMFCS Level I, 18 at Level II and three at Level III. There was no change in GPS or ankle GVS for the cohort as a whole, nor for unilateral or bilateral CP subgroups. M

Objective: Botulinum Neurotoxin-A (BoNT-A) injections are considered the standard of care for children with spastic equinus resulting from cerebral palsy (CP). Few studies have reported objective measures such as 3-dimensional (3D) kinematics, or examined injection effects on overall gait function, instead focusing on subjective or objective measures of ankle function. Study Design: Prospective cohort study of children who received BoNT-A injections for spastic equinus, in conjunction with injection of proximal muscles when clinically indicated. Three-dimensional kinematics were collected before and after injection. The study was IRB approved and no external funding was received. Method(s): Children with unilateral (hemiplegia) and bilateral (diplegia) spastic CP were included, GMFCS Levels I-III, if capable of completing a 3D gait analysis, with or without a gait aid (crutches or posterior walker). Using electrical stimulation for muscle localisation, a fixed 6U/Kg dose of Botox (Allergan Corporation) was injected into the gastrocnemius in children with bilateral, and gastrocsoleus in children with unilateral CP, following published guidelines. Three-dimensional kinematics were captured 1-4 weeks before and 4-8 weeks after injection, with the aim of detecting peak injection effects. Gait Profile Scores (GPS), Gait Variable Scores (GVS) and selected ankle and knee kinematic parameters were calculated from 3D kinematics. Results were expressed as medians with confidence intervals (CIs). Kruskal-Wallis testing was used to compare pre-post injection differences. Usual orthoses and physiotherapy were continued and serial casting was not permitted. Result(s): There were 20 boys and 17 girls, mean age 5y7m (range 4y1m - 8y2m). Nineteen had unilateral and 18 had bilateral CP, with 16 children functioning at GMFCS Level I, 18 at Level II and three at Level III. There was no change in GPS or ankle GVS for the cohort as a whole, nor for unilateral or bilateral CP subgroups. M

The blood-brain barrier (BBB) is the primary obstacle for efficient drug delivery to the central nervous system (CNS). One promising strategy to enhance brain delivery is to utilize nanocarriers (NC), e.g., liposomes, encapsulating CNS drugs. However, there is still a lack of understanding of how carrier- and payload-associated factors with liposomal brain delivery may influence brain drug uptake and ultimately therapeutic performance. In this thesis, the impact of factors including the liposomal formulation, the addition of a BBB-targeting ligand and the BBB transport properties of the payload itself on brain drug delivery were quantitatively investigated in vivo with microdialysis. Furthermore, by using a model-based approach, the benefits of NCs with different properties to increase the therapeutic index of CNS drugs were studied and key parameters influencing the therapeutic performance were identified. The formulation of PEGylated (PEG) liposomes could significantly influence brain delivery of methotrexate (MTX). Compared to free MTX, PEG liposomes based on egg-yolk phosphatidylcholine (EYPC) increased brain uptake of MTX by 3-fold, while the formulation based on hydrogenated soy phosphatidylcholine (HSPC) did not affect the uptake at all. Also, PEG liposomes could influence the BBB transport of payloads differently, depending on if the payload itself show active uptake or efflux at the BBB. For diphenhydramine (DPH), a drug with active uptake at the BBB, PEG-EYPC liposomes significantly reduced its uptake into the brain. Moreover, the brain-targeting effect of glutathione (GSH)-tagged PEG liposomal MTX was highly dependent on the liposomal formulation that is combined with GSH. Compared to the PEG control formulations, GSH-PEG-HSPC liposomes increased brain delivery of MTX 4-fold, while GSH-coating on PEG-EYPC liposomes did not further enhance the uptake. In the last simulation study, two independent processes of nanodelivery to the brain were identified. A NC

A simple, accurate, rapid and precise method was developed for the simultaneous estimation of Ibuprofen and Diphenhydramine in Pharmaceutical dosage form. Chromatogram was run through Inertsil ODS (250x4.6mm) 5µ. Mobile phase used was Acetonitrile and Phosphate buffer (45:55) at a flow rate of 1.0 ml/min and detection wavelength was found to be 260 nm. The retention time was found to be 2.32 min and 2.93 min for Ibuprofen and Diphenhydramine respectively. The accuracy and reliability of the method was assessed by evaluation of linearity, precision (intra-day and inter-day % RSD >2), accuracy (98-102%), specificity, LOD, LOQ values in accordance with ICH guidelines. The developed method is applicable for routine quality control analysis of selected combined dosage forms.

A simple, accurate, rapid and precise method was developed for the simultaneous estimation of Ibuprofen and Diphenhydramine in Pharmaceutical dosage form. Chromatogram was run through Inertsil ODS (250x4.6mm) 5µ. Mobile phase used was Acetonitrile and Phosphate buffer (45:55) at a flow rate of 1.0 ml/min and detection wavelength was found to be 260 nm. The retention time was found to be 2.32 min and 2.93 min for Ibuprofen and Diphenhydramine respectively. The accuracy and reliability of the method was assessed by evaluation of linearity, precision (intra-day and inter-day % RSD >2), accuracy (98-102%), specificity, LOD, LOQ values in accordance with ICH guidelines. The developed method is applicable for routine quality control analysis of selected combined dosage forms.

The blood-brain barrier (BBB) is the primary obstacle for efficient drug delivery to the central nervous system (CNS). One promising strategy to enhance brain delivery is to utilize nanocarriers (NC), e.g., liposomes, encapsulating CNS drugs. However, there is still a lack of understanding of how carrier- and payload-associated factors with liposomal brain delivery may influence brain drug uptake and ultimately therapeutic performance. In this thesis, the impact of factors including the liposomal formulation, the addition of a BBB-targeting ligand and the BBB transport properties of the payload itself on brain drug delivery were quantitatively investigated in vivo with microdialysis. Furthermore, by using a model-based approach, the benefits of NCs with different properties to increase the therapeutic index of CNS drugs were studied and key parameters influencing the therapeutic performance were identified. The formulation of PEGylated (PEG) liposomes could significantly influence brain delivery of methotrexate (MTX). Compared to free MTX, PEG liposomes based on egg-yolk phosphatidylcholine (EYPC) increased brain uptake of MTX by 3-fold, while the formulation based on hydrogenated soy phosphatidylcholine (HSPC) did not affect the uptake at all. Also, PEG liposomes could influence the BBB transport of payloads differently, depending on if the payload itself show active uptake or efflux at the BBB. For diphenhydramine (DPH), a drug with active uptake at the BBB, PEG-EYPC liposomes significantly reduced its uptake into the brain. Moreover, the brain-targeting effect of glutathione (GSH)-tagged PEG liposomal MTX was highly dependent on the liposomal formulation that is combined with GSH. Compared to the PEG control formulations, GSH-PEG-HSPC liposomes increased brain delivery of MTX 4-fold, while GSH-coating on PEG-EYPC liposomes did not further enhance the uptake. In the last simulation study, two independent processes of nanodelivery to the brain were identified. A NC

The blood-brain barrier (BBB) is the primary obstacle for efficient drug delivery to the central nervous system (CNS). One promising strategy to enhance brain delivery is to utilize nanocarriers (NC), e.g., liposomes, encapsulating CNS drugs. However, there is still a lack of understanding of how carrier- and payload-associated factors with liposomal brain delivery may influence brain drug uptake and ultimately therapeutic performance. In this thesis, the impact of factors including the liposomal formulation, the addition of a BBB-targeting ligand and the BBB transport properties of the payload itself on brain drug delivery were quantitatively investigated in vivo with microdialysis. Furthermore, by using a model-based approach, the benefits of NCs with different properties to increase the therapeutic index of CNS drugs were studied and key parameters influencing the therapeutic performance were identified. The formulation of PEGylated (PEG) liposomes could significantly influence brain delivery of methotrexate (MTX). Compared to free MTX, PEG liposomes based on egg-yolk phosphatidylcholine (EYPC) increased brain uptake of MTX by 3-fold, while the formulation based on hydrogenated soy phosphatidylcholine (HSPC) did not affect the uptake at all. Also, PEG liposomes could influence the BBB transport of payloads differently, depending on if the payload itself show active uptake or efflux at the BBB. For diphenhydramine (DPH), a drug with active uptake at the BBB, PEG-EYPC liposomes significantly reduced its uptake into the brain. Moreover, the brain-targeting effect of glutathione (GSH)-tagged PEG liposomal MTX was highly dependent on the liposomal formulation that is combined with GSH. Compared to the PEG control formulations, GSH-PEG-HSPC liposomes increased brain delivery of MTX 4-fold, while GSH-coating on PEG-EYPC liposomes did not further enhance the uptake. In the last simulation study, two independent processes of nanodelivery to the brain were identified. A NC

Background: Although intravenous lipid emulsion (ILE) was first used to treat life-threatening local anesthetic (LA) toxicity, its use has expanded to include both non-local anesthetic (non-LA) poisoning and less severe manifestations of toxicity. A collaborative workgroup appraised the literature and provides evidence-based recommendations for the use of ILE in poisoning. Method(s): Following a systematic review of the literature, data were summarized in four publications: LA and non-LA poisoning efficacy, adverse effects, and analytical interferences. Twenty-two toxins or toxin categories and three clinical situations were selected for voting. Voting statements were proposed using a predetermined format. A two-round modified Delphi method was used to reach consensus on the voting statements. Disagreement was quantified using RAND/UCLA Appropriateness Method. Result(s): For the management of cardiac arrest, we recommend using ILE with bupivacaine toxicity, while our recommendations are neutral regarding its use for all other toxins. For the management of life-threatening toxicity, (1) as first line therapy, we suggest not to use ILE with toxicity from amitriptyline, non-lipid soluble beta receptor antagonists, bupropion, calcium channel blockers, cocaine, diphenhydramine, lamotrigine, malathion but are neutral for other toxins, (2) as part of treatment modalities, we suggest using ILE in bupivacaine toxicity if other therapies fail, but are neutral for other toxins, (3) if other therapies fail, we recommend ILE for bupivacaine toxicity and we suggest using ILE for toxicity due to other LAs, amitriptyline, and bupropion, but our recommendations are neutral for all other toxins. In the treatment of non-life-threatening toxicity, recommendations are variable according to the balance of expected risks and benefits for each toxin. For LA-toxicity we suggest the use of Intralipid 20% as it is the formulation the most often reported. There is no evidence to support a reco

Background: Although intravenous lipid emulsion (ILE) was first used to treat life-threatening local anesthetic (LA) toxicity, its use has expanded to include both non-local anesthetic (non-LA) poisoning and less severe manifestations of toxicity. A collaborative workgroup appraised the literature and provides evidence-based recommendations for the use of ILE in poisoning. Method(s): Following a systematic review of the literature, data were summarized in four publications: LA and non-LA poisoning efficacy, adverse effects, and analytical interferences. Twenty-two toxins or toxin categories and three clinical situations were selected for voting. Voting statements were proposed using a predetermined format. A two-round modified Delphi method was used to reach consensus on the voting statements. Disagreement was quantified using RAND/UCLA Appropriateness Method. Result(s): For the management of cardiac arrest, we recommend using ILE with bupivacaine toxicity, while our recommendations are neutral regarding its use for all other toxins. For the management of life-threatening toxicity, (1) as first line therapy, we suggest not to use ILE with toxicity from amitriptyline, non-lipid soluble beta receptor antagonists, bupropion, calcium channel blockers, cocaine, diphenhydramine, lamotrigine, malathion but are neutral for other toxins, (2) as part of treatment modalities, we suggest using ILE in bupivacaine toxicity if other therapies fail, but are neutral for other toxins, (3) if other therapies fail, we recommend ILE for bupivacaine toxicity and we suggest using ILE for toxicity due to other LAs, amitriptyline, and bupropion, but our recommendations are neutral for all other toxins. In the treatment of non-life-threatening toxicity, recommendations are variable according to the balance of expected risks and benefits for each toxin. For LA-toxicity we suggest the use of Intralipid 20% as it is the formulation the most often reported. There is no evidence to support a reco

Antihistamines have been shown to degrade poorly, and should be considered as contaminants that may pose risks to the aquatic ecosystem. Diphenhydramine (DPH) is a first generation antihistamine detected up to lower micrograms per litre downstream of wastewater treatment facilities. Freshwater snails like Planorbis corneus are ectotherms and behaviour plays an important role for the regulation of snail body temperature. In a laboratory experiment, it was tested if DPH affects the behavioural traits thermoregulation and righting time in P. corneus. Righting time was measured as the time snails took to right themselves from an upside down position. After a 24 hour exposure to three different sublethal concentrations (nominal concentrations: 10, 100, and 1000 µg/L) of DPH two thermoregulatory experiments (thermal preference (TPref) and maximum critical temperature (CTmax)) and one righting time experiment were performed. CTmax increased significantly from 37.5 °C to 39.7°C after exposure to 949 µg/L DPH. Minimal righting time was significantly increased in the lowest exposure concentration (8.21 µg/L DPH). No significant results were found in the TPref analyses. Collectively these results suggest that exposure to non-lethal concentrations of DPH affect behavioral traits like thermoregulation and righting time in freshwater snails.

ObjectiveTo determine outcomes among patients with migraine in the emergency department (ED) who receive IV hydromorphone vs IV prochlorperazine + diphenhydramine.MethodsThis study was conducted in 2 EDs in New York City. Patients who met international criteria for migraine were eligible for participation if they had not used an opioid within the previous month. Clinicians, participants, investigators, and research personnel were blinded to treatment. Patients were randomized in blocks of 4. Participants received hydromorphone 1 mg or prochlorperazine 10 mg + diphenhydramine 25 mg. Diphenhydramine was administered to prevent akathisia, a common side effect of IV prochlorperazine. The primary outcome was sustained headache relief, defined as achieving a headache level of mild or none within 2 hours of medication administration and maintaining that level for 48 hours without the requirement of rescue medication. A planned interim analysis was conducted once 48-hour data were available for 120 patients.ResultsThe trial was halted by the data monitoring committee after 127 patients had been enrolled. The primary outcome was achieved in the prochlorperazine arm by 37 of 62 (60%) participants and in the hydromorphone arm by 20 of 64 (31%) participants (difference 28%, 95% confidence interval 12-45, number needed to treat 4, 95% confidence interval 2-9).ConclusionsIV hydromorphone is substantially less effective than IV prochlorperazine for the treatment of acute migraine in the ED and should not be used as first-line therapy.Clinicaltrialsgov identifierNCT02389829.Classification of evidenceThis study provides Class I evidence that for patients in the ED with migraine, IV prochlorperazine + diphenhydramine is superior to IV hydromorphone.

Orf is a zoonotic parapoxvirus typically transmitted to humans by a bite from goats or sheep. We present an unusual case of multiple orf lesions on the fingers of a 13-month-old child who was bitten by a goat and subsequently developed progressive swelling, blistering, and necrotic papulonodules of the hand followed by an additional diffuse, pruritic, papular rash. A primary diagnosis of orf infection was confirmed using real-time polymerase chain reaction, and the diffuse eruption was clinically consistent with an id reaction. Extensive necrosis and papular id reaction associated with orf rarely have been described.

Antihistamines have been shown to degrade poorly, and should be considered as contaminants that may pose risks to the aquatic ecosystem. Diphenhydramine (DPH) is a first generation antihistamine detected up to lower micrograms per litre downstream of wastewater treatment facilities. Freshwater snails like Planorbis corneus are ectotherms and behaviour plays an important role for the regulation of snail body temperature. In a laboratory experiment, it was tested if DPH affects the behavioural traits thermoregulation and righting time in P. corneus. Righting time was measured as the time snails took to right themselves from an upside down position. After a 24 hour exposure to three different sublethal concentrations (nominal concentrations: 10, 100, and 1000 µg/L) of DPH two thermoregulatory experiments (thermal preference (TPref) and maximum critical temperature (CTmax)) and one righting time experiment were performed. CTmax increased significantly from 37.5 °C to 39.7°C after exposure to 949 µg/L DPH. Minimal righting time was significantly increased in the lowest exposure concentration (8.21 µg/L DPH). No significant results were found in the TPref analyses. Collectively these results suggest that exposure to non-lethal concentrations of DPH affect behavioral traits like thermoregulation and righting time in freshwater snails.

Premenopausal women may be most vulnerable to acute coronary syndromes at a point in their menstrual cycle when their plasma estrogen levels are the lowest during and immediately after menstruation. Metoprolol is a first-line drug in the management of patients with acute coronary syndrome; however, when metoprolol was marketed in 1982, women were largely excluded from clinical trials. Furthermore, the over-the-counter antihistamine diphenhydramine inhibited the metabolism of the CYP2D6 substrate metoprolol in healthy, young men with pharmacokinetic and pharmacodynamic consequences. The pharmacokinetics and pharmacodynamics of metoprolol and its interaction with diphenhydramine were investigated in a randomized, double-blind, crossover, placebo-controlled manner in healthy, premenopausal extensive (EM; n = 16) and poor metabolizer (PM; n = 4) women immediately after menstruation. During the placebo phase, EMs had between 5.2- and 8.4-fold higher total clearance (CL/F) of R- and S-metoprolol compared with PMs, whereas the latter had a 35% greater area under the effect curve (AUEC) and 60% greater EC(50) value for heart rate reduction than EMs (all P < 0.05). Diphenhydramine coadmininstration caused a 2.2- to 3.2-fold decrease in CL/F of metoprolol enantiomers with a resulting 21% increase in AUEC and 29% increase in EC(50) value for heart rate reduction in EMs (all P < 0.05). This is the first study to report an in-depth elucidation of metoprolol's pharmacokinetics and hemodynamics in premenopausal EM and PM women at a point in their menstrual cycle when vulnerability for acute coronary events may be greatest. Caution is warranted when the over-the-counter antihistamine diphenhydramine is part of a chronic therapeutic regimen

Background: Since all antihistamines are capable of crossing the blood-brain barrier, they may also cause sedation which may impair daily activities such as driving a car. The purpose of this review was to examine the effects of antihistamines on driving ability. Method: A literature search revealed 18 double-blind placebo-controlled clinical trials that applied the on-road highway driving test. In this test, subjects are instructed to drive 100-km on a public highway with a steady lateral position and a constant speed (95 km/h). Primary outcome measure is the Standard Deviation of Lateral Position (SDLP, cm), i.e. the weaving of the car. Results: The literature search yielded 18 clinical trials. At therapeutic doses, a single dose of diphenhydramine, emedastine and hydroxizine impaired driving comparable or greater than the effects of BAC 0.08%. Clemastine, triprolidine, mizolastine, acrivastine, dexchlorpheniramine CR and mequitazine impaired driving performance to the same extent as BAC 0.05%. For mizolastine significant impairment was only seen after higher than therapeutic doses. Results for cetirizine were mixed, illustrating the drug has the potential to impair driving performance, especially in sensitive subjects. Terfenadine, loratadine, levocetirizine, desloratadine, ebastine, bilastine fexofenadine and rupatadine showed no driving impairment in the standard driving test after acute administration of their recommended dose. Several studies examined subchronic effects of antihistamines on driving performance. After 4 days of daily treatment significant driving impairment was found for emedastine (2 and 4 mg bid), diphenhydramine (50 mg), clemastine (2 mg bid), triprolidine (5 mg bid), after 5 days of ebastine (30 mg), and after 8 days of hydroxyzine (50 mg). Mixed results were found for cetirizine (10 mg), terfenadine (120 mg) and loratadine (20 mg). No significant differences from placebo were observed after 4 days of subchronic treatment with triprolidine

The present study investigated if and to what extent murine stem cell-derived beating cardiomyocytes within embryoid bodies can be used as a broad screening in vitro assay for neurotoxicity testing, replacing for example in vivo tests for marine neurotoxins. Effect of nine model compounds, acting on either the Na+, K+, or Ca2+ channels or the Na+/K+ ATP-ase pump, on the beating was assessed. Diphenhydramine, veratridine, isradipine, verapamil and ouabain induced specific beating arrests that were reversible and none of the concentrations tested induced cytotoxicity. Three K+ channel blockers, amiodarone, clofilium and sematilide, and the Na+/K+ ATPase pump inhibitor digoxin had no specific effect on the beating. In addition, two marine neurotoxins i.e. saxitoxin and tetrodotoxin elicited specific beating arrests in cardiomyocytes. Comparison of the results obtained with cardiomyocytes to those obtained with the neuroblastoma neuro-2a assay revealed that the cardiomyocytes were generally somewhat more sensitive for the model compounds affecting Na+ and Ca2+ channels, but less sensitive for the compounds affecting K+ channels. The stem cell-derived cardiomyocytes were not as sensitive as the neuroblastoma neuro-2a assay for saxitoxin and tetrodotoxin. It is concluded that the murine stem cell-derived beating cardiomyocytes provide a sensitive model for detection of specific neurotoxins and that the neuroblastoma neuro-2a assay may be a more promising cell-based assay for the screening of marine biotoxins

Diphenhydramine toxicity commonly manifests with antimuscarinic features, including dry mucous membranes, tachycardia, urinary retention, mydriasis, tachycardia, and encephalopathy. Severe toxicity can include seizures and intraventricular conduction delay. We present here a case of a 23-year-old male presenting with recurrent seizures, hypotension and wide complex tachycardia who had worsening toxicity despite treatment with sodium bicarbonate. The patient was ultimately treated with intravenous lipid emulsion therapy that was temporally associated with improvement in the QRS duration. We also review the current literature that supports lipid use in refractory diphenhydramine toxicity. [West J Emerg Med. 2014;15(7):–0.]

Diphenhydramine toxicity commonly manifests with antimuscarinic features, including dry mucous membranes, tachycardia, urinary retention, mydriasis, tachycardia, and encephalopathy. Severe toxicity can include seizures and intraventricular conduction delay. We present here a case of a 23-year-old male presenting with recurrent seizures, hypotension and wide complex tachycardia who had worsening toxicity despite treatment with sodium bicarbonate. The patient was ultimately treated with intravenous lipid emulsion therapy that was temporally associated with improvement in the QRS duration. We also review the current literature that supports lipid use in refractory diphenhydramine toxicity. [West J Emerg Med. 2014;15(7):–0.]

Obj:Compare IV fat emulsion(IFE) and sodium bicarbonate(SB) in critically ill diphenhydramine(DPH) swine to determine which better improves hypotension(hypo). Method:Swine 45-55kg infused with DPH 1mg/kg/min IV until MAP fell to 60% of baseline (BL), randomized to IFE or SB. Measured HR, SBP, MAP, CO, SVR, & SvO2. Labs for pH, pCO2, bicarb, lactate, & DPH level. DPH level found by liquid chromatography. Results:24 swine, 12 each to IFE & SB group. At BL, vital signs similar in each group. IFE & SB group had similar amt of DPH to hypo(IFE: 31.21mg/kg; SB: 33.28mg/kg). IFE to hypo at mean 32:13min; SB at 34:08min. Post hypo, no difference in IFE & SB groups for CO, SVR, SvO2, QRS, or QTc; though, better HR in SB, SBP in IFE, & MAP in IFE. IFE group died at mean 12:33min; SB at 07:48min. One IFE and two SB pigs survived. Mean total serum DPH levels end of study similar. Mean DPH in lipid layer was 6.8mcg/mL, in aqueous layer 8.6mcg/mL. Conc:No difference in hypo between IFE & SB. IFE didn't improve QRS widening in DPH toxic swine. DPH level similar in aqueous & lipid layers., The original document contains color images. Protocol number FWH20100054A. Prepared in collaboration with the San Antonio Military Medical Center, Lackland AFB, TX.

Journal of Clinical Anesthesia, 24(6), pp.513-516; 2012

The FAA Office of Aerospace Medicine sets medical standards needed to protect the public and pilots from death or injury due to incapacitation of the pilot. As a part of this process, toxicology testing is performed by the FAA on almost every pilot who is fatally injured in an aviation accident to determine the medical condition of the pilot, medications used by the pilot at the time of the accident, and the extent of impairment, if any. The data were extracted from the FAA toxicology database for all pilots who died from 2004 and 2008 in aviation accidents. The laboratory received and tested specimens from 1,353 pilots who died in aviation accidents between 2004 and 2008. Findings were classified into three separate categories: Controlled Dangerous Substance, Prescription, and Over-the-Counter drugs. The study was conducted to determine the extent of drug use in pilots who have died in aviation accidents from 2004 to 2008 and to determine the types of drugs most commonly found. A comparison of previously published reports with this study's report was made to determine trends in drug use by pilots who have died in aviation accidents over the past 20 years. Factors were examined that could influence drug trends noted over the years. Diphenhydramine, an H1 antihistamine with impairing properties, is the most common drug found in pilots who have died in aviation accidents. The FAA has taken steps to warn pilots of the dangers of using this medication, which is dispensed as both a prescription and an over-the-counter medication. Because significant aviation performance impairment can be associated with diphenhydramine, the Office of Aerospace Medicine will continue to take steps to help pilots decide when it is safe to resume flying duties after taking such an impairing medication., Work was accomplished under approved task AM-B-10-TOX-206.

BACKGROUND AND PURPOSE: The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders. The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction, for example, as associated with the use of centrally active antihistamines. Of the selective second generation antihistamines, cetirizine has been found to have central nervous system effects. The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction. EXPERIMENTAL APPROACH: The study was conducted according to a three-way, double-blind, cross-over design. Treatments were single oral doses of cetirizine 10 and 20 mg and placebo. Effects on cognition were assessed using tests of word learning, memory scanning, vigilance, divided attention, tracking and visual information processing speed. KEY RESULTS: Cetirizine 10 mg impaired tracking performance and both doses impaired memory scanning speed. None of the other measures indicated impaired performance. CONCLUSION AND IMPLICATIONS: Cetirizine affects information processing speed, but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders.

Over 90 million patients have been prescribed clopidogrel since its US FDA approval in 1997. Clopidogrel hypersensitivity affects up to 6% of patients, most commonly in the form of a pruritic rash. Symptoms are severe enough to result in drug discontinuation in 1.5% of patients. Premature discontinuation of clopidogrel is problematic following percutaneous coronary intervention because of the risk of stent thrombosis leading to myocardial infarction and death. Accordingly, the management of patients with clopidogrel hypersensitivity is of significant clinical importance. Conventional clopidogrel desensitization protocols, while successful in most patients, employ a washout period off medication to enable accurate detection of a reaction during the desensitization. However, interruption of therapy is potentially hazardous in patients with recent stent placement. Our clinical experience demonstrates that clopidogrel hypersensitivity can be successfully treated without drug interruption using short-course corticosteroids and antihistamines to enable the development of physiologic tolerance while the medication is continued. The role of newer agents, such as prasugrel, as surrogate therapy in patients with clopidogrel hypersensitivity is yet to be defined.

Over 90 million patients have been prescribed clopidogrel since its US FDA approval in 1997. Clopidogrel hypersensitivity affects up to 6% of patients, most commonly in the form of a pruritic rash. Symptoms are severe enough to result in drug discontinuation in 1.5% of patients. Premature discontinuation of clopidogrel is problematic following percutaneous coronary intervention because of the risk of stent thrombosis leading to myocardial infarction and death. Accordingly, the management of patients with clopidogrel hypersensitivity is of significant clinical importance. Conventional clopidogrel desensitization protocols, while successful in most patients, employ a washout period off medication to enable accurate detection of a reaction during the desensitization. However, interruption of therapy is potentially hazardous in patients with recent stent placement. Our clinical experience demonstrates that clopidogrel hypersensitivity can be successfully treated without drug interruption using short-course corticosteroids and antihistamines to enable the development of physiologic tolerance while the medication is continued. The role of newer agents, such as prasugrel, as surrogate therapy in patients with clopidogrel hypersensitivity is yet to be defined.

BACKGROUND AND PURPOSE: The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders. The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction, for example, as associated with the use of centrally active antihistamines. Of the selective second generation antihistamines, cetirizine has been found to have central nervous system effects. The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction. EXPERIMENTAL APPROACH: The study was conducted according to a three-way, double-blind, cross-over design. Treatments were single oral doses of cetirizine 10 and 20 mg and placebo. Effects on cognition were assessed using tests of word learning, memory scanning, vigilance, divided attention, tracking and visual information processing speed. KEY RESULTS: Cetirizine 10 mg impaired tracking performance and both doses impaired memory scanning speed. None of the other measures indicated impaired performance. CONCLUSION AND IMPLICATIONS: Cetirizine affects information processing speed, but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders.

Over 90 million patients have been prescribed clopidogrel since its US FDA approval in 1997. Clopidogrel hypersensitivity affects up to 6% of patients, most commonly in the form of a pruritic rash. Symptoms are severe enough to result in drug discontinuation in 1.5% of patients. Premature discontinuation of clopidogrel is problematic following percutaneous coronary intervention because of the risk of stent thrombosis leading to myocardial infarction and death. Accordingly, the management of patients with clopidogrel hypersensitivity is of significant clinical importance. Conventional clopidogrel desensitization protocols, while successful in most patients, employ a washout period off medication to enable accurate detection of a reaction during the desensitization. However, interruption of therapy is potentially hazardous in patients with recent stent placement. Our clinical experience demonstrates that clopidogrel hypersensitivity can be successfully treated without drug interruption using short-course corticosteroids and antihistamines to enable the development of physiologic tolerance while the medication is continued. The role of newer agents, such as prasugrel, as surrogate therapy in patients with clopidogrel hypersensitivity is yet to be defined.

Study objective: Intravenous (IV) prochlorperazine with diphenhydramine is superior to subcutaneous sumatriptan in the treatment of migraine patients presenting to the emergency department (ED). Methods: In this randomized, double-blind, placebo-controlled trial, after providing written informed consent, patients presenting to the ED with a chief complaint of migraine received a 500-mL bolus of IV saline solution and either 10 mg prochlorperazine with 12.5 mg diphenhydramine IV plus saline solution placebo subcutaneously or saline solution placebo IV plus 6 mg sumatriptan subcutaneously. Pain intensity was assessed with 100-mm visual analog scales (visual analog scale at baseline and every 20 minutes for 80 minutes). The primary outcome was change in pain intensity from baseline to 80 minutes or time of ED discharge if subjects remained in the ED for fewer than 80 minutes after treatment. Sedation and nausea were assessed every 20 minutes with visual analog scale scales, and subjects were contacted within 72 hours to assess headache recurrence. Results: Sixty-eight subjects entered the trial, with complete data for 66 subjects. Baseline pain scores were similar for the prochlorperazine/diphenhydramine and sumatriptan groups (76 versus 71 mm). Mean reductions in pain intensity at 80 minutes or time of ED discharge were 73 mm for the prochlorperazine/diphenhydramine group and 50 mm for those receiving sumatriptan (mean difference 23 mm; 95% confidence interval 11 to 36 mm). Sedation, nausea, and headache recurrence rates were similar., Pub. in Annals of Emergency Medicine, p1-6, 2009.

Antipsychotic-induced extrapyramidal symptoms should be recognised and adequately treated. We report an unusual complication of not doing so: a patient’s self-medicating to control these symptoms, which produced diphenhydramine-dependence.

Antipsychotic-induced extrapyramidal symptoms should be recognised and adequately treated. We report an unusual complication of not doing so: a patient’s self-medicating to control these symptoms, which produced diphenhydramine-dependence.

Premenopausal women may be most vulnerable to acute coronary syndromes at a point in their menstrual cycle when their plasma estrogen levels are the lowest during and immediately after menstruation. Metoprolol is a first-line drug in the management of patients with acute coronary syndrome; however, when metoprolol was marketed in 1982, women were largely excluded from clinical trials. Furthermore, the over-the-counter antihistamine diphenhydramine inhibited the metabolism of the CYP2D6 substrate metoprolol in healthy, young men with pharmacokinetic and pharmacodynamic consequences. The pharmacokinetics and pharmacodynamics of metoprolol and its interaction with diphenhydramine were investigated in a randomized, double-blind, crossover, placebo-controlled manner in healthy, premenopausal extensive (EM; n = 16) and poor metabolizer (PM; n = 4) women immediately after menstruation. During the placebo phase, EMs had between 5.2- and 8.4-fold higher total clearance (CL/F) of R- and S-metoprolol compared with PMs, whereas the latter had a 35% greater area under the effect curve (AUEC) and 60% greater EC(50) value for heart rate reduction than EMs (all P < 0.05). Diphenhydramine coadmininstration caused a 2.2- to 3.2-fold decrease in CL/F of metoprolol enantiomers with a resulting 21% increase in AUEC and 29% increase in EC(50) value for heart rate reduction in EMs (all P < 0.05). This is the first study to report an in-depth elucidation of metoprolol's pharmacokinetics and hemodynamics in premenopausal EM and PM women at a point in their menstrual cycle when vulnerability for acute coronary events may be greatest. Caution is warranted when the over-the-counter antihistamine diphenhydramine is part of a chronic therapeutic regimen

The prototype “classic” over-the-counter antihistamine diphenhydramine was shown to interact with the polymorphic P450 enzyme CYP2D6. This project was undertaken to investigate (1) whether diphenhydramine inhibits the biotransformation of the clinically relevant CYP2D6 substrate metoprolol in vitro and (2) whether this in vitro interaction results in a clinically significant pharmacokinetic and pharmacodynamic drug interaction in vivo. In vitro incubations were carried out with microsomes obtained from lymphoblastic cells transfected with CYP2D6 complementary deoxyribonucleic acid to determine the type and extent of inhibition. We then randomized 16 subjects with genetically determined high (extensive metabolizers) or low (poor metabolizers) CYP2D6 activity to receive metoprolol (100 mg) in the presence of steady-state concentrations of diphenhydramine or placebo. In vitro, diphenhydramine was a potent competitive inhibitor of metoprolol α-hydroxylation, exhibiting an inhibitory constant of 2 µmol/L and increasing the Michaelis-Menten constant of metoprolol sixfold. In vivo, diphenhydramine decreased metoprolol oral and nonrenal clearances twofold and metoprolol→α-hydroxymetoprolol partial metabolic clearance 2.5-fold in extensive metabolizers (all P < .05) but not in poor metabolizers (P > .2). Although the hemodynamic response to metoprolol was unaltered by diphenhydramine in poor metabolizers (P > .05), metoprolol-related effects on heart rate, systolic blood pressure, and Doppler-derived aortic blood flow peak velocity were more pronounced and lasted significantly longer in extensive metabolizers receiving diphenhydramine compared with poor metabolizers and extensive metabolizers receiving placebo. We conclude that diphenhydramine inhibits the metabolism of metoprolol in extensive metabolizers, thereby prolonging the negative chronotropic and inotropic effects of the drug. Clinically relevant drug interactions may occur between diphenhydramine and many CYP2D6 su

Maintenance and/or enhancement of performance during sustained operations (SUSOPS) is of vital concern to all military services, and if possible may contribute to the successful outcome of conflicts. Adding the contingency of an NBC defensive posture in hot environments during SUSOPS significantly increases logistics, tactical and medical requirements. The purpose of this work unit was to quantify Marine Corps combatant cognitive and physical performance changes as a function of sustained mental and physical work with drug (antihistamines), sleep loss and Individual Protective Ensembles (IPE) as measured by the Tri-Service Cognitive and Physiological Performance Assessment Batteries (PABs). A series of studies deliniated into five phases were conducted in either laboratory or controlled field environments. Marine Corps and highly fit civilian volunteers performed cognitive and physical tasks in simulations of sustained reconnaissance missions in which a number of complicating factors and conditions were progressively added and measured. These manipulated factors were various levels of respiratory, circadian, thermoregulatory, sleeploss, workload, fitness, drug and clothing (various MOPP levels). When appropriate either between or within group repeated measures designs were utilized. The effects were measured by established medical, psychological and physiological methods as described in Tri-service PABs that were developed by the Army's Chemical Defense Program of which this project was a part of.

Airborne Warning and Control System (AWACS) Weapons Director (WD) cognitive and psychomotor skills were evaluated with terfenadine (Seldane) and diphenhydramine (Benadryl) using a performance assessment battery (PAB). After nondrug Day 1 training, twelve 3 member teams were tested with Placebo on Day 2, then randomly assigned to Seldane (60 mg/12h TID), Benadryl (25 mg/4h QID), or Placebo groups on Days 3 and 4. An 8-test PAB was given at 1230 and 1330 each testing day. The Seldane and Placebo groups did not differ appreciably from each other on Days 3 or 4, but differed significantly from the Benadryl group. The group showed degraded performance for 7 variables on Day 3 and for 3 variables on Day 4 compared to the Seldane and/or Placebo groups. Subjective measures of fatigue and antihistamine symptoms supported the Day 3 Benadryl impairment. Overall results were consistent with previous research demonstrating cognitive and psychomotor task impairment with Benadryl but not with Seldane. Support for awarding medical flying waivers to non-pilot aircrew who are taking Seldane under the supervision of flight surgeons is offered., Prepared in cooperation with NTI, Inc., Dayton, OH.