Intravenous Ascorbic Acid Research Articles

Methemoglobinemia caused by nitrobenzene ingestion treated with methylene blue and ascorbic acid: A case report

Nitrobenzene (NBZ) is a pale-yellow coloured compound, moderately water-soluble oily liquid, and odour similar to bitter almonds. It is commonly used in the manufacture of aniline, benzidine, quinolone, drugs, dyes, solvent in shoe, metal polishes, and in screen printing]. It is a potent oxidizer of the iron moiety of haemoglobin causing methemoglobinemia leading to its inability to transport oxygen. Clinical features of nitrobenzene poisoning include gastric irritation, nausea, vomiting, cyanosis, drowsiness, seizures, coma and finally respiratory failure culminating in death. Intravenous methylene blue and ascorbic acid are commonly used for treatment of significant poisoning.

Intravenous Ascorbic Acid for the Prevention of Postreperfusion Syndrome in Orthotopic Liver Transplantation: Protocol for a Randomized Controlled Trial.

Liver transplantation is the last therapeutic option for patients with end-stage liver disease. Postreperfusion syndrome (PRS), defined as a fall in mean arterial pressure of more than 30% within the first 5 minutes after reperfusion of at least 1 minute, can occur in liver transplantation as a deep hemodynamic instability with associated hyperfibrinolysis immediately after reperfusion of the new graft. Its incidence has remained unchanged since it was first described in 1987. PRS is related to ischemia-reperfusion (I/R) injury, whose pathophysiology involves the release of several mediators from both the donor and the recipient. The antioxidant effect of ascorbic acid has been studied in resuscitating patients with septic shock and burns. Even today, there are publications with conflicting results, and there is a need for further studies to confirm or rule out the usefulness of this drug in this group of patients. The addition of ascorbic acid to preservation solutions used in solid organ transplantation is under investigation to harness its antioxidant effect and mitigate I/R injury. Since PRS could be considered a manifestation of I/R injury, we believe that the possible beneficial effect of ascorbic acid on the occurrence of PRS should be investigated. The aim of this randomized controlled trial is to assess the benefits of ascorbic acid over saline in the development of PRS in adult liver transplantation. We plan to conduct a single-center randomized controlled trial at the Hospital Universitario Ramón y Cajal in Spain. A total of 70 participants aged 18 years or older undergoing liver transplantation will be randomized to receive either ascorbic acid or saline. The primary outcome will be the difference between groups in the incidence of PRS. The randomized controlled trial will be conducted under conditions of respect for fundamental human rights and ethical principles governing biomedical research involving human participants and in accordance with the international recommendations contained in the Declaration of Helsinki and its subsequent revisions. The enrollment process began in 2020. A total of 35 patients have been recruited so far. Data cleaning and analysis are expected to occur in the first months of 2024. Results are expected around the middle of 2024. We believe that this study could be particularly relevant because it will be the first to analyze the clinical effect of ascorbic acid in liver transplantation. Moreover, we believe that this study fills an important gap in the knowledge of the potential benefits of ascorbic acid in the field of liver transplantation, particularly in relation to PRS. European Union Drug Regulating Authorities Clinical Trials Database 2020-000123-39; https://tinyurl.com/2cfzddw8; ClinicalTrials.gov NCT05754242; https://tinyurl.com/346vw7sm. DERR1-10.2196/50091.

Phase II Study Assessing Safety and Preliminary Efficacy of High Dose Intravenous Ascorbic Acid in Patients with TET2 Mutant Clonal Cytopenias

Background: Clonal cytopenia(s) of undetermined significance ( CCUS) is defined as persistent cytopenias arising in the context of myeloid neoplasm ( MN)-associated somatic mutations ( MT) in hematopoietic stem cells. Patients ( PTs) with TET2MT CCUS have a high probability of progression to MN. To date, no FDA-approved therapies exist for CCUS, and PTs often have similar cytopenias/transfusion needs as those with myelodysplastic syndromes ( MDS). TET2 is an ascorbic acid (AA)-dependent dioxygenase that catalyzes the conversion of 5-methylcytosine ( 5mC) to 5-hydroxymethylcytosine ( 5hmC), providing rationale to study high-dose IV (HI)-AA in TET2MT CCUS. Here we report the final results of this pilot trial. Methods: This is an investigator-initiated, single-institutional, phase II trial assessing the safety and efficacy of HI-AA in PTs with TET2MT CCUS (NCT03418038). PTs≥ 18 years with ≥1 TET2MT with or without additional somatic MTs, without prior treatment, and with any of the following laboratory criteria: (1) hemoglobin ( Hb) ≤10g/dL, (2) absolute neutrophil count ( ANC) ≤1(10^9/L), (3) platelet count ( PLT)≤100 (10^9/L) were eligible. HI-AA (1g/kg, maximum 100g) was given 3 times weekly for 12 weeks. The primary endpoint was hematologic response rates determined by MDS IWG 2018 criteria at week 20. (Platzbecker Blood 2018) and reported as hematologic improvement ( HI)- erythropoietic ( HI-E), platelets ( HI-P), neutrophils ( HI-N). Secondary endpoints include safety and adverse events ( AEs), graded by NCI-CTCAE v4.03. Correlative studies include changes in TET2MT variant allele fraction ( VAF), in vitro colony formation and differentiation, global and sequence-specific DNA methylation/hydroxymethylation, and quantitative 5hmC estimated by IHC in bone marrow biopsy specimens. Results: Ten patients were enrolled, with a median age of 71.4 (range: 65, 79) years, 8 (80%) males. The median number of mutations was 3, with 9 (90%) having co-mutations. All PTs but one [-Y] had normal karyotype. Baseline Hb levels were normal in all but one who was red blood transfusion dependent. Five (50%) PTs were thrombocytopenic, and 5 (50%) PTs had ANC<1 (10^9/L). ( Table). HI-AA was well tolerated with the most common AEs being infusion-related polyuria (40%) and polydipsia (40%, 3 Grade 1, 1 Grade 2). One (10%) PT had constipation and headaches (both Grade 1), and 1 (10%) experienced dyspepsia. No treatment-related Grade 3 or 4 AEs' or deaths were reported. The median follow-up duration was 16.8 months (range: 9.4, 24.1). Overall, no PTs met the criteria for HI. There were no significant differences with regards to median Hb, PLT, and ANC values at baseline, week 20, and 1-year (median Hb: 13.3, 12.5, and 12.7 g/dL, p=0.93; PLT: 97 vs. 120 vs. 92.5X10^9/L, p>0.99, and ANC: 0.9 vs. 1.2 vs. 1.3X10^9/L, p=0.99). By CTCAE grading criteria for cytopenias, 3 (30%) PTs had an improvement in severity of cytopenias, while 2 had worsening. One (10%) PT had an improvement in PLT (baseline vs. week 20: 62 vs 192X10^9/L) but was morphologically deemed to meet criteria for CMML-1 at week 20. Four (40%) PTs met criteria for disease progression (PT_4, 7,8,10); CMML-1- 2 and MDS-2. The median time to progression was 5 months (95% CI: 4.9, unreached). Two PTs had mutational clonal evolution, with 1 (PT_8) acquiring a RUNX1 (VAF: 20%) and 1 (PT_9) acquiring 2 CBL mutations (both VAF:4%) at one-year follow-up. There were no significant differences regarding the clinical characteristics or the TET2 variants between PTs who had stable disease vs. progression. There were no significant differences in TET2 VAF at baseline, week 20, and 1-year (median: 39% vs. 43% vs. 42%, p=0.54). We profiled changes in 5-mC and 5-hmC (Ilumina EpicArray) in PTs pre- and post-IV AA treatment and did not observe global changes. However, we were able to highlight site-specific changes in differentially methylated regions, largely resulting in hypomethylation at enhancer sites and affecting actively transcribed states in PTs with an improvement in cytopenia(s) severity by CTACE criteria ( Figure). Conclusion: We report the final safety and efficacy analysis of HI-AA in PTs with TET2 MT CCUS. The trial data suggest that HI-AA is safe and well tolerated. Although there were no significant responses by IWG MDS criteria, alleviation in severity of cytopenias in a subset of PTs (n=3) along with correlative epigenetic changes in enhancer regions, needs further exploration.

NCMP-24. RECURRENT BOUTS OF SCURVY DURING GLIOBLASTOMA REMISSION

Abstract Various nutritional deficiencies are more common in patients with cancer, including thiamine, iron and vitamin B12 deficiences, and can be associated with metabolic stress, treatments given and reduced nutritional intake or absorption. Vitamin C deficiency and scurvy have also been reported as a rare complication in cancer patients, but are not frequently seen in the developed countries. We report a 29 year old woman who underwent partial resection of a bifrontal isocitrate dehydrogenase, methylated glioblastoma followed by radiation and temozolomide four years prior. Her tumor remained stable since that time, but she had ongoing decreased appetite and sensitivity to food smells and tastes, which restricted her diet substantially. She had mild chronic anemia and was underweight, but had remained stable. She presented to us with acutely worsening fatigue, lower limb edema and a new rash that was superficially petechial in appearance. She had gingival hyperplasia and friability, and a jaundiced appearance. No deep venous thrombosis was found and liver tests were normal, giving a picture of scurvy. Her serum vitamin C level was undetectable, B12 was 75, folate 3.4, hemoglobin 6.1, albumin 3.2 and vitamin D 11.5. She was given intravenous and oral ascorbic acid as well as other supplementation and had immediate resolution of limb swelling and greatly improved appetite and energy. One year later, with glioblastoma still stable off treatment, she had recurrent worsening fatigue, appetite and gingivitis, and typical petechia-like rash appeared within minutes of IV placement for MRI contrast in the associated vein. She declined repeat serum testing but symptoms resolved on resuming high dose oral vitamin supplementation. Vitamin C has been studied as a supplement in glioblastomas, but also shown to reduce etoposide toxicity. Vitamin C and other nutritional deficiencies may be more common in brain tumor patients, but under-diagnosed.

Effect of adjuvant thiamine and ascorbic acid administration on the neurologic outcomes of out-of-hospital cardiac arrest patients: A before-and-after study

AimThis study aimed to evaluate the impact of early thiamine and ascorbic acid administration on the neurologic outcome in out-of-hospital cardiac arrest (OHCA) patients treated with targeted temperature management (TTM). MethodsThis before-and-after cohort study used data extracted from two hospitals of the Korean Hypothermia Network prospective registry. The treatment group incorporated patients enrolled from December 2019 to May 2021, that received intravenous thiamine (200 mg) and ascorbic acid (3 g) at 12-hour intervals for a total of six doses. The control group incorporated those enrolled from May 2018 to November 2019. The one-month good neurologic outcome, defined as a Cerebral Performance Category score ≤ 2, between the groups was evaluated using inverse probability of treatment weighting (IPTW). ResultsAmong the 234 OHCA survivors with TTM, 102 were included in the treatment group and 132 were included in the control group. The one-month (31.4 % vs. 29.5 %, respectively; P = 0.76) good neurologic outcome rates did not differ between the treatment and control groups. After adjusting using the IPTW, vitamin supplementation was not associated with good neurologic outcome (odds ratio [OR], 1.134; 95 % confidence interval [CI], 0.644–1.999; P = 0.66). In subgroup analysis, vitamin administration was significantly associated with a good neurologic outcome in older (≥65 years) patients (adjusted OR, 5.53; 95 % CI, 1.21–25.23; P = 0.03). ConclusionAdjuvant thiamine and ascorbic acid administration in OHCA survivors with TTM did not improve their neurologic outcome after one month. Further clinical trials are warranted.

Effect of high-dose intravenous ascorbic acid on microcirculation and endothelial glycocalyx during sepsis and septic shock: a double-blind, randomized, placebo-controlled study

Previous studies indicate supplemental vitamin C improves microcirculation and reduces glycocalyx shedding in septic animals. Our randomized, double-blind, placebo-controlled trial aimed to investigate whether a high dose of intravenous ascorbic acid (AA) might improve microcirculation and affect glycocalyx in septic patients. In our study, 23 septic patients were supplemented with a high dose (50 mg/kg every 6 h) of intravenous AA or placebo for 96 h. Sublingual microcirculation was examined using a handheld Cytocam-incident dark field (IDF) video microscope. A sidestream dark field video microscope (SDF), connected to the GlycoCheck software (GlycoCheck ICU®; Maastricht University Medical Center, Maastricht, the Netherlands), was employed to observe glycocalyx. We found a significantly higher proportion of perfused small vessels (PPV) 6 h after the beginning of the trial in the experimental group compared with placebo. As an indicator of glycocalyx thickness, the perfused boundary region was lower in capillaries of the 5–9 μm diameter in the AA group than placebo after the first dose of AA. Our data suggest that high-dose parenteral AA tends to improve microcirculation and glycocalyx in the early period of septic shock. The study was retrospectively registered in the clinicaltrials.gov database on 26/02/2021 (registration number NCT04773717).

#2633 ROLE OF INTRAVENOUS ASCORBIC ACID IN THE MANAGEMENT OF ANEMIA IN HEMODIALYSIS PATIENTS

Abstract Background and Aims Patients with end-stage kidney disease (ESKD) suffer from functional iron deficiency where despite the presence of sufficient iron stores in the body, adequate iron is unavailable for heme synthesis. This study hypothesis was that in patients undergoing hemodialysis (HD), administration of intravenous (IV) ascorbic acid (AA) exerts a good effect on the management of anemia, either by increasing the mobilization of iron from tissue stores or acting as an antioxidant to overcome the inflammatory block and increase the erythropoietin sensitivity. Method Fifty patients with ESRD who were on regular HD were included in the study. Patients’ ferritin levels ranged from 500 to 1200 ng/mL with transferrin saturation of 30% or more. However, all patients were anemic and received erythropoietin therapy. Iron therapy was discontinued in the first group, whereas it was continued in the second group that received IV AA. Results A significant increase in the levels of Hb was observed in the second group after 6 months despite the decrease in ferritin levels in both the groups. Transferrin saturation decreased in both groups, the decrease being more in the first group. The levels of C-reactive protein (CRP) decreased in the second group, whereas these increased in the first group. Conclusion Intravenous AA as an adjuvant therapy with iron exerts a favorable and significant effect on the Hb, serum ferritin, and CRP levels in patients with ESKD having anemia. The discontinuation of iron therapy only decreases the serum ferritin levels and does not improve the Hb or CRP levels.

Methemoglobinemia caused by fungicide poisoning: A case report

Methemoglobinemia is a potentially fatal condition at a level of more than 70%. It occurs when the ferrous iron inHaemoglobin is oxidized to ferric iron, forming methemoglobin (MetHb), causing decreased capability of hemoglobinto bind and deliver oxygen to tissues. Methemoglobinemia has been linked to a wide array of substances, includingfungicides and industrial chemicals. We describe a patient who developed a high MetHb level of 70.7%, afterdeliberately consuming a fungicide, namely Mancozeb. The "oxygen saturation gap" is the difference between thecalculated oxygen saturation from a standard blood gas machine and the reading from a pulse oximeter. If it is greaterthan 5%, the patient's hemoglobin may be abnormal, representing carbon monoxide poisoning, methemoglobinemia,or sulfhemoglobinemia. Disproportionate cyanosis not responding to supplemental oxygen, chocolate brown blood,and saturation gap of >5% raised the suspicion of methemoglobinemia secondary to ingestion of fungicide. Analternative approach to treatment including intravenous ascorbic acid, NAC, and multiple blood transfusions wasgiven due to the unavailability of methylene blue. A high index of suspicion, early recognition, and an alternativeapproach to management resulted in a favorable outcome.
 Bangladesh Crit Care J March 2023; 11 (1): 46-50

331 A Randomized Controlled Clinical Trial using α-Tocopherol and Ascorbic Acid in the Treatment of Moderate Traumatic Brain Injury

INTRODUCTION: Traumatic Brain Injury (TBI) is a major public health concern and a leading cause of disability worldwide. It accounts for 40% of all deaths from acute injuries worldwide. Oxidative brain damage is one of the most validated pathophysiologic hallmark of secondary traumatic brain injury. METHODS: 120 patients admitted to Jos University Teaching Hospital with moderate TBI were included in this study. Patients were randomized into 4 equally sized groups: control, enteral α-Tocopherol, intravenous ascorbic acid, or a combination of the latter treatments. Patients were administered the designated drugs for a period of one week in addition to the standard management of head injuries. The control group received neither of these drugs but just the standard management of head injury. Outcome data were collected prospectively including demographics, head injury characteristics, mortality, length of stay (LoS) and Glasgow outcome score (GOS). RESULTS: 92.5% (n = 111) of patients were male. The most common cause for TBI was road traffic accidents (n = 102). GOS was significantly higher in all treatment groups when compared to the control group at discharge (ascorbic acid p < 0.01, α-Tocopherol p < 0.001, combination p < 0.001), and at 1 and 3 months follow up. Overall mortality was significantly lower in patients treated with either α-Tocopherol (n = 1, 3.3%), ascorbic acid (n = 1, 3.3%) or a combination (n = 0, 0%) compared to the placebo group (n = 8, 26.7%, p < 0.05). The lenght of hospital stay was significantly reduced in the α-Tocopherol (p < 0.05) and the combination groups (p < 0.001) CONCLUSIONS: The use of ascorbic acid and/or α-Tocopherol improved survival in this cohort. A combination of both drugs had a potentially synergistic effect in these patients.

Nitrobenzene Ingestion Treated with Intravenous Methylene Blue and Ascorbic Acid in a Limited Resource Condition: A Case Study

Nitrobenzene Ingestion Treated with Intravenous Methylene Blue and Ascorbic Acid in a Limited Resource Condition: A Case Study

Phase II Study Assessing Safety and Preliminary Efficacy of High Dose Intravenous Ascorbic Acid in Patients with TET2 Mutant Clonal Cytopenias of Undetermined Significance

Background: Clonal cytopenia(s) of undetermined significance (CCUS) is defined as persistent cytopenias arising in the context of myeloid neoplasm (MN)-associated somatic mutations (MT) in hematopoietic stem cells. Patients (PTs) with TET2 mutant (TET2MT) CCUS have a high probability of progression to MN. To date, no FDA-approved treatment for CCUS exist, with PTs often having similar cytopenias and transfusion needs as those with myelodysplastic syndromes (MDS). High dose intravenous ascorbic acid (HI-AA) demonstrates anti-cancer activity via two mechanisms: (1) hydrogen peroxide-induced oxidative stress and (2) DNA demethylation mediated by TET activation (cofactor for TET1/2/3). TET2 is an AA and oxoglutarate-dependent dioxygenase that catalyzes the conversion of 5-methylcytosine to 5-hydroxymethylcytosine (5hmC), providing the rationale to study HI-AA in TET2MT CCUS. Methods: This is an investigator-initiated, single-arm, single-institution, phase II trial assessing the safety and preliminary efficacy of HI-AA for PTs with TET2MT CCUS (NCT03418038). PTs³ 18 years with TET2MT CCUS (≥1 TET2MT with or without additional somatic MTs) and with any of the following laboratory criteria: (1) hemoglobin (Hb) ≤10g/dL, (2) absolute neutrophil count (ANC) ≤1(10^9/L), (3) platelet count (PLT)≤100 (10^9/L) are eligible. HI-AA (1g/kg, maximum 100g) is given 3 times weekly for 12 weeks through a PICC line, with response assessments before each cycle (4 weeks), at 20 weeks, and one year. The primary endpoint is the hematologic response rates determined by the proposed MDS IWG 2018 criteria at week 20. (Platzbecker Blood 2018) and reported as hematologic improvement (HI)- erythropoietic (HI-E), platelets (HI-P), neutrophils (HI-N). Secondary endpoints include safety and adverse events (AEs). AEs were graded using NCI-CTCAE v4.03. Correlative studies include changes in TET2MT variant allele fraction (VAF), TET2 activity, DNA methylation, hydroxymethylation, and 5hmC in bone marrow cells as determined by immunohistochemistry (IHC). Results: As of July 22, 2022, 8 (89%) of 9 enrolled PTs completed 12 weeks of therapy. The mean age was 74 (SD: 5.4) years, 7 (87.5%) males. One PT (PT_X) came off study after cycle one due to a PICC line-associated thrombosis. All PT were TET2MT (44% truncating), with 8 of 9 (89%) having co-mutations (4- 2 MTs, 3- 3 MTs, and 1- 4 MTs; 2 had ≥1 TET2MT). Comutations included SRSF2 (55%), ASXL1 (22%), ZRSR2 and KRAS (11% each). HI-AA was well tolerated with the most common AEs being infusion-related polyuria (56%) and polydipsia (44%, 3 Grade 1, 1 Grade 2). One (11%) PT had constipation and headaches (both Grade 1), and 1 (11%) experienced dyspepsia. No treatment-related Grade 3 or 4 AEs or deaths were observed. Six of 8 (75%) assessable PTs had post-treatment response assessments at week 20, with 3 PTs having completed 1-year assessments. All PTs' baseline Hb was within the normal range, except for 1 (17%) (PT_5- TET2MT/SRSF2MT) PT who continued to remain red blood transfusion dependent. Five (63%) PTs were thrombocytopenic PLT <100 (10^9/L), with 2 (25%) PTs (PT_1 and PT_7) having PLT £50 (10^9/L) and 5 (83%) PTs had ANC<1 (10^9/L) with 1 (17%) (PT_8) with ANC <0.5 (10^9/L). One (17%) PT met criteria for HI-P (PT_6 had an increment to 118 (10^9/L) at week 20- TET2MT/SRSF2MT/KRASMT) and 1 (17%) PT met criteria for HI-N (PT_2, ANC baseline:1.08 vs. week 20: 1.76(10^9/L)-TET2MT/SRSF2MT). PT_1, who had a baseline PLT of 25 (10^9/L) and ANC of 0.72 (10^9/L), had disease progression to MDS-EB-1 (TET2MT/SRSF2MT) at week 20. The 3 PTs with 1 year follow-up have stable disease. Panel 1 demonstrates changes in blood parameters with treatment. Panel 2 shows IHC determined changes in 5hmC changes with two control samples: normal control and TET2MT CMML. In 5 assessable PTs, there were no changes in TET2 VAF at 20 weeks (mean VAF : baseline 37.2% vs. week 20: 36.6%, p=0.3). Additional correlative studies are ongoing. Conclusion: We report safety and preliminary efficacy analysis for the first clinical trial dedicated to TET2MT CCUS. The early results of this pilot demonstrate that HI-AA is safe and has potential for biological and clinical effects. At last follow-up, 2 (33%) PTs met criteria for HI (HI-P-1 and HI-N-1), 3 PTs (50%) had stable disease, and 1 (17%) PT progressed to MDS. Future studies assessing potential synergy of adding HI-AA to standard of care therapies for TET2MT clonal processes are planned. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Perspectives of vitamin C upregulating regulatory T cells in the era of thrombopoietin receptor agonists for immune thrombocytopenia

Background Immune thrombocytopenia (ITP) is a rare disorder involving excessive peripheral destruction of platelets and inadequate bone marrow platelet production due to autoimmune reactions against megakaryocytes. Diagnosis is usually by the exclusion of primary causes; its rarity would only permit trial and error therapy experience. Historically, for ITP, oral ascorbic acid (AA) gave inconsistent results. However, unlike other nutrients, AA is found to have an exceptionally tight intestinal absorption restriction mandating intravenous delivery for any therapeutic purposes. Recently, as there is more pre-clinical evidence of AA restoring regulatory T cells (Tregs) by robust demethylation, the historical oral route was likely to be the “bottle neck” restricting effective blood levels. During this era of thrombopoietin receptor agonists (TPO-RAs), planned tapering is often required upon discontinuation but unplanned discontinuations, for example, due to side effects, are more problematic. Moreover, combinations with TPO-RAs are currently being tried using steroids and rituximab except rituximab is inappropriate during pandemics. Notably, with the indirect (but prognostically relevant) action of TPO-RAs on Tregs, boosting Treg functions by adding other Treg active agents, for example, steroids or AA, seems appropriate, especially if without added toxicity upon combining. Conclusions With updated pharmacokinetic concepts, it is timely to repeat AA clinical trials for ITP but using intravenous administration. Initially, this may be on compassionate grounds for its probable role as an adjunct to TPO-RAs for unsuccessful tapering and, especially, for all unplanned discontinuations of TPO-RAs. Such off-label usage of AA is justified because of AA's robust pre-clinical evidence on demethylation and initial clinical experience (despite the inappropriate administrative route). Moreover, moderate intravenous AA dosages have one of the best safety profiles, let alone its eminent affordability. Admittedly, after the initial clinical experience, more systematic trials on AA are required, especially for the most appropriate dosage range and its efficacy as monotherapy.

Intravenous Ascorbic Acid and Lung Function in Severely Ill COVID-19 Patients.

Current evidence suggests that ascorbic acid improves the host’s immune system and, therefore, may play a role in reducing the severity of infectious diseases. Coronavirus disease 2019 (COVID-19) is a potentially life-threatening viral infection that mainly infects the lungs. The objective of this review was to synthesize the existing findings from studies related to the effect of intravenous ascorbic acid on lung function in COVID-19 patients. For this review, PubMed, Cochrane, SCOPUS, EMBASE, Clinical Trial Registry, and Google Scholar databases were searched from December 2019 to May 2022. There was a total of six studies that investigated the large dose of ascorbic acid infusion intravenously on lung function in severely ill subjects with COVID-19. Out of six, three studies found that high-dose intravenous ascorbic acid improved lung function markers, and three studies found null results. Infusions of 12 g/d and 24 g/d of intravenous ascorbic acid had shown a significant improvement in lung function markers in two clinical trials. Studies that administered 8 g/d, 2 g/d, and 50 mg/kg/d of intravenous ascorbic acid found no influence on mechanical ventilation need and other lung function markers in critically ill subjects with COVID-19. Overall, the effect of intravenous ascorbic acid on the lung function of subjects with COVID yielded equivocal findings. More double-blinded, randomized, clinical studies with a larger sample size are required to confirm the effect of ascorbic acid in ameliorating the lung pathologies associated with COVID infection.

Vitamin C and its therapeutic potential in the management of COVID19.

COVID19 has emerged as one of the worst pandemics in the history of mankind. Several vaccines have been approved by different government agencies worldwide, but data on their efficacy and safety are limited, and distribution remains a massive challenge. As per WHO, personal immunity is vital for protection against COVID19. Earlier, Vitamin C-mediated pathways have been shown to play critical role in boosting immunity attributed to its antioxidant properties. Recently, the involvement of such pathways in protection against COVID19 has been suggested. The controlled doses of Vitamin C administered through intravenous (IV) injections are being studied for determining its role in the prognosis of COVID19. In this article, we have discussed the potential role of Vitamin C in the management in COVID19 patients and presented recent clinical trials data. Additionally, we have elaborated the possibility of administering Vitamin C through inhalers in order to achieve local high concentration and the challenges of such approach.

High Dose Intravenous Ascorbic Acid (Vitamin C) and Glutathione as Integrative Therapy in a Patient with Diffuse Large B-Cell Lymphoma: Case Report

Diffuse Large B-Cell Lymphoma is the most common Non-Hodgkin’s Lymphoma. Given its prevalence, there is an interest in studying the treatments available and how these can be improved. The standard treatment is a chemotherapeutic regimen known as R-CHOP. The goal of this paper is to inform of an integrative approach to R-CHOP, implementing high dose intravenous Vitamin C (AA) with glutathione (GSH). In the case presented herein, the patient attained complete remission with a minimal toxicity profile and an excellent performance status. These results present a possible viable approach for patients suffering of Diffuse Large B-Cell Lymphoma. In this paper, we also briefly review the literature available on the aforementioned treatment.

Phase II trial assessing safety and preliminary efficacy of high-dose intravenous ascorbic acid in patients with TET2-mutant clonal cytopenias of undetermined significance.

TPS7076 Background: Clonal cytopenias of undetermined significance (CCUS) is operationally defined as unexplained persistent cytopenias arising in the context of leukemia-associated somatic driver mutations in hematopoietic stem and progenitor cells, without morphologic evidence for an underlying hematological neoplasm. Patients with TET2 mutant ( TET2MT) CCUS have a high probability of progression to myeloid neoplasms, with approximated 10-year cumulative rates of progression being 90%. To date, no FDA-approved treatment for CCUS has been established, and we have shown that these patients can have transfusion burdens akin to patients with myelodysplastic syndrome (MDS) (Li M et al. Blood Adv 2020). Thus there is an urgent and unmet need for therapies for these patients. Intravenous (IV) ascorbic acid (AA) dosed at pharmacologic concentrations could have anti-cancer activity via two mechanisms: (1) hydrogen peroxide-induced oxidative stress and (2) DNA demethylation mediated by TET activation (cofactor for TET1/2/3). TET2, the primary enzyme for catalyzing oxidative reactions, converts 5-methylcytosine to 5-hydroxymethylcytosine, a crucial step leading to iterative DNA demethylation. Our study hypothesis is that IV AA in TET2MT CCUS will restore hematopoiesis and limit clonal progression by stimulating TET2 (the unmutated allele) and TET3 activities. Methods: LS1781 (NCT03418038) is an investigator-initiated, prospective, single-arm, single-institution, phase II trial assessing the safety and preliminary efficacy of high dose of IV AA for patients with TET2MT CCUS (harboring ≥1 TET2MT or TET2MT combined with concurrent spliceosome MTs). IV AA (1g/kg, maximum 100g) is given 3 times weekly for 12 weeks through a central line with assessments being carried out before each cycle (4 weeks), at 12 weeks, and one year. The primary endpoint is the hematologic response rates determined by MDS IWG 2018 criteria. Secondary endpoints include safety and side effects. Exploratory endpoints include the impact of AA on TET2MT variant allele fraction, plasma cytokine levels, DNA methylation, and hydroxymethylation (as measured by Infinium MethylationEPIC array), and TET activity. Patients 18 years or older with TET2MT CCUS, and with any of the following laboratory criteria: (1) hemoglobin ≤10g/dL, (2) absolute neutrophil count (ANC) ≤1000/mm3, (3) platelet count ≤100,000/mm3 are eligible. Fifteen patients will be enrolled at Mayo Clinic Rochester and the Mayo Clinic Health System. Dose modifications have been established and will be considered based on adverse events. Treatment will be discontinued for disease progression or in the event of ≥Grade 3 adverse events that don’t resolve promptly. Enrollment to the trial began in June 2021, with 7 patients enrolled at abstract submission. Clinical trial information: NCT03418038.

Effect of intravenous ascorbic acid administration on hemorrhage and wound complications in total abdominal hysterectomy: A prospective randomized clinical trial

Previous studies mentioned the beneficial effects of vitamin C on the hemorrhage and wound healing. We evaluated the effects of vitamin C on the hemorrhage, hemoglobin concentration, and wound complications in total abdominal hysterectomy. In this randomized, double-blind, placebo-controlled trial, 80 patients with total abdominal hysterectomy were randomly divided into the study and control groups to receive either intravenous 2g of vitamin C in normal saline or solely normal saline therapy. The first 1-g dose of ascorbic acid was administrated the night before surgery, and the second 1g was administrated during surgery. The mean age of the participants was 37.8±4.8 years with a mean preoperative plasma vitamin C concentration of 5.07±2.1mg/dL, close to the subclinical deficiency. The basal characteristics of both groups were the same. The hemorrhage volume was slightly higher in the control group (345.2±31.8ml vs. 388.1±28.3ml, P<0.001). Intravenous vitamin C administration had a positive effect on reducing hemorrhage during total abdominal hysterectomy. Clinicaltrials.gov.identifier: NCT03965637.

Triple Negative Breast Cancer (TNBC) Cells Growth is Inhibited by High Dose Ascorbic Acid

ObjectiveAccording to the World Health Organization report, the incidence of breast cancer mortality is very high worldwide with 2.1 million women are being affected each year and death are estimated at 627,000 women. There are several subtypes of breast cancer. One of these subtypes is known as triple‐negative breast cancer (TNBC). TNBC doesn’t have the receptors for the hormone estrogen, nor progesterone, nor express HER2/neu; therefore, TNBC doesn’t respond to hormonal nor targeted therapies which makes TNBC difficult to treat.The desired outcome of the cancer therapies is to decrease the proliferative activity of the cancer cells, to minimize drug resistance, and to decrease the toxicity of the anticancer drugs. Ascorbic acid has gained popularity as preventive agent for cancer due to its minimal cytotoxic to normal cellular tissue; however, the use of ascorbic acid for the treatment of cancer has controversial history. Taking oral ascorbic acid had no or little effect on cancer treatment, but recent discovery that intravenous ascorbic acid can provide 100‐fold higher plasma levels than oral intake has renewed interest on the role of ascorbic acid in the cancer treatment.HypothesisAt high dose (pharmacological concentrations), ascorbic acid may act as a prodrug to deliver extracellular H2O2 that is selectively toxic to cancer cells, but non‐toxic and well tolerated to normal cells. It is postulated that TNBC cells growth will be inhibited by high dose of ascorbic acid.MethodsAscorbic acid was buffered to pH 7 with sodium hydroxide and prepared immediately before use. MDA‐MB‐231 cells was used as TNBC model. MTT assay, Hoechst33342, H2DCFDA, and Rhodamine123 staining using fluorescent microscope were conducted to determine cell viability, chromatin inducing apoptosis, intracellular generation of ROS, and mitochondrial membrane potential, respectively. Western Blot to detect different signaling protein expressions such as Poly (ADP‐Ribose) polymerase (PARP), Casp‐3, Casp‐9, P‐53, Bax, Bcl2, Apaf‐1, MMP2, MMP 9, BRCA1, BRCA2, Bim, Map kinases were conducted to test the hypothesis that ascorbic acid was effective to kill TNBC cells.ConclusionThis finding suggests that high dose ascorbic acid has a potential candidate as effective anti‐cancer for TNBC. At 1.6 mM, ascorbic acid killed MDA‐MB‐231, a TNBC cells by causing increased in caspase 3‐9 activities and by decreasing cell cycle regulatory proteins, Mitogen activated kinase 1‐4, and reactive oxygen species.

Pharmacologic Ascorbic Acid as Early Therapy for Hospitalized Patients with COVID-19: A Randomized Clinical Trial.

Despite the widespread availability of effective vaccines, new cases of infection with severe acute respiratory syndrome coronavirus-2, the cause of coronavirus disease 2019 (COVID-19), remain a concern in the settings of vaccine hesitancy and vaccine breakthrough. In this randomized, controlled, phase 2 trial, we hypothesized that high-dose ascorbic acid delivered intravenously to achieve pharmacologic concentrations may target the high viral phase of COVID-19 and thus improve early clinical outcomes. Sixty-six patients admitted with COVID-19 and requiring supplemental oxygen were randomized to receive either escalating doses of intravenous ascorbic acid plus standard of care or standard of care alone. The demographic and clinical characteristics were well-balanced between the two study arms. The primary outcome evaluated in this study was clinical improvement at 72 h after randomization. While the primary outcome was not achieved, point estimates for the composite outcome and its individual components of decreased use of supplemental oxygen, decreased use of bronchodilators, and the time to discharge were all favorable for the treatment arm. Possible favorable effects of ascorbic acid were most apparent during the first 72 h of hospitalization, although these effects disappeared over the course of the entire hospitalization. Future larger trials of intravenous ascorbic acid should be based on our current understanding of COVID-19 with a focus on the potential early benefits of ascorbic in hospitalized patients.

Undetectable triglycerides related to the combined intake of ascorbic acid and tacrolimus.

Management of triglyceride (TG) levels is essential in intensive care units (ICU), especially to manage the risk of pancreatitis induced by propofol. However, some therapeutics in ICU such as intravenous ascorbic acid protocol, especially used in the context of Covid-19 could lead to false decrease of triglycerides by analytical disruption of Trinder reaction. We report here the case of a sample with unmeasurable triglyceride levels partly due to high plasma ascorbic acid levels. However, repeated measure on the same sample four days later revealed that interference mechanism on TG was still present whereas the level of ascorbic acid was very reduced by oxidation degradation. Hence, additional interference mechanism was suspected. After clinical investigation, we found that the patient had also received high doses of tacrolimus due to a transplant. As previous studies reported that tacrolimus treatment lead to a decrease of the measured plasma activity of lipoprotein lipase (LPL), we hypothesized that tacrolimus or related metabolites could also interfere by direct inhibition of LPL involved in TG analytical method used.