bims-sicedi 2024-11-03 papers

Medicina (Kaunas). 2024 Sep 26. pii: 1581. [Epub ahead of print]60(10):

GBT1118, a Voxelotor Analog, Ameliorates Hepatopathy in Sickle Cell Disease.

Elio Haroun, Seah H Lim, Dibyendu Dutta.

Background and Objectives: In sickle cell disease (SCD), hepatopathy is a cumulative consequence of ischemia/reperfusion (I/R) injury from a vaso-occlusive crisis, tissue inflammation, and iron overload due to blood transfusion. Hepatopathy is a major contributing factor of shortened life span in SCD patients. We hypothesized that the voxelotor, a hemoglobin allosteric modifier, ameliorates sickle hepatopathy. Materials and Methods: Townes SCD mice and their controls were treated with either chow containing GBT1118, a voxelotor analog, or normal chow. We evaluated inflammation, fibrosis, apoptosis and ferroptosis in their livers using qPCR, ELISA, histology, and immunohistochemistry. Results: GBT1118 treatment resulted in reduced hemolysis, iron overload and inflammation in the liver of SCD mice. There were significant reductions in the liver enzyme levels and bile acids. Furthermore, GBT1118-treated mice exhibited reduced apoptosis, necrosis, and fibrosis. Increased ferroptosis as evident from elevated 4-hydroxynonenal (4-HNE) staining, malondialdehyde (MDA) levels, and expression of Ptgs2 and Slc7a11 mRNAs, were also significantly reduced after GBT1118 treatment. To explain the increased ferroptosis, we evaluated iron homeostasis markers in livers. SCD mice showed decreased expression of heme oxygenase-1, ferritin, hepcidin, and ferroportin mRNA levels. GBT1118 treatment significantly increased expressions of these genes. Conclusions: Our results suggest GBT1118 treatment in SCD confers the amelioration of sickle hepatopathy by reducing inflammation, fibrosis, apoptosis, iron overload and ferroptosis.

Keywords: GBT1118; ferroptosis; hepatopathy; iron overload; liver injury; sickle cell disease

DOI: https://doi.org/10.3390/medicina60101581

Lancet Haematol. 2024 Nov;pii: S2352-3026(24)00272-2. [Epub ahead of print]11(11): e812-e813

Haematopoietic stem-cell transplantation for sickle cell disease in low-income and middle-income countries: the experience in India.

Vineeta Gupta, Lakshmanan Krishnamurti.

DOI: https://doi.org/10.1016/S2352-3026(24)00272-2

Hemasphere. 2024 Nov;8(11): e70030

Mitochondrial retention in mature red blood cells from patients with sickle cell disease is associated with stress erythropoiesis but not with proinflammatory state.

Marc Romana, Sandrine Laurance, Marie-Dominique Hardy-Dessources, Laetitia Claer, Sylvie Ravion, Karim Dorgham, Yohann Garnier, Lea Kuznicki, Vanessa Tarer, Benoit Tressières, Sophie D Lefevre, Veronique Baccini, Mariano A Ostuni, Caroline Le Van Kim, Maryse Etienne-Julan.

DOI: https://doi.org/10.1002/hem3.70030

Curr Med Res Opin. 2024 Oct 28. 1-16

Clinical burden and healthcare resource utilization associated with managing sickle cell disease with recurrent vaso-occlusive crises in France.

Jessica Baldwin, Chuka Udeze, Nanxin Li, Lyes Boulmerka, Lila Dahal, Giancarlo Pesce, Nadia Quignot, Heng Jiang, Frédéric Galactéros.

OBJECTIVE: This retrospective, real-world claims database analysis described the clinical burden and healthcare resource utilization (HCRU) among patients with sickle cell disease (SCD) with recurrent vaso-occlusive crises (VOCs) in France.
METHODS: The French National Health Data System database (système national des données de santé) was used to identify eligible patients from January 1, 2012, to March 1, 2019. Inclusion criteria were a SCD diagnosis, ≥2 VOCs/year for ≥2 consecutive years following the diagnosis, and ≥1 year of follow-up data to March 1, 2020. Patients with hereditary persistence of fetal hemoglobin or hematopoietic stem cell transplant in their medical records were excluded. Clinical complications, mortality, treatment use, and HCRU were evaluated during follow-up.
RESULTS: Overall, 4602 patients with SCD with recurrent VOCs were eligible; their mean (standard deviation [SD]) age was 19.8 (13.5) years, and 51.8% were female. Patients experienced a mean (SD) of 3.82 (3.57) VOCs per patient per year (PPPY). Prevalent complications were anemia or leukocytosis (44.1%), infections (42.0%), and organ failure (38.2%). In total, 101 (2.2%) patients died during follow-up (mean age of death [SD]: 39.3 [17.5] years; mortality rate: 0.64 deaths per 100 person-years). Most patients received opioids (89.1%) and hydroxycarbamide (72.8%). Patients had a mean of 5.7 inpatient hospitalizations, 6.0 emergency room visits, 6.6 outpatient visits, and 13.4 outpatient prescriptions PPPY.
CONCLUSIONS: Patients with SCD with recurrent VOCs in France have substantial clinical complications, mortality, and HCRU despite currently available treatment options. Innovative treatments that reduce frequency of or eliminate VOCs are needed to alleviate the burden associated with SCD.

Keywords: clinical complications; economics; healthcare resource utilization; mortality; sickle cell disease; vaso-occlusive crises

DOI: https://doi.org/10.1080/03007995.2024.2421287

Br J Haematol. 2024 Oct 28.

Burden of vaso-occlusive crisis, its management and impact on quality of life of Indian sickle cell disease patients.

Sickle cell disease (SCD) with vaso-occlusive pain crisis (VOC) significantly impacts patient well-being and often results in extensive healthcare resource utilization. This study assessed the VOC burden, its management and its impact on patients' quality of life (QoL). A cross-sectional observational study was conducted between November 2021 and June 2022, including 1000 SCD patients from high-prevalence states in India. Data on demographics, clinical characteristics, VOC severity, management and QoL were collected. The study revealed that 33.5% of patients reported at least one VOC episode during the study period. In the year prior to their enrolment, 836 (83.60%) patients reported at least one VOC episode, with an equal proportion of 407/487 (83.6%) adults and 429/513 (83.6%) paediatric patients, reducing their QoL across all domains compared to patients without VOC. Of these, 469/1000 patients (46.9%) experienced ≥3 VOC episodes. Additionally, 764/1000 (76.40%) patients managed their VOCs at healthcare facilities, with 501/1000 (50.1%) requiring inpatient admissions. Further, 71.80% of patients received Hydroxyurea (HU) therapy. The study depicts the severity of the Arab-Indian haplotype in Indian SCD patients visiting healthcare settings based on high VOC burden. This highlights the urgent need for better management strategies and resource allocation for these patients.

Keywords: healthcare utilization; quality of life; sickle cell disease; vaso‐occlusive crisis

DOI: https://doi.org/10.1111/bjh.19829

Pharmaceuticals (Basel). 2024 Oct 17. pii: 1386. [Epub ahead of print]17(10):

Hydroxyurea Pharmacokinetic Evaluation in Patients with Sickle Cell Disease.

Daniela Di Grazia, Cristina Mirabella, Francesco Chiara, Maura Caudana, Francesco Maximillian Anthony Shelton Agar, Marina Zanatta, Sarah Allegra, Jenni Bertello, Vincenzo Voi, Giovanni Battista Ferrero, Giuliana Abbadessa, Silvia De Francia.

Background: Hydroxyurea (HU), also known as hydroxycarbamide, is an oral ribonucleotide reductase inhibitor. In 1999, the United States Food and Drug Administration (FDA) approved HU for the treatment of sickle cell disease (SCD). Since then, it has become the cornerstone in the management of SCD patients, helping to reduce vaso-occlusive crises, acute chest syndrome, the need for blood transfusions, hospitalizations and mortality. There is considerable variability among individuals in HU pharmacokinetic (Pk) parameters that can influence treatment efficacy and toxicity. The objective of this work is part of a clinical study aimed at investigating HU Pk and determining the optimal sampling time to estimate the Area Under the Curve (AUC) in SCD patients. Methods: HU plasma concentration in 80 patients at various time points (2, 4, 6, 24 h) following a 48-h drug washout was quantified using High-Pressure Liquid Chromatography (HPLC) coupled with an ultraviolet (UV) detection method previously described in the literature and adapted to new conditions with partial modifications. Results: The mean HU administered dose was 19.5 ± 5.1 mg/kg (range: 7.7-37.5 mg/kg). The median AUC quantified in plasma patients was 101.3 mg/L/h (Interquartile Range (IQR): 72.5-355.9) and it was not influenced by the weight-based dose. However, there was a strong positive correlation between AUC and Body Mass Index (BMI) as well as dose per Body Surface Area (BSA). Along with a three-point approach for AUC determination present in the literature, we show results obtained from a four-point sampling strategy, which is more useful and effective for better optimizing dose escalation to the maximum tolerated dose (MTD). Moreover, we observed that most patients achieved the maximum HU plasma concentration two hours after drug administration, regardless of age differences. Conclusions: HU treatment, which represents a milestone in the treatment of SCD due to its ability to reduce disease complications and improve patients' quality of life, requires careful monitoring to optimize the individual dose for saving potential side effects and/or adverse events.

Keywords: area under the curve; high-pressure liquid chromatography; maximum tolerated dose; sex; therapeutic drug monitoring; variability

DOI: https://doi.org/10.3390/ph17101386