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This study presents the first set of data on the removal of proton pump inhibitors (PPIs) and histamine H2 receptor antagonists (HRAs) and their transformation products in two Romanian wastewater treatment plants (WWTPs), as well as the impact of these organic pollutants on freshwater receiving effluents. The research investigated eight target pharmaceuticals and three metabolites using a newly developed and validated Liquid Chromatography - Mass Spectrometry (LC-MS/MS) method. The combined determination had a range of quantification limits varying from 0.13 ng/L to 0.18 ng/L for surface water and from 0.28 ng/L to 0.43 ng/L for wastewater. All analytes except cimetidine and 5-hydroxy-omeprazole were identified in water samples. The study found similar overall removal efficiencies for both WWTPs (43.2 % for Galati and 51.7 % for Ramnicu-Valcea). The research also showed that ranitidine and omeprazole could pose a low to high ecological risk to aquatic organisms. The findings suggest that the treatment stages used in the two Romanian WWTPs are insufficient to remove the target analytes completely, leading to environmental risks associated with the occurrence of pharmaceutical compounds in effluents and freshwater.

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Histamine receptor antagonists, which can bind to specific histamine receptors on target cells, exhibit substantial therapeutic efficacy in managing a variety of histamine-mediated disorders. Notably, histamine H1 and H2 receptor antagonists have been extensively investigated and universally acknowledged as recommended treatment agents for numerous allergic diseases and acid-related disorders, respectively. Historically, the combination of H1 and H2 receptor antagonists has been considered a classic treatment strategy, demonstrating relatively superior efficacy compared with single-drug therapies in the treatment of diverse histamine-mediated diseases. The latest emerging studies have additionally suggested the underlying roles of histamine and H1R and H2R in the development of anxiety disorders, arthritic diseases, and postexercise hypotension. Nevertheless, there is still a lack of systematic reviews on the clinical efficacy of combination therapy, greatly limiting our understanding of its clinical application. Here, we present a comprehensive overview of the current knowledge and perspectives regarding the combination of H1 and H2 histamine receptor antagonists in various histamine-mediated disorders. Furthermore, we critically analyze the adverse effects and limitations associated with combination therapy while suggesting potential solutions. Our review can offer a systematic summary and promising insights into the in-depth and effective application of the combination of H1 and H2 receptor antagonists.

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Background: : Proton pump inhibitors (PPI) are associated with Clostridium difficile infection (CDI). Impact of the route of administration is unknown.Research Design and Methods: Patients in Multiparameter Intelligent Monitoring in Intensive Care II database (MIMIC-II) from 2001 to 2008, >18 years old, admitted to medical, surgical, or cardiac ICUs were included. PPI exposures were omeprazole, esomeprazole, lansoprazole, and pantoprazole. PPI administration routes were oral or intravenous. Patients who received histamine receptor antagonists (H2RA) were the control arm. CDI was identified using ICD-9 diagnostic code 008.45. Multiple logistic regression analysis was performed to calculate odds ratios (OR).Results: The study included 16,820 patients (57% male) with a mean age of 63 (SD±17) years and hospitalization duration of 10.2 days (SD±11). Pantoprazole was the most common PPI (94%). CDI occurred in 2.4% and more in patients receiving PPIs than H2RAs (3.0% vs. 0.8%, p < 0.001). CDI prevalence increased with intravenous (95%CI = 1.69-3.39, OR 2.4) and oral (95%CI = 1.59-3.27, OR 2.3) PPI use compared to H2RAs. CDI prevalence was not associated with PPI route in the multivariable model (OR 1.07, 95%CI 0.86-1.34).Conclusions: Both intravenous and oral PPI use in the ICU were independently associated with CDI.

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To discover effective drugs for COVID-19 treatment amongst already clinically approved drugs, we developed a high throughput screening assay for SARS-CoV-2 virus entry inhibitors using SARS2-S pseudotyped virus. An approved drug library of 1800 small molecular drugs was screened for SARS2 entry inhibitors and 15 active drugs were identified as specific SARS2-S pseudovirus entry inhibitors. Antiviral tests using native SARS-CoV-2 virus in Vero E6 cells confirmed that 7 of these drugs (clemastine, amiodarone, trimeprazine, bosutinib, toremifene, flupenthixol, and azelastine) significantly inhibited SARS2 replication, reducing supernatant viral RNA load with a promising level of activity. Three of the drugs were classified as histamine receptor antagonists with clemastine showing the strongest anti-SARS2 activity (EC50 = 0.95 ± 0.83 µM). Our work suggests that these 7 drugs could enter into further in vivo studies and clinical investigations for COVID-19 treatment.

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Many patients regularly take histamine receptor antagonists, such as cetirizine, to prevent allergic reactions, but these antiallergic drugs may have inadvertent effects on orthodontic treatment. In previous studies, histamine has been shown to modulate the sterile inflammatory reaction underlying orthodontic tooth movement. Pertinent effects of histamine antagonization via cetirizine during orthodontic treatment, however, have not been adequately investigated. We thus treated male Fischer344 rats either with tap water (control group) or cetirizine by daily oral gavage corresponding to the clinically used human dosage adjusted to the rat metabolism (0.87 mg/kg) or to a previously published high dosage of cetirizine (3 mg/kg). Experimental anterior movement of the first upper left molar was induced by insertion of a nickel-titanium (NiTi) coil spring (0.25 N) between the molar and the upper incisors. Cone-beam computed tomography (CBCT), micro-computed tomography (µCT) images, as well as histological hematoxylin-eosin (HE), and tartrate-resistant acid phosphatase (TRAP) stainings were used to assess the extent of tooth movement, cranial growth, periodontal bone loss, root resorptions, and osteoclast activity in the periodontal ligament. Both investigated cetirizine dosages had no impact on the weight gain of the animals and, thus, animal welfare. Neither the extent of tooth movement, nor cranial growth, nor root resorption, nor periodontal bone loss were significantly influenced by the cetirizine dosages investigated. We, thus, conclude that histamine receptor antagonist cetirizine can be used during orthodontic treatment to prevent allergic reactions without clinically relevant side effects on orthodontic tooth movement.

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Urticaria is a common cause for patient consultations in Primary Care (PC). However, the optimal approach to managing urticaria in PC is controversial and not well-established. For this reason, there is a clear need to clarify the causes of urticaria and to develop treatment protocols to improve urticaria management in the PC setting. The present work has been developed with this objective. A group of experts in PC and dermatology, with specific expertise in treating urticaria, have reviewed the main clinical guidelines and publications on urticaria in order to develop clear, interdisciplinary recommendations on managing urticaria. In this article, consensus-based recommendations are presented that include simple, practical diagnostic, and treatment algorithms. These guidelines will help to optimise the management of patients with urticaria, increasing their quality of life and reducing the socioeconomic costs associated with this illness.

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BACKGROUND/AIM: Previously, we showed that KBV20C cancer cells highly resistant to antimitotic drugs were sensitized by co-treatment with a repositioned drug fluphenazine. MATERIALS AND METHODS: Considering that fluphenazine plays a role as a histamine receptor antagonist, we investigated low doses of 21 other histamine receptor antagonists (lidocaine, cimetidine, chlorpromazine, diphenhydramine, promethazine, ranitidine, famotidine, clemastine, chlorpheniramine, desloratadine, loratadine, cyproheptadine, azelastine, brompheniramine, carbinoxamine, fexofenadine, hydroxyzine, levocetirizine, meclizine, nizatidine, and pemirolast) to identify repositioned drugs for their sensitizing effects on antimitotic drug-resistant KBV20C cells at relatively low doses. RESULTS: Co-treatment with loratadine, and with azelastine highly sensitized KBV20C cells to vincristine treatment. Loratadine and azelastine reduced cell viability, increased G2 arrest, and up-regulated apoptosis when co-administered with vincristine. In detailed quantitative analysis, combination of vincristine with loratadine had a higher sensitization effect than that with azelastine. Azelastine had a higher P-glycoprotein (P-gp)-inhibitory activity, similar to that of verapamil, indicating that sensitization by vincristine-azelastine involved the P-gp-inhibitory effects of azelastine. However, loratadine had a very low P-gp-inhibitory activity, suggesting that loratadine sensitization to vincristine is independent of the P-gp-inhibition. Co-treatment with eribulin and loratadine increased the sensitization of KBV20C cells, suggesting that loratadine can be combined with other antimitotic drugs to sensitize resistant cancer cells. CONCLUSION: These findings provide important information regarding the sensitization of drug-resistant cells and indicate that loratadine may be used in patients with potentially resistant cancer without any toxic effects from P-gp inhibition.

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OBJECTIVE: Stress gastropathy is a rare complication of the intensive care unit stay with high morbidity and mortality. There are data that support the concept that patients tolerating enteral nutrition have sufficient gut blood flow to obviate the need for prophylaxis; however, no robust studies exist. This study assesses the incidence of clinically significant gastrointestinal bleeding in surgical trauma intensive care unit (STICU) patients at risk of stress gastropathy secondary to mechanical ventilation receiving enteral nutrition without pharmacologic prophylaxis. DESIGN: A retrospective cohort study of records from 2008 to 2013. SETTING: Adult patients in a single-center STICU were included. PATIENTS: Patients were included if they received full enteral nutrition while on mechanical ventilation. Exclusion criteria were coagulopathy, glucocorticoid use, prior-to-admission acid-suppressive therapy use, direct trauma or surgery to the stomach, failure to tolerate goal enteral nutrition, orders to allow natural death, and deviation from the intervention. INTERVENTION: Pharmacologic stress ulcer prophylaxis was discontinued once enteral nutrition was providing full caloric requirements for patients requiring mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: A total of 200 patients were included. The median age was 42 years, 83.0% were male, and 96.0% were trauma patients. The incidence of clinically significant gastrointestinal bleeding was 0.50%, with a subset analysis of traumatic brain injury patients yielding an incidence of 0.68%. Rates of ventilator-associated pneumonia and Clostridium difficile infection were low at 1.0 case/1000 ventilator days and 0.2 events/1000 patient days, respectively. Hospital all-cause mortality was 2.0%. Cost savings of US$121/patient stay were realized. CONCLUSION: Stress gastropathy is rare in this population. Surgical and trauma patients at risk for stress gastropathy did not benefit from continued pharmacologic prophylaxis once they tolerated enteral nutrition. Pharmacologic prophylaxis may safely be discontinued in this patient population. Further investigation is warranted to determine whether continued prophylaxis after attaining enteral feeding goals is detrimental.

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BACKGROUND: The present study was aimed to investigate the effects of microinjection of histamine and its H1, H2 and H3 receptor antagonists, mepyramine, ranitidine and thioperamide, respectively, into the anterior cingulate cortex (ACC) on pain-related behaviors induced by formalin in rats. METHODS: Two stainless steel guide canulas were bilaterally implanted into the ACC of anaesthetized rats. For induction of pain, intraplantar (ipl) injection of a 2.5% formalin solution was performed. The duration of paw licking/biting and the number of paw flinching were recorded in 5 min blocks for 60 min. Locomotor activity was assessed using an open-field test. RESULTS: Formalin produced a marked biphasic pattern of pain. Histamine reduced the second phases of paw licking/biting and flinching. Mepyramine (2 µg/side) prevented the suppressive effect of histamine (1 µg/side) on second phase of pain, but at a dose of 8 µg/side it did not inhibit the suppressive effects of 4 µg/side of histamine. Ranitidine at doses of 2 and 8 µg/side prevented histamine (1 and 4 µg/side)-induced antinociception. Thioperamide not only suppressed the second phases of pain, but also increased the suppressive effect of histamine. Naloxone prevented suppressive effects of histamine and thioperamide on pain. Mepyramine (8 µg/side) suppressed locomotor activity. CONCLUSION: The results of the present study showed pain suppressing effects for histamine. Histamine H2 and H3, and to a lesser extent, H1 receptors might be involved in histamine-induced antinociception. Opioid receptors might be involved in suppressive effects of histamine and thioperamide.

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Histamine receptors are expressed on bone cells and histamine may be involved in regulation of bone metabolism. The aim of the present study was to investigate the effects of loratadine (an H(1) receptor antagonist), ranitidine (an H(2) receptor antagonist) and betahistine (an H(3) receptor antagonist and H(1) receptor agonist) on bone mechanical properties in rats. Loratadine (5 mg/kg/day, po), ranitidine (50 mg/kg/day, po), or betahistine dihydrochloride (5 mg/kg/day, po), were administered for 4 weeks to non-ovariectomized and bilaterally ovariectomized (estrogen-deficient) 3-month-old rats, and their effects were compared with appropriate controls. Serum levels of bone turnover markers, bone mineralization and mechanical properties of the proximal tibial metaphysis, femoral diaphysis and femoral neck were studied. In rats with normal estrogen level, administration of loratadine slightly favorably affected mechanical properties of compact bone, significantly increasing the strength of the femoral neck (p < 0.05), and tending to increase the strength of the femoral diaphysis. Ranitidine did not significantly affect the investigated parameters, and betahistine decreased the strength of the tibial metaphysis (cancellous bone, p < 0.01). There were no significant effects of the drugs on serum bone turnover markers. In estrogen-deficient rats, the drugs did not significantly affect the investigated skeletal parameters. In conclusion, the effects of histamine H(1), H(2) and H(3) receptor antagonists on the skeletal system in rats were differential and dependent on estrogen status.

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OBJECTIVE(S): The present study investigated the effects of microinjection of histamine and histamine H1, H2, and H3 receptor antagonists, chlorpheniramine, ranitidine and thioperamide, respectively into the primary somatosensory cortex (PSC) on inflammatory pain. MATERIAL AND METHODS: Two stainless steel guide canulas were bilaterally implanted into the PSC of anaesthetized rats. Inflammatory pain was induced by subcutaneous (SC) injection of formalin (50 µl, 2.5%) in the ventral surface of right hind paw. Time durations of licking/biting of the injected paw were recorded as a pain measure. RESULTS: Formalin produced a biphasic pattern of licking/biting of the injected paw. Histamine at doses of 0.5, 1, and 2 µg decreased the intensity of pain. Chlorpheniramine and ranitidine at the same doses of 1 and 4 µg had no effects, whereas thioperamide at a dose of 4 µg suppressed both phases of formalin-induced pain. Pretreatments with chlorpheniramine and ranitidine at the same dose of 4 µg prevented histamine (2 µg)-induced antinociception. Antinociceptive effects were observed when thioperamide at doses of 1 and 4 µg was used with 0.25 and 1 µg of histamine, respectively. The antinociceptive effects induced by histamine (2 µg) and thioperamide (4 µg) were prevented by prior treatment with naloxone (4 µg). CONCLUSION: These results indicate that at PSC levels, histamine through post-synaptic H1, H2, and pre-synaptic H3 receptors might be involved in pain modulation. The endogenous opioid system may be involved in histamine- and thioperamide-induced antinociception.