Pharmaceuticals entering Lake Champlain and their combination effects on developing Zebrafish Embryos

Human-derived pharmaceuticals have been identified entering surface waters in the United States through wastewater effluent. While there is ample literature about what each compound alone does to aquatic life, little is known about the effects aquatic life may experience from the exposure to many different pharmaceuticals present in the environment. More specifically, are the combination of pharmaceuticals in the environment more detrimental to aquatic life than each pharmaceutical alone? Zebrafish embryos were used to model what aquatic life in Lake Champlain may experience. Vatovec et al (2016) determined that there are 51 environmentally-relevant human derived pharmaceuticals entering Lake Champlain through wastewater effluent. Out of the 51, acetaminophen, carbamazepine, and diphenhydramine were studied. Embryos were exposed to each pharmaceutical for three days at various concentrations and observed for any developmental defects. The sub-lethal concentration of each pharmaceutical was determined and then this specific concentration was used in subsequent combination experiments. Results indicated that the exposure to all three pharmaceuticals were more detrimental to embryonic development than each pharmaceutical alone. However, when pharmaceuticals were combined in groups of two, one of the groups was more detrimental to embryos than the combination of all three pharmaceuticals. Although concentrations used in this experiment were much higher than that found in the environment, the implications of this study are still important. It is necessary to determine and demonstrate at what concentration pharmaceuticals are detrimental to aquatic life so that environmental concentrations never reach the concentrations used in the current experiment. The outcome of this research stands as a warning as to what may occur if nothing is done about pharmaceuticals entering water sources. Future studies should determine combination effects of pharmaceuticals at environmental concentrations

Effects of Inhaled Brevetoxins in Allergic Airways: Toxin–Allergen Interactions and Pharmacologic Intervention

During a Florida red tide, brevetoxins produced by the dinoflagellate Karenia brevis become aerosolized and cause airway symptoms in humans, especially in those with pre-existing airway disease (e.g., asthma). To understand these toxin-induced airway effects, we used sheep with airway hypersensitivity to Ascaris suum antigen as a surrogate for asthmatic patients and studied changes in pulmonary airflow resistance (R(L)) after inhalation challenge with lysed cultures of K. brevis (crude brevetoxins). Studies were done without and with clinically available drugs to determine which might prevent/reverse these effects. Crude brevetoxins (20 breaths at 100 pg/mL; n = 5) increased R (L) 128 ± 6% (mean ± SE) over baseline. This bronchoconstriction was significantly reduced (% inhibition) after pretreatment with the glucocorticosteroid budesonide (49%), the β (2) adrenergic agent albuterol (71%), the anticholinergic agent atropine (58%), and the histamine H(1)-antagonist diphenhydramine (47%). The protection afforded by atropine and diphenhydramine suggests that both cholinergic (vagal) and H(1)-mediated pathways contribute to the bronchoconstriction. The response to cutaneous toxin injection was also histamine mediated. Thus, the airway and skin data support the hypothesis that toxin activates mast cells in vivo. Albuterol given immediately after toxin challenge rapidly reversed the bronchoconstriction. Toxin inhalation increased airway kinins, and the response to inhaled toxin was enhanced after allergen challenge. Both factors could contribute to the increased sensitivity of asthmatic patients to toxin exposure. We conclude that K. brevis aerosols are potent airway constrictors. Clinically available drugs may be used to prevent or provide therapeutic relief for affected individuals

Diphenhydramine as an adjunct to conscious sedation in bronchoscopy

Intravenous benzodiazepines are commonly used to achieve conscious sedation in outpatient bronchoscopy. Though effective, dose-dependent-adverse events may be encountered with the use of these sedatives. Diphenhydramine, a hypnotic, is sometimes used as an adjunctive agent in bronchoscopy to decrease sedative usage. However, data to support this practice is lacking. Our goal was to determine if adjunctive diphenhydramine significantly decreases doses of benzodiazepine in outpatient bronchoscopy. METHODS: We conducted a single-center retrospective analysis of all outpatient bronchoscopies from November 2013 to February 2016. Subjects included were those who each had two bronchoscopies: no diphenhydramine used (control) versus diphenhydramine used (intervention). The procedure time, total doses of midazolam and opiates (in morphine equivalence) for each procedure were collected. A multiple regression analysis was used to compare differences between bronchoscopy groups in midazolam and opiate use. RESULTS: Of 1164 patients with greater than 1 outpatient bronchoscopies, 61 unique subjects (female 56%) fulfilled the primary inclusion criteria thus resulting to 122 procedures. Mean body mass index was 32 kg/m2. Procedure time was 22.9 ± 16 mins in diphenhydramine group and 23.2 ± 17.8 mins in control group. Mean morphine equivalents administered was 5.6 ± 2.6 mg in diphenhydramine group and 6.2 ± 2.4 mg in control group. Mean midazolam use was 8.4 ± 3.2 mg in diphenhydramine group and 10.2 ± 3.8 mg in control group (difference: -1.795, p-value = 0.005). The mean dose of diphenhydramine used was 38.32 ± 15.12 mg. In a multivariate model, mean midazolam use remained less in the diphenhydramine group after adjusting for procedure time and morphine equivalents, (difference -1.28 mg, p-value = 0.005). CONCLUSIONS: Intravenous administration of diphenhydramine during outpatient bronchoscopy reduces midazolam usage, however, the absolute amount of dose reduction may not be clinically significant

Diphenhydramine against cisplatin nephrotoxicity

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

Initial Development toward Non-Invasive Drug Monitoring via Untargeted Mass Spectrometric Analysis of Human Skin.

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

Diphenhydramine induced QT prolongation and torsade de pointes: An uncommon effect of a common drug

The histamine I receptor antagonist diphenhydramine is a freely available, over the counter medication for sleep and the most frequently used antihistamine drug. It inhibits the fast sodium channels and, at higher concentrations, the repolarising potassium channels, particularly Ikr which leads to prolongation of the action potential and the QT interval. The toxicity of diphenhydramine is dose-dependent, with a critical dose limit of 1.0 g. We report a case of a young woman who consumed more than 3 g of diphenhydramine in the setting of alcohol intoxication and developed QTc prolongation with nonsustained polymorphic ventricular tachycardia. These changes reverted to normal with supportive treatment. An overdose of diphenhydramine with concomitant alcohol use can induce torsade de pointes in an otherwise normal heart. (Cardiol J 2010; 17, 5: 509-511