Urothelial toxicity of esketamine in the treatment of depression

Rationale Ketamine is the first widely used substance with rapid-onset antidepressant action. However, there are uncertainties regarding its potential urothelial toxicity, particularly after repeated application. In the context of rising recreational ketamine use, severe side effects affecting the human urinary tract have been reported. It is assumed that ketamine interacts with bladder urothelial cells and induces apoptosis. Objectives This study aimed to assess whether single or repeated doses of esketamine used in an antidepressant indication are associated with urinary toxicity. Methods We included male and female inpatients with a current episode of depression and a diagnosis of recurrent depressive disorder, bipolar disorder or schizoaffective disorder according to ICD-10 criteria (n = 25). The esketamine treatment schedule involved a maximum of 3× weekly dosing at 0.25–0.5 mg/kg i.v. or s.c. The primary outcome was the change in urine toxicity markers (leukocytes, erythrocytes, protein and free haemoglobin). Description of demographic, clinical and laboratory data was conducted using means, standard deviations, frequencies and percentages. Changes in urinary toxicity markers over time were evaluated using linear mixed models with gender as a covariate. Results The participants received an average of 11.4 (SD 8) esketamine treatments, and an average number of 11.2 (SD 8) urine samples were analysed over the course of treatment. Neither urinary leukocyte concentration (F(20; 3.0) = 3.1; p = 0.2) nor erythrocyte concentration (F(20;2.2) = 4.1; p = 0.2) showed a significant trend towards increase during the course of esketamine treatment. Similarly, free haemoglobin and protein concentrations, which were analysed descriptively, did not display a rise during treatment. There was a significant improvement in depression ratings after esketamine treatment (p < 0.001). Conclusions This study is, to the best of our knowledge, the first to focus on urothelial toxicity of esketamine used in antidepressant indication and dose. The results indicate that the use of single or repeated doses of esketamine is unlikely to cause urothelial toxicity. The results are in need of confirmation as sample size was small.

Blood Donors’ Age, Haemoglobin Type, G6PD Status, and Blood Group Impact Storability of CPDA-1 Banked Whole Blood: A Repeated-Measure Cohort Study in Cape Coast, Ghana

Background. The high prevalence of haemoglobin variants and glucose 6-phosphate dehydrogenase disorder (G6PDd) in sub-Saharan Africa means that substantial proportions of donor blood units carry these red cell abnormalities. Aim. This study investigated the impact that inherited haemoglobin variants and/or G6PD status have on whole blood banked at 4–6°C for 35 days. Method. This repeated-measure cohort study was undertaken on 103 donor blood units collected into blood bag containing CPDA-1 anticoagulant. On days 0, 7, 14, 21, and 35, full blood count, osmotic-induced haemolysis, and plasma K+ levels were estimated. Also, on day 0, G6PD status, haemoglobin variants, % foetal haemoglobin, and blood group of donor units were determined using methaemoglobin reductase, cellulose acetate electrophoresis, modified Bekte alkali denaturation assay, and slide haemagglutination test, respectively. Result. Overall, although plasma K+ levels increased during storage, donor units from individuals ≥20 years, G6PD normal, Hb AC, or blood group B had comparatively higher percentage change in plasma K+ during storage. Osmotically induced haemolysis of donor units was significantly decreased in Hb AC (compared with Hb A or AS) donor units on days 7, 14, 21, and 35 (p<0.0001 in each case). G6PDd donor units had comparatively reduced osmotic-induced lysis compared with G6PD normal units, reaching a statistical significance on day 35 (p=0.043). Also, Hb AC units had comparatively nonstatistically higher plasma K+ at all time points (compared with Hb A or AS). Furthermore, whereas donor units from individuals ≥20 years showed significantly higher median free haemoglobin on day 21 (compared to donor <20 years), when donor units were stratified per Hb variants, only Hb AS units had median free haemoglobin below the 0.8% threshold after 35 days’ storage. Conclusion. Age of donor, blood group, Hb AC variant, and G6PD status may be important considerations in the storability of whole blood.

Proeryptotic Activity of 4-Hydroxynonenal: A New Potential Physiopathological Role for Lipid Peroxidation Products

Background: Eryptosis is a physiological, apoptosis-like death of injured erythrocytes crucial to prevent premature haemolysis and the pathological sequalae generated by cell-free haemoglobin. When dysregulated, the process is associated to several inflammatory-based pathologies. 4-Hydroxy-trans-2-nonenal (HNE) is an endogenous signalling molecule at physiological levels and, at higher concentrations, is involved in the pathogenesis of several inflammatory-based diseases. This work evaluated whether HNE could induce eryptosis in human erythrocytes. Methods: Measurements of phosphatidylserine, cell volume, intracellular oxidants, Ca++, glutathione, ICAM-1, and ceramide were assessed by flow cytometry. Scanning electron microscopy evaluated morphological alterations of erythrocytes. Western blotting assessed caspases. PGE2 was measured by ELISA. Adhesion of erythrocytes on endothelial cells was evaluated by gravity adherence assay. Results: HNE in the concentration range between 10–100 µM induces eryptosis, morphological alterations correlated to caspase-3 activation, and increased Ca++ levels. The process is not mediated by redox-dependent mechanisms; rather, it strongly depends on PGE2 and ceramide. Interestingly, HNE induces significant increase of erythrocytes adhesion to endothelial cells (ECs) that are in turn dysfunctionated as evident by overexpression of ICAM-1. Conclusions: Our results unveil a new physiopathological role for HNE, provide mechanistic details of the HNE-induced eryptosis, and suggest a novel mechanism through which HNE could exert pro-inflammatory effects.

Study of haemolytic properties of a disk-type pump

<p><strong>Background.</strong> A shortage of donor organs is one of the urgent problems of transplantology. Despite the current level of technology, there are a number of difficult barriers to overcome. Because of the high demand for assisted circulatory devices, the work caused by the creation of the most physiological and biocompatible model of the apparatus, exceptional relevance is provided.</p><p><strong>Aim</strong>. To evaluate the haemolytic properties of the auxiliary circulatory apparatus based on a disk-type pump.</p><p><strong>Methods.</strong> A hydrodynamic bench was created to conduct haemolysis tests of a disk-type pump. The bench consisted of a tank, a heat exchanger, hydrodynamic resistance, connecting tubes, a blood sampling port, a pressure and flow measurement system, and a test pump. The test method consisted of assessing the level of free plasma haemoglobin (pHb) obtained by taking blood samples during pump operation in the operating mode (2300–2500 rpm, 5–6 l/min, pressure drop at the clamp level of 100 mmHg). Standardized haemolysis indices (NIH and MIH) were calculated based on the data obtained. The indices were calculated based on the analysis of free haemoglobin in the plasma of blood samples, haematocrit, total haemoglobin, blood flow, and pump operating time.</p><p><strong>Results.</strong> Bench tests (n = 5) revealed that the average level of free haemoglobin was 2.2 mg/%. This confirms the absolute atraumatic nature of the design of a new type of pump. The calculated values of the haemolysis indices were: NIH - 0.0013 and MIH - 1.88. This proves the fundamental possibility of using a disk-type pump as a basis for creating auxiliary circulatory devices.<br /><strong>Conclusion.</strong> The developed methodology for assessing the mechanical stability of red blood cells allows you to give objective information about one of the most important safety criteria for auxiliary circulatory devices i.e., the level of haemolysis. The results obtained revealed that it is possible and safe to use a disk-type pump as an auxiliary circulatory device.</p><p>Received 16 December 2019. Revised 10 March 2020. Accepted 13 March 2020.</p><p><strong>Funding:</strong> The research is supported by a grant of the Russian Science Foundation (project No. 19-19-00186).</p><p><strong>Conflict of interest:</strong> Authors declare no conflict of interest.</p><p><strong>Author contributions</strong> <br />Conception and study design: M.O. Zhulkov<br />Data collection and analysis: M.O. Zhulkov, A.S. Grenadyorov, A.M. Golovin, E.O. Golovina, A.V. Fomichev, S.A. Alsov<br />Drafting the article: M.O. Zhulkov, A.S. Grenadyorov <br />Critical revision of the article: M.O. Zhulkov, A.M. Chernyavskiy<br />Final approval of the version to be published: M.O. Zhulkov A.S. Grenadyorov, A.M. Golovin, E.O. Golovina, A.V. Fomichev, S.A. Alsov, A.M. Chernyavskiy</p>

Haptoglobin phenotypes and susceptibility of Schistosoma parasites infection in central Sudan

Haptoglobin (Hp) is an acute phase protein that binds the free haemoglobin (Hb), thus preventing iron loss and renal damage. Hp also has anti-oxidative and immunomodulatory properties. Three Hp phenotypes have been identified in human: Hp1-1, Hp2-1 and Hp2-2. Hp polymorphisms have been related to susceptibility of various diseases. In this study we aimed to assess the possible association of Hp phenotypes polymorphism to Schistosoma parasites infection in central Sudan. We have investigated the Hp phenotypes polymorphism distribution in the serum of 125 (93 S. mansonai, 13 S. haematobium and 19 infected with both ‘’co-infection’’) parasitologically confirmed infected individuals and 208 healthy individuals served as control. Hp phenotypes have been determined by polyacrylamide gel electrophoresis followed by benzidine staining. Our study revealed that Hp1-1 percentage frequency was significantly higher in infected individuals than healthy control individuals 51% and 26% respectively. Our data suggest that Hp1-1 phenotype may upsurge the susceptibility to Schistosoma parasites infection in central Sudan.

Haptoglobin and Free Haemoglobin during Cardiac Surgery—is there a Link to Acute Kidney Injury?

Acute kidney injury (AKI) is frequently observed after cardiac surgery (CS) with cardiopulmonary bypass (CPB). Multiple mechanisms underlie this phenomenon, including CPB-dependent haemolysis. Haemoglobin is released during haemolysis, and free haemoglobin (frHb) causes tubular cell injury after exceeding the binding capacity of haptoglobin (Hp). The objective of this study was to investigate the influence of perioperative changes in frHb and Hp levels on the incidence of CS-associated (CSA) AKI. After receiving local ethics committee approval and obtaining informed consent from our patients, we analysed the data pertaining to 154 patients undergoing CPB surgery. We recorded frHb and Hp concentrations pre-, intra- and postoperatively and defined AKI using the Kidney Disease Improving Global Outcomes (KDIGO) classification. We observed that frHb levels increased significantly during surgery and then decreased at ten hours thereafter and that Hp levels decreased during surgery and remained at low levels until the first postoperative day. We noted a moderate negative correlation between frHb and Hp levels. AKI was identified in 45.5% of patients; however, there was no significant difference in frHb or Hp levels between patients with and without AKI. We did not observe a relationship between frHb or Hp levels and CSA AKI and thus could not confirm the hypothesis that patients with higher baseline Hp concentrations experience a lower incidence of AKI than patients with lower baseline Hp concentrations.