A phase 1 study in healthy participants to characterize the safety and pharmacology of inclacumab, a fully human anti-P-selectin antibody, in development for treatment of sickle cell disease.

PURPOSE: We evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of intravenous (IV) inclacumab, a fully human IgG4 anti-P-selectin monoclonal antibody in development for the treatment of sickle cell disease, at doses up to and exceeding those previously tested in healthy individuals. METHODS: In this phase 1, open-label, single-ascending-dose study, 15 healthy participants were enrolled into cohorts receiving 20 mg/kg (n = 6) or 40 mg/kg (n = 9) IV inclacumab and observed for up to 29 weeks post-dose. Safety, PK parameters, thrombin receptor-activating peptide (TRAP)-activated platelet-leukocyte aggregate (PLA) formation, P-selectin inhibition, plasma soluble P-selectin, and anti-drug antibodies were characterized. RESULTS: Two inclacumab-related treatment-emergent adverse events were reported in 1 participant; no dose-limiting toxicities were observed. Plasma PK parameters were generally dose-proportional, with a terminal half-life of 13 to 17 days. Mean TRAP-activated PLA formation decreased within 3 h from the start of infusion, and inhibition was sustained for ~ 23 weeks. Mean P-selectin inhibition > 90% was observed up to 12 weeks post-dose. The mean ratio of free to total soluble P-selectin decreased rapidly from pre-dose to end of infusion, then increased gradually to 78% of the baseline ratio by week 29. Treatment-emergent anti-drug antibodies were observed in 2 of 15 participants (13%), without apparent impact on safety, PK, or PD. CONCLUSIONS: Inclacumab was well tolerated, with PK as expected for a monoclonal antibody against a membrane-bound target and a long duration of PD effects after both single IV doses, supporting a prolonged dosing interval. TRIAL REGISTRATION: ACTRN12620001156976; registered November 4, 2020.

Suboptimal vancomycin levels in critically ill children with sickle cell disease and acute chest syndrome.

OBJECTIVES: This is a pilot retrospective study to assess the effect of glomerular hyper-filtration (GHF) related to sickle cell disease (SCD) on vancomycin clearance and ultimately on therapeutic drug levels in children admitted to the pediatric intensive care unit (PICU) with acute chest syndrome (ACS). METHOD: The patients' steady-state vancomycin trough levels (VTL) and the area under the curve (AUC) were compared with those of age- and gender-matched control group; matching was made at a 1:3 ratio. RESULTS: Twelve SCD patients with ACS and treated with vancomycin were compared with 36 non-SCD patients (control group). Compared with the control patients, the ACS patients had significantly lower initial serum VTL (median = 6.00 mcg/mL vs. 9.75 mcg/mL) (p = 0.007), and their average VTL were still lower (median = 6.65 mcg/mL vs. 10.00 mcg/mL) post vancomycin dose adjustment (p = 0.039). The time to achieve the therapeutic vancomycin level was significantly longer for the ACS patients (median = 4.75 days) than for the control group (median = 1 day) (p = 0.009). The AUC was also significantly lower in the ACS patients (median = 293 mg*h/L) than in the control group (median = 405.5 mg*h/L) (p = 0.007). The AUC was negatively associated with creatinine clearance (Beta Coefficient = -0.366, p-value=<0.001) even when adjusted for receiving loading dose, standard dose per weight, and severity of critical illness. CONCLUSION: These findings support the attributed role of the GHF associated with SCD leading to lower vancomycin level in ACS cases. Therefore, the standard dosing approach for vancomycin in ACS patients may be ineffective. We thus advocate for individualized dosing with careful monitoring of drug levels to account for GHF.

Quail (Coturnix japonica) egg attenuated 2-butoxyethanol-induced enzymatic dysregulation, disseminated thrombosis and hemolytic impairment in female wistar rats.

Influence of quail egg on pathologies has increased research interests and series of investigations are currently being done on its influence against these pathologies. The influence of quail egg against 2-butoxyethanol induced hemolysis and disseminated thrombosis was investigated to determine the enzymatic regulations that ensue in the amelioration of deleterious hemolytic and disseminated thrombosis displayed in female Wistar rats. Quail egg was separated into three (3) components (extracts)-quail egg yolk water soluble (QYWS) and fat soluble (QYFS), and albumen extract (QA) and the inorganic and organic compositions were characterized. Depranocytotic assaults was achieved by 250 mg/kg of 2-Butoxyethanol administered for 4 days, the clinical observation revealed a dark purple-red discoloration on the distal tails of the rats and therapeutic applications followed with 1000 mg/kg BWT of QYWS, QYFS and QA, and 15 mg/kg BWT of hydroxyurea. Morphological evaluation, haematological estimations and biochemical evaluations of the influence on the activities of sphingosine kinase-1, RNase, red cell carbonic anhydrase, lactate dehydrogenase, glutathione peroxidase and caspase-3, vis a vis the concentrations of sphingosine-1 phosphate, selenium and zinc (plasma and urine). In vitro anti-inflammatory influence of quail egg components were investigated against hemolysis and key enzymes of inflammation-cycloxygenase, lipoxygenase and ß-glucuronidase. The in vitro anti-inflammatory effects of QYWS, QYFS and QA were concentration dependent from 200 to 800 µg/ml against hemolysis and the key enzymes of inflammation. The characterization of inorganic and organic bioactive composition of the yolk and albumen revealed the presence of folic acid, cobalamin, pyridine, riboflavin, ascorbic acid as well as vitamins D and E, selenium, zinc, iron and calcium. These had reflected in the attenuation of the induced hemolytic and disseminated thrombosis by regulations of enzymes linked to the infarction, apoptosis and oxidative stress characterized in sickle cell index.

Mouse Models of Pain in Sickle Cell Disease.

Sickle cell disease (SCD) is a genetic blood disorder that impacts millions of individuals worldwide. SCD is characterized by debilitating pain that can begin during infancy and may continue to increase throughout life. This pain can be both acute and chronic. A characteristic feature specific to acute pain in SCD occurs during vaso-occlusive crisis (VOC) due to the blockade of capillaries with sickle red blood cells. The acute pain of VOC is intense, unpredictable, and requires hospitalization. Chronic pain occurs in a significant population with SCD. Treatment options for sickle pain are limited and primarily involve the use of opioids. However, long-term opioid use is associated with numerous side effects. Thus, pain management in SCD remains a major challenge. Humanized transgenic mice expressing exclusively human sickle hemoglobin show features of pain and pathobiology similar to that in patients with SCD. Therefore, these mice offer the potential for investigating the mechanisms of pain in SCD and allow for development of novel targeted analgesic therapies. © 2018 by John Wiley & Sons, Inc.

Knowledge of and attitudes toward heel prick screening for sickle cell disease in Saint Lucia.

OBJECTIVES: In the Caribbean country of Saint Lucia, umbilical-cord-blood screening for sickle cell disease (SCD) was the testing method that health care workers (HCWs) on the maternity wards of the hospitals preferred until the new heel prick (HP) testing method was introduced in the country in 2014. This SCD study sought to assess HCWs' knowledge of and attitude toward HP screening and also determine new mothers' favorability toward HP screening. METHODS: A total of 70 HCWs and 132 new mothers answered survey questionnaires in three hospitals. In addition, four focus group discussions were held, two with HCWs and two with the mothers. RESULTS: Among the HCWs interviewed, 85.7% of them had knowledge of the HP test. However, only 25.7% had attended training sessions on the procedure. Among the HCWs, 64.3% of them felt the HP test should be mandatory, 27.1% said it should not be mandatory, and 8.6% did not know if it should be mandatory. In their focus groups, the HCWs said they believed the mothers would accept the HP method. For their part, 22.0% of the mothers said they had heard about the HP test, and 63.6% reported knowing the reason why the baby would be tested. Further, 83.3% indicated that the test would be beneficial for the baby. In addition, 88.6% of the mothers said that more information on the HP test was needed. In their focus group discussions, the mothers said they were generally not concerned about the pain the heel prick method might cause the baby. CONCLUSIONS: The HCWs' knowledge of the HP screening method was high. The mothers trust HCWs, and the mothers would accept the HP procedure irrespective of their knowledge of the test and any discomfort associated with this screening method.

Knowledge of and attitudes toward heel prick screening for sickle cell disease in Saint Lucia / Conocimiento y actitudes hacia la prueba del talón para la detección de la anemia de células falciformes en Santa Lucía / Conhecimento e atitudes em relação ao “teste do pezinho” para triagem de doença falciforme em Santa Lúcia

ABSTRACT Objectives In the Caribbean country of Saint Lucia, umbilical-cord-blood screening for sickle cell disease (SCD) was the testing method that health care workers (HCWs) on the maternity wards of the hospitals preferred until the new heel prick (HP) testing method was introduced in the country in 2014. This SCD study sought to assess HCWs’ knowledge of and attitude toward HP screening and also determine new mothers’ favorability toward HP screening. Methods A total of 70 HCWs and 132 new mothers answered survey questionnaires in three hospitals. In addition, four focus group discussions were held, two with HCWs and two with the mothers. Results Among the HCWs interviewed, 85.7% of them had knowledge of the HP test. However, only 25.7% had attended training sessions on the procedure. Among the HCWs, 64.3% of them felt the HP test should be mandatory, 27.1% said it should not be mandatory, and 8.6% did not know if it should be mandatory. In their focus groups, the HCWs said they believed the mothers would accept the HP method. For their part, 22.0% of the mothers said they had heard about the HP test, and 63.6% reported knowing the reason why the baby would be tested. Further, 83.3% indicated that the test would be beneficial for the baby. In addition, 88.6% of the mothers said that more information on the HP test was needed. In their focus group discussions, the mothers said they were generally not concerned about the pain the heel prick method might cause the baby. Conclusions The HCWs’ knowledge of the HP screening method was high. The mothers trust HCWs, and the mothers would accept the HP procedure irrespective of their knowledge of the test and any discomfort associated with this screening method.

RESUMEN Objetivo En el país caribeño de Santa Lucía, el hemocribado del cordón umbilical para la detección de la anemia de células falciformes o drepanocitosis era el método de tamizaje preferido por el personal de salud en las salas de maternidad de los hospitales hasta que se introdujo la nueva prueba del talón en el 2014. Este estudio sobre la anemia de células falciformes tuvo por objetivo evaluar el conocimiento y las actitudes del personal de salud hacia la prueba del talón, así como determinar si las madres tenían una actitud favorable hacia este método de tamizaje. Método Un total de 70 trabajadores de salud y 132 madres participaron en los cuestionarios realizados en tres hospitales. Además, se celebraron cuatro grupos de debate: dos con el personal de salud y dos con las madres. Resultados Del personal de salud entrevistado, 85,7% tenía conocimientos acerca de la prueba del talón. Sin embargo, únicamente 25,7% había asistido a sesiones de capacitación sobre el procedimiento. Además, 64,3% del personal de salud opinaba que la prueba debía ser obligatoria, 27,1% afirmaba que no debía ser obligatoria y 8,6% manifestó que no lo sabía. En los grupos de debate, el personal de salud manifestó su creencia de que las madres aceptarían este método de tamizaje. Por su parte, 22,0% de las madres afirmaron conocer la prueba del talón y 63,6% manifestó conocer los motivos por los que se sometería al bebé a dicha prueba. Asimismo, 83,3% de las madres señaló que la prueba sería beneficiosa para el bebé. Además, 88,6% de las madres indicó que era necesaria más información sobre la prueba del talón. En sus grupos de debate, las madres expresaron que, por lo general, no les preocupaba el dolor que pudiese suponer para el bebé la prueba del pinchazo en el talón. Conclusiones El personal de salud tiene un nivel alto de conocimiento acerca de la prueba del talón. Las madres confían en el personal de salud, y aceptarían este procedimiento independientemente de sus conocimientos sobre la prueba y cualquier malestar asociado a este método de tamizaje.

RESUMO Objetivos No país caribenho de Santa Lúcia, o exame de sangue de cordão umbilical para detecção da doença falciforme (DF) era o método de triagem preferido pelos profissionais da saúde atuantes em maternidades, até a introdução do “teste do pezinho” (TP) no país em 2014. Este estudo sobre DF buscou avaliar o conhecimento e atitudes de profissionais da saúde em relação à triagem pelo TP e também determinar a favorabilidade das novas mães em direção à triagem de TP. Métodos Setenta profissionais da saúde e 132 novas mães responderam a questionários de pesquisa em três hospitais. Além disso, foram realizadas quatro discussões com grupos focais: dois de profissionais da saúde e dois de mães. Resultados Entre os profissionais da saúde entrevistados, 85,7% tinham conhecimento acerca do TP. Porém, somente 25,7% haviam comparecido às sessões de capacitação sobre o procedimento. Entre os profissionais da saúde, 64,3% opinaram que o TP deveria ser obrigatório, 27,1% disseram que não deveria ser obrigatório e 8,6% não sabiam se deveria ser obrigatório. Em seus grupos focais, os profissionais da saúde disseram acreditar que as mães aceitariam o método do TP. Por sua vez, 22,0% das mães disseram ter ouvido falar sobre o TP, e 63,6% relataram saber o motivo pelo qual o exame seria realizado; ademais, 83,3% indicaram que o exame seria benéfico para o bebê. Além disso, 88,6% das mães disseram que precisavam de maiores informações sobre o TP. Em seus grupos focais, as mães disseram que, em geral, não estavam preocupadas com dor que o teste do pezinho poderia causar ao bebê. Conclusões Os profissionais da saúde apresentaram alto nível de conhecimento acerca do método de triagem pelo TP. As mães confiam nos profissionais da saúde, e aceitariam o procedimento de TP independentemente de seu conhecimento acerca do teste e de qualquer desconforto associado a este método de triagem.

Adverse events in cancer patients with sickle cell trait or disease: case reports.

PURPOSE: Given the relatively high prevalence of sickle cell trait and disease among African Americans and established racial disparities in cancer outcomes, we reviewed the literature regarding adverse events in cancer patients with these hematologic genotypes. Erythrocyte sickling can result from extreme hypoxia and other physiologic stressors, as might occur during cancer therapy. Further, tumoral hypoxia, a poor prognostic and predictive factor, could lead to a cycle of local sickling and increased hypoxia. METHODS: A search of PubMed produced 150 publications, most of which were excluded because of incidental relevance. Eleven case reports of patients diagnosed from 1993 to 2013 were reviewed. RESULTS: Two reports of patients with sickle cell trait describe an abundance of sickled erythrocytes within tumors, and a third report describes sickling-related events requiring multiday hospitalization. Eight reports of patients with sickle cell disease delineated multiorgan failure, vaso-occlusive crises, and rapid renal deterioration. Hypothesized triggers are delayed clearance of anticancer agents attributable to baseline kidney damage, activation of vasoadherent neutrophils from treatment to counter chemotherapy-induced neutropenia, hypoxia from general anesthesia, and intratumoral hypoxia. CONCLUSION: Clinical implications include pretreatment genotyping for prophylaxis, dose adjustment, and enhanced patient monitoring. With the current lack of high-quality evidence, however, the scope of poor outcomes remains unknown.

Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice.

Inhibition of leukocyte adhesion to the vascular endothelium represents a novel and important approach for decreasing sickle cell disease (SCD) vaso-occlusion. Using a humanized SCD-mouse-model of tumor necrosis factor-α-induced acute vaso-occlusion, we herein present data demonstrating that short-term administration of either hydroxyurea or the phosphodiesterase 9 (PDE9) inhibitor, BAY73-6691, significantly altered leukocyte recruitment to the microvasculature. Notably, the administration of both agents led to marked improvements in leukocyte rolling and adhesion and decreased heterotypic red blood cell-leukocyte interactions, coupled with prolonged animal survival. Mechanistically, these rheologic benefits were associated with decreased endothelial adhesion molecule expression, as well as diminished leukocyte Mac-1-integrin activation and cyclic guanosine monophosphate (cGMP)-signaling, leading to reduced leukocyte recruitment. Our findings indicate that hydroxyurea has immediate beneficial effects on the microvasculature in acute sickle-cell crises that are independent of the drug's fetal hemoglobin-elevating properties and probably involve the formation of intravascular nitric oxide. In addition, inhibition of PDE9, an enzyme highly expressed in hematopoietic cells, amplified the cGMP-elevating effects of hydroxyurea and may represent a promising and more tissue-specific adjuvant therapy for this disease.

Possible links between sickle cell crisis and pentavalent antimony.

For over 60 years, pentavalent antimony (Sb(v)) has been the first-line treatment of leishmaniasis. Sickle cell anemia is a disease caused by a defect in red blood cells, which among other things can cause vasooclusive crisis. We report the case of a 6-year-old child with leishmaniasis who during treatment with meglumine antimoniate developed a sickle cell crisis (SCC). No previous reports describing the relationship between antimonial drugs and sickle cell disease were found. Reviews of both the pathophysiology of SCC and the mechanism of action of Sb(v) revealed that a common pathway (glutathione) may have resulted in the SCC. ChemoText, a novel database created to predict chemical-protein-disease interactions, was used to perform a more expansive and systematic review that was able to support the association between glutathione, Sb(v), and SCC. Although suggestive evidence to support the hypothesis, additional research at the bench would be needed to prove Sb(v) caused the SCC.

The Gardos channel is responsible for CDNB-induced dense sickle cell formation.

The red blood cells (RBCs) derived from blood taken from homozygous sickle cell (SS) patients demonstrate densities that are inversely proportional to the intracellular reduced glutathione (GSH) content. Addition of 1 mM 1-chloro-2,4-dinitrobenzene (CDNB) to low-density sickle cells (LDSS), at 4 degrees C, results in a shift of LDSS erythrocytes to high-density sickle cells (HDSS), with corresponding decreases in GSH. We have previously demonstrated that this CDNB effect was due to increased K(+) leakage and that dense cell formation could be inhibited by clotrimazole (specific for the Gardos channel) but not DIOA (specific for the K(+)-Cl(-) co-transport system) at pH 7.4 (Shartava et al. Am. J. Hematol. 1999;62:19-24). Here we demonstrate that clotrimazole (10 microM) inhibits dense cell formation at pH 7.1 and 6.8, while DIOA (1 mM) has no effect. As pH 6.8 is the optimal pH for the K(+)-Cl(-) co-transport system, we can now reasonably conclude that damage to the Gardos channel is responsible for CDNB-induced dense cell formation.

Sickle cell crisis following intraarticular steroid therapy for rheumatoid arthritis.

We describe 2 patients who had coexistent rheumatoid arthritis and sickle cell disease. Both patients developed sickle cell crises following intraarticular injection of corticosteroids to control their arthritis. The mechanism of this phenomenon is not clear, but it is suggested that intraarticular steroids be used with caution in patients with sickle cell disease.