scholarly journals GBT440 reverses sickling of sickled red blood cells under hypoxic conditions in vitro

2018 ◽  
Vol 10 (2) ◽  
Author(s):  
Kobina Dufu ◽  
Donna Oksenberg
Keyword(s):  
Sickle Cell Disease ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Blood Cells ◽  
Oxygen Affinity ◽  
Microvascular Blood Flow ◽  
Cell Disease ◽  
Hypoxic Conditions

Sickle cell disease is characterized by hemolytic anemia, vasoocclusion and early mortality. Polymerization of hemoglobin S followed by red blood cell sickling and subsequent vascular injury are key events in the pathogenesis of sickle cell disease. Sickled red blood cells are major contributors to the abnormal blood rheology, poor microvascular blood flow and endothelial injury in sickle cell disease. Therefore, an agent that can prevent and or reverse sickling of red blood cells, may provide therapeutic benefit for the treatment of sickle cell disease. We report here that GBT440, an anti-polymerization agent being developed for the chronic treatment of sickle cell disease, increases hemoglobin oxygen affinity and reverses in vitro sickling of previously sickled red blood cells under hypoxic conditions. Our results suggest that besides preventing sickling of red blood cells, GBT440 may mitigate vasoocclusion and microvascular dysfunction by reversing sickling of circulating sickled red blood cells in vivo.

IHP-Loaded Red Blood Cells as Preventive Therapy In Sickle Cell Disease

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1625-1625
Author(s):  
Vanessa Bourgeaux ◽  
Yannick Campion ◽  
Emeline Aufradet ◽  
Cyril Martin ◽  
Yann Godfrin
Keyword(s):  
Sickle Cell Disease ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Blood Cells ◽  
Cell Disease ◽  
Transfusion Therapy ◽  
Platelet Counts ◽  
Hypoxic Conditions ◽  
Hypotonic Lysis

Abstract Abstract 1625 Sickle cell disease (SCD) is a genetic disorder characterized by abnormal hemoglobin S (HbS) that polymerizes under hypoxic conditions leading to sickled-shape red blood cells (RBCs). Vaso-occlusive crisis (VOC) is one of the major clinical manifestations of the disease, very painful for patients and causing irreversible organ damages. RBC exchange is commonly used as preventive and curative treatment of the disease. However, the therapeutic action of RBC exchange only relies on the removal of HbS-containing RBCs (SS-RBCs) and their transient replacement by normal RBCs (AA-RBCs). Recent works have shown that sickled reticulocytes, activated platelets and leukocytes play a critical role in the onset of VOC. They aggregate with endothelial cells creating local hypoxia, enhancing sickling and thus capillary blockade. Oxygen deprivation that occurs in venous capillaries may widely contribute to the severity of the occlusion. Therefore, increasing the oxygenation level in capillaries could help to prevent SS-RBCs from sickling and avoid crisis. This may be possible by transfusing patients with AA-RBCs loaded with Inositol HexaPhosphate (IHP), an allosteric effector that binds tightly to hemoglobin. The resulting suspension (IHP-RBCs) has the ability to increase oxygen release by 2 to 3 fold compared to normal AA-RBCs. The objective of the present study was to evaluate in vivo the benefit of using IHP-RBCs treatment in SCD. We used BERK transgenic mouse model that fully mimics human SCD in childhood with specific features of splenomegaly, reticulocytosis and leukocytosis. IHP-RBCs were prepared by loading IHP into murine C57BL6J RBCs using reversible hypotonic lysis method. RBCs subjected to reversible hypotonic lysis but without IHP were used as control suspension. Study was designed with repeated RBC exchanges scheduled every 2 weeks. First RBC exchange using IHP-RBCs or control suspension was performed on 6–7 week-old mice followed by 2 further injections. Mice were sacrificed one week after last RBC exchange and critical hematological parameters (reticulocyte, leukocyte, platelet counts and sickled cells) as well as serum inflammation markers were used as readouts to evaluate the risk of VOC. The first study was performed in normoxic conditions. After the therapy, approximately 42% of mouse RBCs had been replaced by IHP-RBCs or control suspension. Strong reduction of spleen weight (50%) and circulating sickled RBCs was observed in both cases due to the dilution of SS-RBCs. Interestingly, IHP-RBCs treatment enabled to significantly lower reticulocytes (18% vs 31%), leukocytes (5.3 vs 8.4 103/μl) and platelet counts (1057 vs 1518 103/μl) compared to not treated mice. Additionally, Serum Amyeloid Protein (SAP), an inflammation marker analogous of human C-Reactive Protein was also significantly reduced with IHP-RBCs (450 vs 750 μg/ml) indicating lowered severity of inflammation. The analysis of VCAM and HIF-1 factors in both spleen and lungs were very low in both treated and not treated mice. Further experiments demonstrated that hypoxic stress is needed to induce significative inflammation at the organ level. The study will thus be repeated in hypoxic conditions to evaluate the effect of IHP-RBCs treatment on organ damaging. We had in a previous study demonstrated in vitro the ability of IHP-RBCs to reduce sickling of human SS-RBCs (Bourgeaux et al, Transfusion, in press). The present in vivo study brings new evidence of the therapeutic potential of IHP-RBCs with the observation of a significant reduction of VOC risk factors and SAP level in treated mice. These results strongly support the fact that loading IHP into AA-RBCs may improve the effectiveness of conventional transfusion therapy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Reconstruction of Sickle Cell Disease with Circulating Sickling Red Blood Cells in Novel Humanized Cytokines and Liver Mistrg Mice

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-30
Author(s):  
Yuanbin Song ◽  
Rana Gbyli ◽  
Liang Shan ◽  
Wei Liu ◽  
Yimeng Gao ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Mouse Model ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Blood Cells ◽  
Red Cell ◽  
Cell Disease ◽  
Ineffective Erythropoiesis ◽  
Cd34 Cells

In vivo models of human erythropoiesis with generation of circulating mature human red blood cells (huRBC) have remained elusive, limiting studies of primary human red cell disorders. In our prior study, we have generated the first combined cytokine-liver humanized immunodeficient mouse model (huHepMISTRG-Fah) with fully mature, circulating huRBC when engrafted with human CD34+ hematopoietic stem and progenitor cells (HSPCs)1. Here we present for the first time a humanized mouse model of human sickle cell disease (SCD) which replicates the hallmark pathophysiologic finding of vaso-occlusion in mice engrafted with primary patient-derived SCD HSPCs. SCD is an inherited blood disorder caused by a single point mutation in the beta-globin gene. Murine models of SCD exclusively express human globins in mouse red blood cells in the background of murine globin knockouts2 which exclusively contain murine erythropoiesis and red cells and thus fail to capture the heterogeneity encountered in patients. To determine whether enhanced erythropoiesis and most importantly circulating huRBC in engrafted huHepMISTRG-Fah mice would be sufficient to replicate the pathophysiology of SCD, we engrafted it with adult SCD BM CD34+ cells as well as age-matched control BM CD34+ cells. Overall huCD45+ and erythroid engraftment in BM (Fig. a, b) and PB (Fig. c, d) were similar between control or SCD. Using multispectral imaging flow cytometry, we observed sickling huRBCs (7-11 sickling huRBCs/ 100 huRBCs) in the PB of SCD (Fig. e) but not in control CD34+ (Fig. f) engrafted mice. To determine whether circulating huRBC would result in vaso-occlusion and associated findings in SCD engrafted huHepMISTRG-Fah mice, we evaluated histological sections of lung, liver, spleen, and kidney from control and SCD CD34+ engrafted mice. SCD CD34+ engrafted mice lungs showed an increase in alveolar macrophages (arrowheads) associated with alveolar hemorrhage and thrombosis (arrows) but not observed control engrafted mice (Fig. g). Spleens of SCD engrafted mice showed erythroid precursor expansion, sickled erythrocytes in the sinusoids (arrowheads), and vascular occlusion and thrombosis (arrows) (Fig. h). Liver architecture was disrupted in SCD engrafted mice with RBCs in sinusoids and microvascular thromboses (Fig. i). Congestion of capillary loops and peritubular capillaries and glomeruli engorged with sickled RBCs was evident in kidneys (Fig. j) of SCD but not control CD34+ engrafted mice. SCD is characterized by ineffective erythropoiesis due to structural abnormalities in erythroid precursors3. As a functional structural unit, erythroblastic islands (EBIs) represent a specialized niche for erythropoiesis, where a central macrophage is surrounded by developing erythroblasts of varying differentiation states4. In our study, both SCD (Fig. k) and control (Fig. l) CD34+ engrafted mice exhibited EBIs with huCD169+ huCD14+ central macrophages surrounded by varying stages of huCD235a+ erythroid progenitors, including enucleated huRBCs (arrows). This implies that huHepMISTRG-Fah mice have the capability to generate human EBIs in vivo and thus represent a valuable tool to not only study the effects of mature RBC but also to elucidate mechanisms of ineffective erythropoiesis in SCD and other red cell disorders. In conclusion, we successfully engrafted adult SCD patient BM derived CD34+ cells in huHepMISTRG-Fah mice and detected circulating, sickling huRBCs in the mouse PB. We observed pathological changes in the lung, spleen, liver and kidney, which are comparable to what is seen in the established SCD mouse models and in patients. In addition, huHepMISTRG-Fah mice offer the opportunity to study the role of the central macrophage in human erythropoiesis in health and disease in an immunologically advantageous context. This novel mouse model could therefore serve to open novel avenues for therapeutic advances in SCD. Reference 1. Song Y, Shan L, Gybli R, et. al. In Vivo reconstruction of Human Erythropoiesis with Circulating Mature Human RBCs in Humanized Liver Mistrg Mice. Blood. 2019;134:338. 2. Ryan TM, Ciavatta DJ, Townes TM. Knockout-transgenic mouse model of sickle cell disease. Science. 1997;278(5339):873-876. 3. Blouin MJ, De Paepe ME, Trudel M. Altered hematopoiesis in murine sickle cell disease. Blood. 1999;94(4):1451-1459. 4. Manwani D, Bieker JJ. The erythroblastic island. Curr Top Dev Biol. 2008;82:23-53. Disclosures Xu: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Flavell:Zai labs: Consultancy; GSK: Consultancy.

HENNA (Lawsonia inermis) A MEDICINAL HERB EFFECTIVE IN SICKLE CELL DISEASE

2021 ◽  
pp. 01-04
Author(s):  
KRISHNA KUMAR ◽  
Nitish Kumar ◽  
Amresh gupta ◽  
Arpita singh ◽  
Pandey Swarnima ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Blood Cells ◽  
Oxygen Affinity ◽  
Common Disease ◽  
Cell Disease ◽  
Lawsonia Inermis ◽  
Sodium Bisulphite ◽  
Sickle Cells

Sickle cell anemia is a common disease in Oman country. In this disease, sickle-shaped cells are formed. These cells interrupt blood vessels and cause a reduction in oxygen transportation. It was founded that henna (Lawsonia inermis) can prohibit the formation of sickle cells. The Lawsone (2-Hydroxy-1,4-Naphthoquinone) is the constituents of henna which is responsible for the anti-sickling activity, by increasing the oxygen affinity of red blood cells. Hena has the anti-sickling activity which is proved by incubating aqueous and methanolic henna extracts with sickle cell disease patient's whole blood. Then for reduction to oxygen tension 2%, sodium bisulphite was added. Therefore, the percentage of sickled cells to normal red blood cells was observed at 30 minutes intervals. Henna proved a delay in the sickling process in 84% of the tested samples. Both extracts(aqueous and methanolic henna) can delay sickling for about an hour.

scholarly journals Sickle cell disease of transgenic SAD mice

Blood ◽  
1994 ◽  
Vol 84 (9) ◽  
pp. 3189-3197 ◽  
Author(s):  
M Trudel ◽  
ME De Paepe ◽  
N Chretien ◽  
N Saadane ◽  
J Jacmain ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Acute Hypoxia ◽  
Oxygen Affinity ◽  
Premature Death ◽  
Cellular Level ◽  
Cell Disease ◽  
Severe Renal Disease

Erythrocyte sickling on deoxygenation in vitro occurs in transgenic SAD mice, hemizygous for a modified human sickle hemoglobin, HbSAD [alpha 2 beta 2S(beta 6val)Antilles (beta 23 lle)D- Punjab (beta 121Gln)] (SAD- 1, 19% HbSAD; beta-thal/SAD-1, 26% HbSAD). The present study examines the cellular defects in vivo and pathologic changes observed in SAD-1 mice at atmospheric oxygenation as well as the effect of acute hypoxia. The transgenic mice showed generalized congestion and microvascular occlusions, occasionally with thrombosis and infarctions of lung, kidneys, penis, and myocardium. The most prevalent chronic organ lesions were congestive splenomegaly (83% of animals) and renal glomerulopathy, which affected 75% of animals by 10 months of age. Further, SAD mice have a mean lifespan that was reduced by 40% when compared with nontransgenic littermates. Premature death of SAD mice was associated with acute vasoocclusive events or severe renal disease. SAD mice developed lethal vasoocclusive processes when exposed to reduced pO2 conditions, whereas control mice survived normally. The sensitivity to hypoxia appears to depend on the cellular level of HbSAD, because death occurred at pO2 of 42 mmHg for SAD mice and 49 mmHg for beta-thal/SAD. Administration of an antisickling agent that increases oxygen affinity (BW12C79) protected SAD and beta-thal/SAD mice from the lethal hypoxic stress. In conclusion, the transgenic SAD and beta-thal/SAD mice developed a pathophysiology that strongly resembles human sickle cell disease. Moreover, this animal model allows studies on the effect of antisickling agents.

scholarly journals Rheological Effects of L-Glutamine in Patients with Sickle Cell Disease

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3567-3567
Author(s):  
Celeste K. Kanne ◽  
Varun Reddy ◽  
Vivien A. Sheehan
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Blood Viscosity ◽  
Whole Blood ◽  
Blood Cells ◽  
Cell Disease ◽  
Phase 3 ◽  
Whole Blood Viscosity

Background: ENDARITM (oral pharmaceutical L-glutamine powder) received FDA approval in 2017 as a treatment for sickle cell disease (SCD). A pivotal phase 3 clinical study conducted by Emmaus Medical, Inc. showed that L-glutamine resulted in a lower incidence of vaso-occlusive crises (VOC) as well as a lower rate of hospitalizations and shorter hospital stays. No changes in standard clinical laboratory values were noted. The clinical improvements associated with sickle cell complications are believed to be due to an increase in the proportion of the reduced form of nicotinamide adenine dinucleotides in the red blood cells (RBC) of patients with SCD, reducing the oxidative stress. While the endpoints in the phase 3 study are clinically important, it is essential that we identify biomarkers or measurable laboratory changes that can serve as endpoints for future clinical trials assessing dose optimization and the efficacy and safety of L-glutamine in SCD individuals, including those with hepatic and renal dysfunction. RBC rheology is markedly abnormal in SCD; blood is more viscous for a given hematocrit than normal individuals, dense red blood cells (DRBC) are packed with HbS, potentiating sickling, and RBCs are less deformable than those of HbAA or HbAS individuals. High whole blood viscosity, high DRBCs, and poor RBC deformability are associated with higher rates of VOC. Given the demonstrated reduction in pain events, we hypothesized that L-glutamine might improve RBC rheology and sought to test this in vitro and in vivo using a battery of rheological tests. Methods: For the in vitro study, 6 mL of whole blood was drawn into an EDTA vacutainer from ten pediatric patients with sickle cell anemia (HbSS or HbSβ0) during routine clinical checkups under an IRB approved protocol. The cohort included 3 female and 7 male patients, ages 2-19 years old. All patients were on a steady dose of hydroxyurea and did not receive a transfusion within the 3 months prior to sample collection. A 200 mM stock solution of L-glutamine and water was mixed and filtered under light-protected conditions. Aliquots were stored at -20°C to avoid multiple freeze/thaw cycles. L-glutamine was added to 3 mL of whole blood for a final concentration of 1 mM (average in vivo L-glutamine plasma concentration in patients with SCD treated with L-glutamine); 3 mL of the same patient sample with water added served as a control. After a 24-hour incubation period at 4°C, whole blood viscosity was measured using a cone and plate viscometer at 37°C (DV3T Rheometer, AMETEK Brookfield, USA), %DRBCs were measured on an ADVIA 120 Hematology System (Siemens Healthcare Diagnostics, Inc., USA), and deformability measured using a Laser Optical Rotational Red Cell Analyzer (Lorrca®) (RR Mechatronics, the Netherlands) with the Oxygenscan module. The Oxygenscan measures RBC deformability at normoxia (Elmax), deformability upon deoxygenation (EImin), and point of sickling (PoS), the oxygen tension at which deformability begins to decline, reflecting the patient-specific pO2 at which sickling begins. Paired samples (with and without added L-glutamine) were analyzed using Student's t-test. For the in vivo study, rheological tests were performed on peripheral blood from one patient (18-year-old male on hydroxyurea) at baseline and treated with L-glutamine as part of his routine clinical care. Results and conclusions: Addition of L-glutamine in vitro significantly reduced the PoS, meaning RBCs incubated with L-glutamine could tolerate a lower pO2 before sickling compared to the control. RBCs incubated with L-glutamine also had significantly higher EImin, meaning deoxygenated RBCs were more flexible and deformable. Whole blood viscosity at 45s-1 and 225s-1 did not change significantly following incubation with L-glutamine; %DRBCs also did not change significantly (Table 1). The in vivo patient sample tested exhibited a similar improvement in PoS and EImin (Figure 1). We therefore propose to further test the performance of the PoS and EImin as possible biomarkers of response to L-glutamine in vivo. If validated, these biomarkers may also help further elucidate the mechanisms of action of L-glutamine in SCD. Disclosures No relevant conflicts of interest to declare.

scholarly journals In vitro investigation of the antisickling properties of aqueous fruits extracts of Citrus paradisi, Musa acuminata and Malus domestica

2020 ◽  
Vol 13 (3) ◽  
pp. 203-209
Author(s):  
Augustine O. Odibo ◽  
Ifunanya R. Akaniro ◽  
Emmanuel M. Ubah
Keyword(s):  
Sickle Cell Disease ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Malus Domestica ◽  
Blood Cells ◽  
Musa Acuminata ◽  
Citrus Paradisi ◽  
Cell Disease ◽  
In Vitro Investigation

Sickle cell disease (SCD) is a genetic blood disorder that affects the shape and transportation of red blood cells (RBCs) in blood vessels, leading to various clinical complications. Many drugs that are available for treating the disease are insufficiently effective, toxic, or too expensive. Therefore, there is a pressing need for safe, effective, and inexpensive therapeutic agents from indigenous plants used in ethnomedicine. In the current study, the potentials of aqueous extracts of Citrus paradisi, Musa acuminata, Malusdomestica fruit in sickle cell disease management were investigated in vitro using P-hydroxybenzoic acid and normal saline as positive and negative control respectively. The method employed the inhibition of sodium metabisulphite induced sickling of HbSS red blood cells, collected from confirmed sickle cell patients. Results obtained showed that; 50 mg/ml aqueous extract of Musa acuminata showed the lowest sickling inhibition (80.3%) at 60 minutes while 1 mg/ml gave the highest inhibition of 97.3% at 90 minutes. For Citrus paradisi, lowest (83.3%) and highest (98%) sickling inhibitions were obtained with 25 mg/ml and 50 mg/ml fruit extracts at 30 minutes and 60 minutes respectively. Malus domestica had the highest antisickling activities of 99% and 99.33% respectively at 30 and 60 minutes. In all, the sickling inhibition was least with Musa acuminata but highest with Malus domestica. Also, highest inhibitions were observed at 60 minutes (optimum time) and 10 mg/ml (optimum concentration). This study has demonstrated that; Malus domestica, Citrus paradisi and Musa acuminata possess antisickling potentials useful in the management or therapy of sickle cell diseases.

scholarly journals Hypoxia Enhanced Red Cell Adhesion in Vitro May Identify Patients at Risk for Vasculopathy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3672-3672
Author(s):  
Charlotte Yuan ◽  
Erina Quinn ◽  
Sargam Kapoor ◽  
Myeongseop Kim ◽  
Erdem Kucukal ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Research Funding ◽  
Cell Disease ◽  
Hypoxic Conditions ◽  
Significant Difference ◽  
History Of ◽  
Male Subjects

Abstract Background: Priapism is a serious complication associated with Sickle Cell Disease (SCD) that may be a manifestation of underlying vasculopathy. The Centers for the Study of Complex Diseases of Childhood (CSCCD), comprising independent Comprehensive Sickle Cell Centers, demonstrated an association of priapism with hemolysis.1 Previously, we identified two groups of people with SCD based on red blood cell (RBC) adhesion under hypoxic conditions: those patients whose RBCs showed hypoxia-enhanced adhesion (HEA) and those whose did not (non-HEA).2 Patients with HEA had evidence for more hemolysis in vivo. Here, we aimed to examine (1) the association of HEA with hypoxia in vivo, and (2) RBC adhesion in normoxic and hypoxic conditions in male patients with or without a history of priapism. Methods: This retrospective study was conducted at the Adult Sickle Cell Disease Clinic at the University Hospitals Seidman Cancer Center, in Cleveland, OH between 2015 to 2018. Blood samples were obtained from 26 male subjects (29 samples, 25 HbSS and 1 HbSS HPFH). Adhesion experiments were performed as previously reported by passing surplus whole blood through LN-immobilized microchannels at physiological conditions under both normoxic and hypoxic conditions.2,3 Adherent RBCs were then quantified with microscope after a wash step. The median value was used for data analyses from multiple samples obtained from an individual. Chart review was conducted to examine results of hypoxia testing obtained in vivo as part of routine clinical care. Results: Male subjects with HbSS and a history of priapism had higher HEA in comparison to subjects without a history of priapism (3268 ± 5647 vs. 122 ± 1218, p=0.016). However, there was no significant difference between RBC adhesion of the two groups under normoxic conditions (529 ± 1528 vs. 402 ± 280). More male subjects with priapism had hypoxia in vivo (10 out of 14) than subjects without priapism (5 out of 12). Compared to male subjects with a history of priapism, those without a history of priapism had lower lactate dehydrogenase levels (474 ± 267 vs. 290 ± 215, p=0.008). Conclusions: Our data showed that subjects with a history of priapism had a higher HEA and tended to have more evidence for hypoxia in vivo than did subjects without a history of priapism. Further, male subjects with hypoxia in vivo had more HEA than did those without hypoxia in vivo (not shown). Hypoxia in vivo may cause increased RBC damage (reflected by HEA), hemolysis, nitric oxide depletion, and consequent vasculopathy, resulting in priapism. Hypoxia may be treatable, when identified in subjects with a history priapism in vivo or possibly with HEA in vitro. This could plausibly modify disease severity in some cases. References: Nolan VG, Wyszynski DF, Farrer LA, Steinberg MH. Blood. 20015 Nov;106(9):3264-7. doi: 10.1182/blood-2005-04-1594 Kim M, Alapan Y, Adhikari A, Little JA, Gurkan Microcirculation. 2017 Jul;24(5). doi: 10.1111/micc.12374. Alapan Y, Kim C, Adhikari A, Gray KE, Gurkan-Cavusoglu E, Little JA, Gurkan Transl Res. 2016 Jul;173:74-91.e8. doi: 10.1016/j.trsl.2016.03.008. Epub 2016 Mar 19. Disclosures Little: NHLBI: Research Funding; PCORI: Research Funding; Hemex: Patents & Royalties: Patent, no honoraria; Doris Duke Charitable Foundations: Research Funding.

scholarly journals Vaso-Occlusion in Sickle Cell Disease: Is Autonomic Dysregulation of the Microvasculature the Trigger?

2019 ◽  
Vol 8 (10) ◽  
pp. 1690 ◽  
Author(s):  
Saranya Veluswamy ◽  
Payal Shah ◽  
Christopher Denton ◽  
Patjanaporn Chalacheva ◽  
Michael Khoo ◽  
...  
Keyword(s):  
Blood Flow ◽  
Sickle Cell Disease ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Blood Cells ◽  
Critical Role ◽  
Microvascular Blood Flow ◽  
Cell Disease ◽  
Hemoglobin S

Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by polymerization of hemoglobin S upon deoxygenation that results in the formation of rigid sickled-shaped red blood cells that can occlude the microvasculature, which leads to sudden onsets of pain. The severity of vaso-occlusive crises (VOC) is quite variable among patients, which is not fully explained by their genetic and biological profiles. The mechanism that initiates the transition from steady state to VOC remains unknown, as is the role of clinically reported triggers such as stress, cold and pain. The rate of hemoglobin S polymerization after deoxygenation is an important determinant of vaso-occlusion. Similarly, the microvascular blood flow rate plays a critical role as fast-moving red blood cells are better able to escape the microvasculature before polymerization of deoxy-hemoglobin S causes the red cells to become rigid and lodge in small vessels. The role of the autonomic nervous system (ANS) activity in VOC initiation and propagation has been underestimated considering that the ANS is the major regulator of microvascular blood flow and that most triggers of VOC can alter the autonomic balance. Here, we will briefly review the evidence supporting the presence of ANS dysfunction in SCD, its implications in the onset of VOC, and how differences in autonomic vasoreactivity might potentially contribute to variability in VOC severity.

scholarly journals Improving the Solubility and Oral Bioavailability of a Novel Aromatic Aldehyde Antisickling Agent (PP10) for the Treatment of Sickle Cell Disease

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1148
Author(s):  
Tarek A. Ahmed ◽  
Khalid M. El-Say ◽  
Fathy I. Abd-Allah ◽  
Abdelsattar M. Omar ◽  
Moustafa E. El-Araby ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Binary System ◽  
Aromatic Aldehyde ◽  
Sickle Cell ◽  
Oxygen Affinity ◽  
Oral Drug ◽  
Cell Disease ◽  
Sprague Dawley

Background: Aromatic aldehydes, with their ability to increase the oxygen affinity of sickle hemoglobin, have become important therapeutic agents for sickle cell disease (SCD). One such compound, voxelotor, was recently approved for SCD treatment. Methyl 6-((2-formyl-3-hydroxyphenoxy)methyl) picolinate (PP10) is another promising aromatic aldehyde, recently reported by our group. Like voxelotor, PP10 exhibits O2-dependent antisickling activity, but, unlike voxelotor, PP10 shows unique O2-independent antisickling effect. PP10, however, has limited solubility. This study therefore aimed to develop oral and parenteral formulations to improve PP10 solubility and bioavailability. Methods: Oral drug tablets with 2-hydroxypropyl beta cyclodextrin (HP-β-CD), polyvinylpyrrolidone, or Eudragit L100-55 PP10-binary system, and an intravenous (IV) formulation with d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) or HP-β-CD, were developed. The pharmacokinetic behavior of the formulations was studied in Sprague-Dawley rats. PP10, a methylester, and its acid metabolite were also studied in vitro with sickle whole blood to determine their effect on Hb modification, Hb oxygen affinity, and sickle red blood cell inhibition. Results: Aqueous solubility of PP10 was enhanced ~5 times with the HP-β-CD binary system, while the TPGS aqueous micelle formulation was superior, with a drug concentration of 0.502 ± 0.01 mg/mL and a particle size of 26 ± 3 nm. The oral tablets showed relative and absolute bioavailabilities of 173.4% and 106.34%, respectively. The acid form of PP10 appeared to dominate in vivo, although both PP10 forms demonstrated pharmacologic effect. Conclusion: Oral and IV formulations of PP10 were successfully developed using HP-β-CD binary system and TPGS aqueous micelles, respectively, resulting in significantly improved solubility and bioavailability.

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