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Clinical Pharmacology and Therapeutics Sep 2022During its fourth transporter workshop in 2021, the International Transporter Consortium (ITC) provided updates on emerging clinically relevant transporters for drug... (Review)
Review
During its fourth transporter workshop in 2021, the International Transporter Consortium (ITC) provided updates on emerging clinically relevant transporters for drug development. Previously highlighted and new transporters were considered based on up-to-date clinical evidence of their importance in drug-drug interactions and potential for altered drug efficacy and safety, including drug-nutrient interactions leading to nutrient deficiencies. For the first time, folate transport pathways (PCFT, RFC, and FRα) were examined in-depth as a potential mechanism of drug-induced folate deficiency and related toxicities (e.g., neural tube defects and megaloblastic anemia). However, routine toxicology studies conducted in support of drug development appear sufficient to flag such folate deficiency toxicities, whereas prospective prediction from in vitro folate metabolism and transport inhibition is not well enough established to inform drug development. Previous suggestion of a retrospective study of intestinal OATP2B1 inhibition to explain unexpected decreases in drug exposure were updated. Furthermore, when the absorption of a new molecular entity is more rapid and extensive than can be explained by passive permeability, evaluation of the OATP2B1 transport may be considered. Emerging research on hepatic and renal OAT2 is summarized, but current understanding of the importance of OAT2 was deemed insufficient to justify specific consideration for drug development. Hepatic, renal, and intestinal MRPs (MRP2, MRP3, and MRP4) were revisited. MRPs may be considered when they are suspected to be the major determinant of drug disposition (e.g., direct glucuronide conjugates); MRP2 inhibition as a mechanistic explanation for drug-induced hyperbilirubinemia remains justified. There were no major changes in recommendations from previous ITC whitepapers.
Topics: Biological Transport; Folic Acid; Glucuronides; Humans; Membrane Transport Proteins; Prospective Studies; Retrospective Studies
PubMed: 35561119
DOI: 10.1002/cpt.2644 -
Cureus Nov 2021Epilepsy is a disorder that causes unprovoked seizures regularly. It affects between 1% and 3% of the population. After the first seizure, the chances of having another... (Review)
Review
Epilepsy is a disorder that causes unprovoked seizures regularly. It affects between 1% and 3% of the population. After the first seizure, the chances of having another one are almost 40%-52%. The etiology of febrile seizures in children with sickle cell disease is still unknown. In some groups, iron deficiency anemia has been linked to an increased risk of seizures. Although the reason and process are uncertain, some people believe that taking iron supplements can help prevent seizures. This literature covers haptene, non-haptene immune-related hemolysis, and oxidative processes activated by anti-seizure medications (ASMs). In epileptic patients, ASMs can cause anemia. Folic acid can be given to carbamazepine-treated anemic patients. There is growing evidence that it improves hemoglobin and leukocytes in individuals who take it. Therefore, one of the most efficient strategies to avoid future seizures is to take ASMs daily to maintain an even level of anticonvulsant in the body. To prevent further seizures, lifestyle changes are essential. Further studies and clinical trials are warranted to prove a clear association between epilepsy and hematologic disease, which will improve quality of life in the future.
PubMed: 34909297
DOI: 10.7759/cureus.19334 -
American Journal of Lifestyle Medicine 2022Vitamin B12 deficiencies are common in individuals consuming plant-predominant diets, including those who consume diary and/or eggs. Deficiencies can lead to...
Vitamin B12 deficiencies are common in individuals consuming plant-predominant diets, including those who consume diary and/or eggs. Deficiencies can lead to megaloblastic anemia and peripheral neuropathy, among other multi-system manifestations. The prevalence, assessment and prevention of vitamin B12 deficiency in patients following plant-predominant diets will be discussed.
PubMed: 35706595
DOI: 10.1177/15598276221076102 -
The American Journal of Gastroenterology Dec 2023Corpus-restricted atrophic gastritis is a chronic inflammatory disorder leading to possible development of type 1 neuroendocrine tumors (T1gNET), intraepithelial...
INTRODUCTION
Corpus-restricted atrophic gastritis is a chronic inflammatory disorder leading to possible development of type 1 neuroendocrine tumors (T1gNET), intraepithelial neoplasia (IEN), and gastric cancer (GC). We aimed to assess occurrence and predictors of gastric neoplastic lesions in patients with corpus-restricted atrophic gastritis at long-term follow-up.
METHODS
A prospective single-center cohort of patients with corpus-restricted atrophic gastritis adhering to endoscopic-histological surveillance was considered. Follow-up gastroscopies were scheduled according to the management of epithelial precancerous conditions and lesions of the stomach guidelines. In case of new/worsening of known symptoms, gastroscopy was anticipated. Cox regression analyses and Kaplan-Meier survival curves were obtained.
RESULTS
Two hundred seventy-five patients with corpus-restricted atrophic gastritis (72.0% female, median age 61 [23-84] years) were included. At a median follow-up of 5 (1-17) years, the annual incidence rate person-year was 0.5%, 0.6%, 2.8%, and 3.9% for GC/high-grade IEN, low-grade IEN, T1gNET, and all gastric neoplastic lesions, respectively. All patients showed at baseline operative link for gastritis assessment (OLGA)-2, except 2 low-grade (LG) IEN patients and 1 T1gNET patient with OLGA-1. Age older than 60 years (hazard ratio [HR] 4.7), intestinal metaplasia without pseudopyloric metaplasia (HR 4.3), and pernicious anemia (HR 4.3) were associated with higher risk for GC/HG-IEN or LG-IEN development and shorter mean survival time for progression (13.4, 13.2, and 11.1, respectively, vs 14.7 years, P = 0.01). Pernicious anemia was an independent risk factor for T1gNET (HR 2.2) and associated with a shorter mean survival time for progression (11.7 vs 13.6 years, P = 0.04) as well as severe corpus atrophy (12.8 vs 13.6 years, P = 0.03).
DISCUSSION
Patients with corpus-restricted atrophic gastritis are at increased risk for GC and T1gNET despite low-risk OLGA scores, and those aged older than 60 years with corpus intestinal metaplasia or pernicious anemia seem to display a high-risk scenario.
Topics: Humans; Female; Aged; Middle Aged; Male; Gastritis, Atrophic; Incidence; Cohort Studies; Anemia, Pernicious; Prospective Studies; Gastritis; Risk Factors; Stomach Neoplasms; Precancerous Conditions; Metaplasia; Helicobacter Infections; Gastric Mucosa
PubMed: 37207305
DOI: 10.14309/ajg.0000000000002327 -
Journal of Medical Case Reports Sep 2021In ineffective erythropoiesis, hepcidin synthesis is suppressed by erythroid regulators, namely erythroferrone and growth differentiation factor-15. For the first time,...
BACKGROUND
In ineffective erythropoiesis, hepcidin synthesis is suppressed by erythroid regulators, namely erythroferrone and growth differentiation factor-15. For the first time, the hypothesis that iron overload in megaloblastic anemia may be related to ineffective erythropoiesis is explored by describing the kinetics of hepcidin, erythroferrone, and growth differentiation factor-15 levels in a patient diagnosed with megaloblastic anemia associated with iron overload.
CASE PRESENTATION
An 81-year-old Caucasian male was admitted for fatigue. He had type-2 diabetes previously treated with metformin, ischemic cardiac insufficiency, and stage-3 chronic kidney disease. Vitiligo was observed on both hands. Biological tests revealed normocytic non-regenerative anemia associated with hemolysis, thrombocytopenia, and elevated sideremia, ferritin, and transferrin saturation levels. Megaloblastic anemia was confirmed with undetectable blood vitamin B12 and typical cytological findings like hyper-segmented neutrophils in blood and megaloblasts in bone marrow. The patient received vitamin B12 supplementation. At 3 months, biological parameters reached normal values. Hepcidin kinetics from diagnosis to 3 months inversely correlated with those of erythroferrone and growth differentiation factor-15.
CONCLUSIONS
This case suggests that iron-overload mechanisms of dyserythropoietic anemias may apply to megaloblastic anemias.
Topics: Aged, 80 and over; Anemia; Anemia, Megaloblastic; Erythropoiesis; Humans; Iron; Iron Overload; Male
PubMed: 34538261
DOI: 10.1186/s13256-021-03065-0 -
The Journal of the Association of... Apr 2022Pancytopenia is a common cause of hematological consultation. Common underlying causes include vitamin deficiency (vitamin B12, folic acid), drugs (hydroxyurea,... (Observational Study)
Observational Study
Pancytopenia is a common cause of hematological consultation. Common underlying causes include vitamin deficiency (vitamin B12, folic acid), drugs (hydroxyurea, phenytoin, methotrexate), and bone marrow failure syndrome. Aplastic anemia is one of the rarest hematological diseases and presents as pancytopenia. However, it is the most sinister one and is a hematological emergency that needs urgent medical attention. Absolute neutrophil count (ANC) is a measure of disease severity and is expected to be low in patients with pancytopenia of any cause. Aim & Objective: We aimed to analyze the absolute neutrophil count (ANC) level in patients presenting with pancytopenia. Material & Method: This prospective, observational study was conducted at a tertiary care hospital in northern India. We included patients with pancytopenia diagnosed at our center or reported to our center for therapy. ANC was measured before starting therapy. Observation: One hundred twenty-seven patients were included in this study. After evaluation, megaloblastic anemia was the commonest underlying cause in 42 (33%) patients followed by myelodysplastic syndrome in 31 (24.4%) patients. Twenty-three (18.1%) patients having pancytopenia were diagnosed with aplastic anemia. Other causes included leukemia, paroxysmal nocturnal hemoglobinuria and drugs. The median age was 37 years (range 18-75 years), and 67 (52.75%) were male. The mean hemoglobin was 5.5 g/dL (95% CI ±1.9). The median WBC was 2570/cmm (300-3130) and the median platelet was 36000/cmm (2000-92000). The median ANC in patients with aplastic anemia was 594/cmm (range 25- 3850). When compared, the ANC level was significantly lower in aplastic anemia than other causes of pancytopenia (p<0.001). Conclusion: On univariate and multivariate analysis ANC was significantly lower at baseline in patients of aplastic anemia. A longer follow-up of the patients will be required to assess the value of ANC in predicting response to therapy.
Topics: Adolescent; Adult; Aged; Anemia, Aplastic; Anemia, Megaloblastic; Female; Humans; Male; Middle Aged; Neutrophils; Pancytopenia; Prospective Studies; Young Adult
PubMed: 35443536
DOI: No ID Found -
British Journal of Cancer Jun 2021Folate, vitamin B6 and vitamin B12 have been associated with digestive system cancers. We conducted a two-sample Mendelian randomisation study to assess the causality of...
BACKGROUND
Folate, vitamin B6 and vitamin B12 have been associated with digestive system cancers. We conducted a two-sample Mendelian randomisation study to assess the causality of these associations.
METHODS
Two, one and 14 independent single nucleotide polymorphisms associated with serum folate, vitamin B6 and vitamin B12 at the genome-wide significance threshold were selected as genetic instruments. Summary-level data for the associations of the vitamin-associated genetic variants with cancer were obtained from the UK Biobank study including 367,561 individuals and FinnGen consortium comprising up to 176,899 participants.
RESULTS
Genetically predicted folate and vitamin B6 concentrations were not associated with overall cancer, overall digestive system cancer or oesophageal, gastric, colorectal or pancreatic cancer. Genetically predicted vitamin B12 concentrations were positively associated with overall digestive system cancer (OR, 1.12; 95% CI 1.04, 1.21, p = 0.003) and colorectal cancer (OR 1.16; 95% CI 1.06, 1.26, p = 0.001) in UK Biobank. Results for colorectal cancer were consistent in FinnGen and the combined OR was 1.16 (95% CI 1.08, 1.25, p < 0.001). There was no association of genetically predicted vitamin B12 with any other site-specific digestive system cancers or overall cancer.
CONCLUSIONS
These results provide evidence to suggest that elevated serum vitamin B12 concentrations are associated with colorectal cancer.
Topics: Adult; Anemia, Pernicious; Case-Control Studies; Digestive System Neoplasms; Female; Folic Acid; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Testing; Humans; Male; Mendelian Randomization Analysis; Polymorphism, Single Nucleotide; Risk Factors; Sweden; United Kingdom; Vitamin B 12; Vitamin B 6; Vitamin B Complex; Vitamin B Deficiency
PubMed: 33837300
DOI: 10.1038/s41416-021-01383-0 -
Zhonghua Nei Ke Za Zhi Jun 2023To investigate the lifespan of erythrocytes in megaloblastic anemia (MA) patients. A prospective cohort study analysis. Clinical data from 42 MA patients who were...
To investigate the lifespan of erythrocytes in megaloblastic anemia (MA) patients. A prospective cohort study analysis. Clinical data from 42 MA patients who were newly diagnosed at the Department of Hematology, Lanzhou University Second Hospital from January 2021 to August 2021 were analyzed, as were control data from 24 healthy volunteers acquired during the same period. The carbon monoxide breath test was used to measure erythrocyte lifespan, and correlations between erythrocyte lifespan and laboratory test indexes before and after treatment were calculated. Statistical analysis included the -test and Pearson correlation. The mean erythrocyte lifespan in the 42 newly diagnosed MA patients was (49.05±41.60) d, which was significantly shorter than that in the healthy control group [(104.13±42.62) d; =5.13,=0.001]. In a vitamin B-deficient subset of MA patients the mean erythrocyte lifespan was (30.09±15.14) d, and in a folic acid-deficient subgroup it was (72.00±51.44) d, and the difference between these two MA subsets was significant (=3.73, =0.001). The mean erythrocyte lifespan after MA treatment was (101.28±33.02) d, which differed significantly from that before MA treatment (=4.72, =0.001). In MA patients erythrocyte lifespan was positively correlated with hemoglobin concentration (=0.373), and negatively correlated with total bilirubin level (=-0.425), indirect bilirubin level (=-0.431), and lactate dehydrogenase level (=-0.504) (all <0.05). Erythrocyte lifespan was shortened in MA patients, and there was a significant difference between a vitamin B-deficient group and a folic acid-deficient group. After treatment the erythrocyte lifespan can return to normal. Erythrocyte lifespan is expected to become an informative index for the diagnosis and treatment of MA.
Topics: Humans; Longevity; Clinical Relevance; Prospective Studies; Erythrocytes; Anemia, Megaloblastic; Folic Acid; Bilirubin; Vitamins
PubMed: 37263952
DOI: 10.3760/cma.j.cn112138-20221025-00788 -
The Journal of Pediatrics Nov 2022
Topics: Humans; Anemia, Megaloblastic; Folic Acid; Retinal Diseases
PubMed: 35944720
DOI: 10.1016/j.jpeds.2022.07.047 -
Discovery Medicine 2022Pernicious anemia (PA) is an autoimmune disease characterized by cobalamin deficiency (CD) due to immune-mediated chronic atrophic gastritis (CAG). CD results from poor...
Pernicious anemia (PA) is an autoimmune disease characterized by cobalamin deficiency (CD) due to immune-mediated chronic atrophic gastritis (CAG). CD results from poor absorption of dietary cobalamin from the terminal ileum, triggered by positive intrinsic factor (IF) antibodies. It is the most common cause of CD worldwide. Despite advances in understanding biochemistry and pathogenesis of PA, its diagnosis can be extremely challenging as the disease may present with hematological as well as nonhematological manifestations and also because of unreliable serum cobalamin assays. Nonhematological manifestations may present in a patient with PA even in the absence of hematological findings. Herein, an overview of common and uncommon nonhematological manifestations of PA is discussed.
Topics: Humans; Anemia, Pernicious
PubMed: 36476278
DOI: No ID Found