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Pharmacokinetics of oral vitamin C
Abstract
Purpose. To test whether plasma vitamin C levels, following oral doses in supplemented volunteers, are tightly controlled and subject to a maximum in the region of 220 mM L 21 , as suggested by previous researchers for depleted subjects. To determine plasma levels following single, variable-sized doses of standard and liposomal formulations of vitamin C and compare the effects of the different formulations. To determine whether plasma levels above ,280 mM L 21 , which have selectively killed cancer, bacteria or viruses (in laboratory experiments), can be achieved using oral doses of vitamin C. Design. This was a single blind study, measuring plasma levels in two subjects, in samples taken half-hourly or hourly for 6 hours, following ingestion of vitamin C. Data were compared with published results and with data from 10 years of laboratory plasma determinations. Materials and methods. Standard 1 gram tablets of vitamin C; liposomal vitamin C. Plasma levels were analysed using the method of Butts and Mulvihill. Results. Preliminary investigations of the effects of liposomal and standard formulation ascorbate showed that blood plasma levels in excess of the previously assumed maximum of 220 mM L 21 are possible. Large oral doses of liposomal ascorbate resulted in plasma levels above 400 mM L 21 . Conclusions. Since a single oral dose can produce plasma levels in excess of 400 mM L 21 , pharmacokinetic theory suggests that repeated doses could sustain levels well above the formerly assumed maximum. These results have implications for the use of ascorbate, as a nutrient and as a drug. For example, a short in vitro treatment of human Burkitt's lymphoma cells with ascorbate, at 400 mM L 21 , has been shown to result in ,50% cancer cell death. Using frequent oral doses, an equivalent plasma level could be sustained indefinitely. Thus, oral vitamin C has potential for use as a non-toxic, sustainable, therapeutic agent. Further research into the experimental and therapeutic aspects of high, frequent, oral doses of ascorbic acid either alone or (for cancer therapy) in combination with synergistic substances, such as alpha-lipoic acid, copper or vitamin K3, is needed urgently.
... Earlier studies suggested that AA is cytotoxic at millimolar concentrations, which are achievable by intravenous injection but not by oral administration [4,16]. However, revised interpretations and new knowledge about the pharmacokinetic properties of AA showed that a large oral dose can result in plasma concentrations of around 200 μM [4,[16][17][18]. Furthermore, several pharmaceutical formulations of vitamin C (e.g. ...
... Furthermore, several pharmaceutical formulations of vitamin C (e.g. liposomal encapsulations) can achieve levels of up to 400 μM [18,19]. These new pharmacokinetic data and the results of previous clinical studies of orally administered vitamin C [3,20] prompted us to investigate the in vitro effect of orally achievable concentrations of AA on CLL B-cells. ...
... As shown in Fig. 1a, apoptosis was induced in a dose-dependent manner. For CLL B-cells, the LC 50 was 213 μM -a dose that could be achieved in vivo by oral administration of the maximal tolerated amount of AA [16,18]. In contrast, the LC 50 for HD B-cells was 800 μM (Fig. 1a). ...
Background
Novel, less toxic, cost-effective and safe therapeutic strategies are needed to improve treatment of chronic lymphocytic leukemia (CLL). Ascorbic acid (AA, vitamin C) has shown a potential anti-cancer therapeutic activity in several cancers. However, the anti-cancer effects of ascorbic acid on CLL B-cells have not been extensively studied. We aimed in this study to evaluate the in vitro therapeutic activity using clinically relevant conditions.
Methods
Primary CLL B-cells and two CLL cell lines were exposed to a dose that is clinically achievable by AA oral administration (250 μM), and cell death and potential mechanisms were assessed. The role of the protective CLL microenvironment was studied. Synergistic interaction between AA and CLL approved drugs (Ibrutinib, Idelalisib and Venetoclax) was also evaluated.
Results
Ascorbic acid is cytotoxic for CLL B-cells at low dose (250 μM) but spares healthy B-cells. Ascorbic-acid-induced cytotoxicity involved pro-oxidant damage through the generation of reactive oxygen species in the extracellular media and in CLL cells, and induced caspase-dependent apoptosis. We also found that AA treatment overcame the supportive survival effect provided by microenvironment including bone marrow mesenchymal stem cells, T-cell cues (CD40L + IL-4), cytokines and hypoxia. Our data suggest that resistance to AA could be mediated by the expression of the enzyme catalase in some CLL samples and by the glucose metabolite pyruvate. We also demonstrated that AA synergistically potentiates the cytotoxicity of targeted therapies used in or being developed for CLL.
Conclusion
These preclinical results point to AA as an adjuvant therapy with potential to further improve CLL treatments in combination with targeted therapies.
... An increasing current response for vitamin C in the stimulated sweat is clearly observed following the intake of 250, 500, and 1000 mg of vitamin C ( Figure 2C), indicating that the sensor responds favorably to variations in vitamin C sweat levels. Note, however, that the response for 500 and 1000 mg of vitamin C are nearly similar, reflecting the body's limitation in absorbing large amounts of vitamin C. 38 It is also important to notice that direct translation of the current response values to concentrations (through in vitro precalibration of the corresponding electrode batch, similar to those of Figure 2A) will facilitate the desired quantitation. Such quantitation is beyond the scope of this proof-of-concept study which aims at introducing a noninvasive sensor for tracking qualitatively the dynamics of vitamin C following food or supplement intake. ...
... The results of the amperometric response of sweat vitamin C of four volunteers at 0, 45, 90, 135, and 180 min after taking the 1000 mg pill are shown in Figure 3B(a−d). The maximum vitamin C signal (ΔI) was achieved 90 min after taking the vitamin supplement, followed by a decreasing signal, approaching the baseline, after 180 min 38 The corresponding sweat vitamin C temporal profiles, shown in Figure 3B(e−h), reflect the pharmacokinetic profile of vitamin Cincluding the changes in plasma vitamin Cas described in previous studies. 38,39 Such different profiles of different subjects to a given amount of vitamin Cwith different maximum currents and specific current changesindicate the potential of the epidermal biosensor toward personalized nutrition applications. ...
... The maximum vitamin C signal (ΔI) was achieved 90 min after taking the vitamin supplement, followed by a decreasing signal, approaching the baseline, after 180 min 38 The corresponding sweat vitamin C temporal profiles, shown in Figure 3B(e−h), reflect the pharmacokinetic profile of vitamin Cincluding the changes in plasma vitamin Cas described in previous studies. 38,39 Such different profiles of different subjects to a given amount of vitamin Cwith different maximum currents and specific current changesindicate the potential of the epidermal biosensor toward personalized nutrition applications. In order to further assess the sensor performance, control evaluations were performed by conducting the same experiments without taking any vitamin pill. ...
Recent advances in wearable sensor technologies offer new opportunities for improving dietary adherence. However, despite their tremendous promise, the potential of wearable chemical sensors to guide personalized nutrition solutions has not been reported. Here we present an epidermal biosensor aimed at following the dynamics of sweat vitamin C after intakes of vitamin C pills and fruit juices. Such skin-worn non-invasive electrochemical detection of sweat vitamin C has been realized by immobilizing the enzyme ascorbate oxidase (AAOx) on flexible printable tattoo electrodes and monitoring changes in the vitamin C level through changes in reduction current of the oxygen co-substrate. The flexible vitamin C tattoo patch was fabricated on a polyurethane substrate and combined with a localized iontophoretic sweat stimulation system along with amperometric cathodic detection of the oxygen depletion during the enzymatic reaction. The enzyme biosensor offers highly selective response compared to common direct (non-enzymatic) voltammetric measurements, with no effect of electroactive species such as uric acid or acetaminophen. Temporal vitamin C profiles in sweat are demonstrated using different subjects taking varying amounts of commercial vitamin C pills or vitamin C-rich beverages. The dynamic rise and fall of such vitamin C sweat levels are thus demonstrated with no interference from other sweat constituents. Differences in such dynamics among the individual subjects indicate the potential of the epidermal biosensor for personalized nutrition solutions. The flexible tattoo patch displayed mechanical resiliency to multiple stretching and bending deformations. In addition, the AAOx biosensor is shown useful as a disposable strip for rapid in-vitro detection of vitamin C in untreated raw saliva and tears following pill or juice intakes. These results demonstrate the potential of wearable chemical sensors for non-invasive nutrition status assessments and tracking of nutrient uptake toward detecting and correcting nutritional deficiencies, assessing adherence to vitamin intake, and supporting dietary behavior change.
... 16 Moreover, liposomal forms lead to higher plasma levels and circulating time compared to standard forms. 17 Considering antioxidant and antihypertensive activity of high doses of standard vitamin C, and superiority of liposomal dosage forms, the present study was designed to compare the antihypertensive as well as vascular modifying activities of liposomal and non-liposomal vitamin C in rat model of two-kidney, one-clip renovascular hypertension. ...
... 25 There is some controversy regarding the antihypertensive properties of ascorbic acid in clinical studies which might be due to different research sample sizes, target group ages, and dose and/or duration of ascorbic acid administrations. According to Hickey and colleagues, following continuous oral administration of liposomal vitamin C, the plasma level reached approximately twice the predicted maximum level with standard form of vitamin C. 17 Accordingly, they concluded that large oral doses of vitamin C could potentially be used as a non-toxic, sustainable, therapeutic agent. 17 To the best of our knowledge, the present study is the first to compare both liposomal and non-liposomal forms of high doses vitamin C regarding chronic antihypertensive and vascular response in renovascular hypertensive rats. ...
... According to Hickey and colleagues, following continuous oral administration of liposomal vitamin C, the plasma level reached approximately twice the predicted maximum level with standard form of vitamin C. 17 Accordingly, they concluded that large oral doses of vitamin C could potentially be used as a non-toxic, sustainable, therapeutic agent. 17 To the best of our knowledge, the present study is the first to compare both liposomal and non-liposomal forms of high doses vitamin C regarding chronic antihypertensive and vascular response in renovascular hypertensive rats. Our findings indicate that compared to the hypertensive group, treatment with vitamin C, in both forms and doses, could effectively decrease the SBP in a dose-dependent manner. ...
Background:
Liposomes constitute a promising drug delivery vehicle, and are believed to improve drugs' effectiveness. This study was aimed to compare antihypertensive and vascular modifying activities of liposomal and non-liposomal forms of ascorbic acid.
Methods:
Forty-nine male Sprague-Dawley rats were randomly divided into seven groups (n=7): A sham vehicle-receiving (Sham-veh), hypertensive (HTN), vehicle-receiving hypertensive (HTN-Veh), two liposomal Ascorbic acid-treated hypertensive at 50 or 100 mg/kg/day (LVC-50 and LVC-100), and two non-liposomal Ascorbic acid-treated hypertensive at 50 or 100 mg/kg/day (VC-50 and VC-100). Systolic blood pressure (SBP) and heart rate (HR) were measured weekly; after 4 weeks, dose-responses to phenylephrine (PE) in the absence and presence of nitro-L-arginine methyl ester (L-NAME), acetylcholine (Ach), and sodium nitroprusside (SNP) were obtained on aortic rings. Data were analyzed with one-way ANOVA and Duncan's multiple range test at a P value of <0.05 using Sigmastat statistical software.
Results:
Compared to the non-liposomal form, the liposomal one was associated with more prominent effects on the final SBP. Both forms of Ascorbic acid decreased SBP dose-dependently. The basal and stimulated release of Nitric Oxide (NO) was significantly recovered by both forms of Ascorbic acid. The PE maximal responses were not significantly different between the liposomal and non-liposomal groups (P=0.08). Although the Emax of Ach-relaxation response was not different in two preparation forms, Ach-relaxation response induced a lower concentration of the liposomal form of Ascorbic acid (P=0.03.
Conclusion:
The liposomal Ascorbic acid exhibited relaxation activity in significantly lower concentrations. The observed effects were partly mediated by the increased basal release of NO.
... The reviewers provide 20 numerous illustrations to suggest that vitamin C "may exert additional health benefits" with respect to chronic disease. However, their claim that studies "have not found consistent benefit with respect to chronic disease prevention" stems from a lack of understanding of the dosing and pharmacokinetics of 25 vitamin C, as has been explained previously, in detail (Duconge et al., 2008;Hickey et al., 2008). The reported belief of Frei et al. that there is a "lack of apparent proof of benefit" from RCTs might be considered in terms of the irrationality of a requirement for scientific proof. ...
... Frei 50 et al. have ignored decades of observations and results reported for high dose supplementation. In particular, the ascorbate requirement variation reported by Cathcart (1985) and others (Pauling, 1987;Hickey et al., 2005Hickey et al., , 2008 are disregarded. Cathcart (1981) reported that, during periods of stress 55 or illness, the body's tolerance to oral doses increases in proportion to the disease severity. ...
... Such reports also suggest a definitive clini-60 cal response, with a clear pharmacokinetic explanation. These data imply that people require a reserve daily intake (Hickey et al., 2008). Importantly, they also invalidate the Frei et al. claims concerning limited "bioavailability." ...
Frei et al's 2012 review entitled "Authors' Perspective: What is the Optimum Intake of Vitamin C in Humans" is both flawed and misleading. RCTs are ill suited to determining the RDA, it is debatable that there is sufficient scientific evidence to determine the optimum intake of vitamin C in humans, observations regarding high-doses of ascorbate have been ignored, and there are inaccuracies of fact with respect to the saturation of blood plasma following low dose intake. Until the limitations of current knowledge are recognised it is unwise to set limits on the dose.
... However, liposomes applied to medical use range between 50 and 450 nm [21]. Previous studies indicated potentially improved absorption of liposomal vitamin C compared to standard vitamin C; however, those studies were either not randomized nor double-blind, lacked a placebo group, used unpractical, extremely high amounts of vitamin C (4-36 g), or were of short duration (6-8 h) [16,[22][23][24]. ...
... At the 5 g dose, the liposomal and standard formulation showed similar plasma responses. Liposomes are absorbed from the gut into the liver, before being released into the blood resulting in a slower onset of peak levels in the 20 g dose [23]. ...
Purpose
L-Ascorbic acid (vitamin C) is an essential water-soluble vitamin that plays an important role in various physiological functions, including immune health. The stability of vitamin C in the gastrointestinal tract its bioavailability is limited. This study aimed to investigate if a liposomal form of vitamin C can increase absorption compared to standard vitamin C.
Methods
In a randomized, double-blind, placebo-controlled, crossover fashion, 19 males and 8 females (n = 27; 36.0 ± 5.1 years, 165.0 ± 6.9 cm, 70.6 ± 7.1 kg) ingested a single-dose of placebo (PLA), 500 mg vitamin C (VIT C), and 500 mg liposomal vitamin C (LV-VIT C, LipoVantage®, Specnova, LLC, Tyson Corner, VA, USA). Venous blood samples were collected 0, 0.5-, 1-, 1.5-, 2-, 3-, 4-, 6-, 8-, 12-, and 24-hours after ingestion and were analyzed for plasma and leukocyte vitamin C concentration.
Results
VIT C and LV-VIT C demonstrated significantly greater Cmax and AUC0 − 24 in plasma and in leukocytes compared to placebo (p < 0.001). Additionally, LV-VIT C had significantly higher Cmax (plasma + 27%, leukocytes + 20%, p < 0.001) and AUC0 − 24 (plasma + 21%, leukocytes + 8%, p < 0.001) values as compared to VIT C.
Conclusion
Liposomal formulation of vitamin C increases absorption into plasma and leukocytes.
Trial Registration
Clinical Trials Registry - India (CTRI/2023/04/051789).
... Although infusion methods via arteries or veins have higher bioavailability of vitamin C than oral administration, the disadvantages are obvious, such as strict administration criteria, risks of pathogen transmission, discomfort, and phlebitis [35][36][37]. The oral administration of vitamin C in the form of a crystalline powder or a liquid solution makes it prone to disintegration in the digestive system, particularly in the presence of metal ions; therefore, it is necessary to retard the breakdown of vitamin C in the stomach, and to enhance its absorption in the body, which can be achieved by encapsulation within the amphiphilic interior of the liposomes [38][39][40][41]. In addition to overcoming the oral bioavailability challenges and therapeutic issues of vitamin C, significant developments in drug optimization can improve orally administered health products, so that they reach the bloodstream by oral administration [42]. ...
... Lipid compounds that are usually regarded as harmless and biodegradable can promote transcellular delivery, by temporarily disrupting cellular lipophilic bilayers, as well as enhancing paracellular uptake of medicinal ingredients. Liposomal formulations of vitamin C not only delay its distribution, but can also increase absorption and prevent disintegration in the gut [38,39]. Generally, a healthy diet should contain lipids as a crucial element, especially phosphatidylcholines, as they have been shown to have a conducive impact on the overall wellness of patients [28,46,47]; in addition, the removal of organic solvents from the manufacturing process makes it challenging to achieve an ideal liposomal formulation; furthermore, the physical and chemical properties of phospholipids can change, upon the hydrolysis of ester linkages (between fatty acids and glycerol), the peroxidation of unsaturated acyl chains, and phospholipid degradation and oxidation, which may affect the quality and stability of the resulting liposomal forms [48,49]. ...
The aim of this study was to develop a facile and novel lipid-based formulation of vitamin C and vitamin D3. Liposomes loaded with vitamin C and D3 were characterized using transmission electron microscopy (TEM) and zeta potential measurements for evaluating morphology, particle size and physical stability. HPLC was employed to quantify the content of vitamin C and vitamin D3 in their liposomal forms. The UHPLC analysis of the lipid-based vitamin formulation is an easy and rapid method for the characterization as well as the quantification of all components. In addition, encapsulation efficiency, vitamin loading and stability analysis were performed by the UHPLC method, in order to evaluate the reliability of the optimized lipid-based formulation. The TEM results provided key support for the core type of liposome structure in the formulations, whereas the HPLC results indicated that the liposomal vitamin C and D3 systems were homogeneous, and did not undergo phase separation. Taken together, the results demonstrate that liposomal encapsulated vitamins (vitamin C and D3) possess a unilamellar vesicle morphology with uniform particle size, despite differences in the hydrophile–lipophile profiles of the vitamins. The highly efficient encapsulation properties of such liposomal constructs are proposed to contribute to enhanced vitamin bioavailability.
... The pharmacokinetics of ascorbic acid was found to be in consonance with the first order kinetics (Hickey et al. 2008) in humans. In studies in humans various route had been exploited in the administration of ascorbic acid (Hickey et al. 2008) used the oral route of administration of ascorbic acid, while Kazemi et al. (2014) explored the intravenous route in their study on gene expression. ...
... The pharmacokinetics of ascorbic acid was found to be in consonance with the first order kinetics (Hickey et al. 2008) in humans. In studies in humans various route had been exploited in the administration of ascorbic acid (Hickey et al. 2008) used the oral route of administration of ascorbic acid, while Kazemi et al. (2014) explored the intravenous route in their study on gene expression. Stephenson et al. (2013) used the intravenous route at a high dose in patients with cancer. ...
This write up is aimed at proffering solution to the problem of transportation stress in ruminants in the tropics. Ascorbic acid is safe as buttressed in this write up for the improvement of meat quality in short and long terms road transportation stress.This review cover an aspect of animal physiology of stress, veterinary pharmacological aspects of ascorbic acid, how ascorbic acid improved meat product of animals exposed to long transportation stress. Ascorbic acid had no withdrawal period and was scientifically proven to be advantageous to meat characteristics and animal welfare. This was given credence to by its advantages as an anti-oxidative agent in solving the menace of road transportation to veterinarians, animal scientists and other professionals in the livestock industry.
... Ascorbic Acid (AA) is a water-soluble antioxidant vitamin, non-toxic, sustainable and readily metabolised by the body of most domestic animals and humans (Padayatty et al., 2003;Hickey et al., 2008). AA is a carbohydrate-like substance involved in metabolic functions, including synthesis of collagen, maintenance of the structure, strength of blood vessels or release of hormones in the adrenal glands (Halliwell, 2012). ...
... AA is a carbohydrate-like substance involved in metabolic functions, including synthesis of collagen, maintenance of the structure, strength of blood vessels or release of hormones in the adrenal glands (Halliwell, 2012). When administered orally, its absorption takes about 30 minutes (Pardue et al., 1984;Hickey et al., 2008). Ascorbic acid has potent antioxidant properties; that is, it is able to reduce damage caused by reactive oxygen species (ROS). ...
... • The toxic effects of hydrogen peroxide on cancer cells were known since 1957, when Reginald Holman published a paper on "Nature", showing that rat implanted with Walker 256 adenocarcinoma, and treated by simply replacing their drinking water with 0.45% hydrogen peroxide, showed a rate of cure of 50-60%. reported, after the administration of a single dose of oral liposomal Vitamin C [109]; e) At times of stress or illnesses (including cancer), the body may absorb extra Vitamin C, as demonstrated by the principle of "bowel tolerance" to the nutrient administered by mouth. According to this principle, when the body is saturated with Vitamin C, a slight diarrhoea may appear, due to intestinal elimination of the nutrient; however, during stress or disease, the amount of oral Vitamin C a patient can tolerate, before the appearance of diarrhoea, increases in proportion with the severity of the condition [110]; ...
... d. The possibility of using "alternative" formulations (such as liposomes), with increased absorption and improved bioavailability [109,173]. ...
... Lipid aggregates, such as liposomes, are well suited for this purpose. They reduce the vitamin C degradation in the gastrointestinal tract, slow down its release and enhance absorption (Hickey et al. 2008, Wechtersbach et al. 2012. Liposomes also mitigate possible perturbances of gastrointestinal tract functioning, what enables application of elevated doses of vitamin C for extended periods of time. ...
... In addition, it is not to be overlooked that lipids, phosphatidylcholines in particular, are an important component of a balanced diet with documented positive effects on the patient overall wellbeing (Alvarez and Rodriguez 2000, Keller 2001, Kullenberg et al. 2012, Blesso 2015, Garcia and Aguero 2015, van der Veen et al. 2017. All that have stimulated numerous works leading to the development of liposomal formulations of vitamin C for varieties of applications (Hickey et al. 2008, Xie and Ji 2008, Marsanasco et al. 2011. The manufacturing of liposomal preparations on an industrial scale requires strict process control of both chemical and physicochemical parameters, which make the production very challenging (van Nieuwenhuyzen andSzuhaj 1998, van Nieuwenhuyzen andTomas 2008). ...
Vitamin C is the exogenous compound necessary for a variety of metabolic processes; therefore, the efficient delivery is critical for the maintenance of body homeostasis. Vitamin C pharmacokinetics and low quantities in processed foodstuff, necessitates its continuous supplementation. In the paper, we present the new liposomal formulation of vitamin C free of harmful organic solvents. The formulation was quantitatively characterized with respect to its chemically composition and nano-structuring. The vitamin C accessibility to cells from the formulation was evaluated using evidence derived from experiments performed on cell cultures. Finally, the enhanced bioavailability of vitamin C from the formulation was demonstrated in the medical experiment.
... On average, the baseline concentrations were slightly lower than recommended values. 15,23 Circulating concentrations of vitamin C prior to and following administration are presented in Figure 2A and B. Plasma vitamin C concentrations were greatest following intravenous administration at all time points compared with each of the other modes of delivery (P , 0.001). At two, three, and four hours, plasma vitamin C concentrations were greater after oral administration of vitamin C encapsulated in liposomes compared with placebo and unencapsulated vitamin C (P , 0.01); and unencapsulated vitamin C produced greater concentrations than placebo (P , 0.01). ...
... To our knowledge, there has been only one other published human study evaluating oral delivery of vitamin C encapsulated in liposomes, and this was a pilot study with only two research participants. 23 Circulating concentrations of vitamin C following oral delivery of 5 g of vitamin C encapsulated in liposomes were compared with concentrations following 5 g of unencapsulated vitamin C. No discernable differences were detected between the plasma concentrations; however, in light of its status as a pilot study, and with only two research participants, this lack of difference could be attributed to insufficient statistical power, that is, a type 2 error. ...
Intravenous administration of vitamin C has been shown to decrease oxidative stress and, in some instances, improve physiological function in adult humans. Oral vitamin C administration is typically less effective than intravenous, due in part to inferior vitamin C bioavailability. The purpose of this study was to determine the efficacy of oral delivery of vitamin C encapsulated in liposomes. On 4 separate randomly ordered occasions, 11 men and women were administered an oral placebo, or 4 g of vitamin C via oral, oral liposomal, or intravenous delivery. The data indicate that oral delivery of 4 g of vitamin C encapsulated in liposomes (1) produces circulating concentrations of vitamin C that are greater than unencapsulated oral but less than intravenous administration and (2) provides protection from ischemia-reperfusion-mediated oxidative stress that is similar to the protection provided by unencapsulated oral and intravenous administrations.
... Although, it has been demonstrated that pigs are capable of synthesizing ascorbic acid (AA), vitamin C, evidences have shown that during stress, the rate of the synthesis is grossly inadequate and plasma AA decreases considerably (De Rodas et al., 1998). AA is a water-soluble antioxidant vitamin, non-toxic, sustainable and readily metabolized by the body of most domestic animals and humans (Hickey et al., 2008;Padayatty et al., 2003), when administered orally its absorption takes about 30 min (Hickey et al., 2008;Pardue et al., 1984;Tsao, 1997). AA has been demonstrated to ameliorate heat and transport stresses in pullets (Ayo et al., 2005;Minka and Ayo, 2008) and increase nervous excitability in transported goats (Ayo et al., 2006). ...
... Although, it has been demonstrated that pigs are capable of synthesizing ascorbic acid (AA), vitamin C, evidences have shown that during stress, the rate of the synthesis is grossly inadequate and plasma AA decreases considerably (De Rodas et al., 1998). AA is a water-soluble antioxidant vitamin, non-toxic, sustainable and readily metabolized by the body of most domestic animals and humans (Hickey et al., 2008;Padayatty et al., 2003), when administered orally its absorption takes about 30 min (Hickey et al., 2008;Pardue et al., 1984;Tsao, 1997). AA has been demonstrated to ameliorate heat and transport stresses in pullets (Ayo et al., 2005;Minka and Ayo, 2008) and increase nervous excitability in transported goats (Ayo et al., 2006). ...
This study was carried out in order to determine the effect of eight-hour road transportation on the excitability scores of pigs administered ascorbic acid (AA) during the hot-dry season in Northern Nigeria. Thirteen experimental pigs were administered with AA orally at 100 mg/kg, while ten control pigs were given only distilled water orally. Excitability score of each pig was determined 30 min before and immediately after transportation by a single 'blind' observer during weighing. An excitability score of 4 indicated the highest excitability. Percent excitability of experimental and control pigs with each score was also determined. Post-transportation, an increase in the percentage of experimental pigs with excitability score of 4 was recorded (38.5 to 69.2%), while a decrease was obtained in the control pigs (40.0 to 10%). Road transportation decreased the excitability scores and percent excitability in control pigs with high scores. In conclusion, administration of AA increased the nervous excitability of pigs transported by road during the hot-dry season in northern Nigeria.
... Ascorbic acid is a water-soluble antioxidant vitamin, non-toxic, sustainable and readily metabolized by the body of most domestic animals and humans (Hickey et al. 2008;Padayatty et al. 2003), when administered orally its absorption takes about 30 min (Hickey et al. 2008;Pardue et al. 1984;Tsao 1997). Thus, ascorbic acid administration in pigs subjected to road transportation during the harmmatan and goats during the hot-dry season in the Northern Guinea Savannah zone of Nigeria has been shown to decrease RBC osmotic fragility and reduced oxidative damage to RBCs Minka and Ayo 2010). ...
... Ascorbic acid is a water-soluble antioxidant vitamin, non-toxic, sustainable and readily metabolized by the body of most domestic animals and humans (Hickey et al. 2008;Padayatty et al. 2003), when administered orally its absorption takes about 30 min (Hickey et al. 2008;Pardue et al. 1984;Tsao 1997). Thus, ascorbic acid administration in pigs subjected to road transportation during the harmmatan and goats during the hot-dry season in the Northern Guinea Savannah zone of Nigeria has been shown to decrease RBC osmotic fragility and reduced oxidative damage to RBCs Minka and Ayo 2010). ...
The experiments were performed in order to determine the effect of 8-h road transportation of pigs on erythrocytes osmotic fragility during the hot-dry season, and the ameliorative role of ascorbic acid. Twenty-three adult pigs comprising of both sexes served as subjects for the study. Thirteen pigs administered ascorbic acid (AA) per os 30 min before transportation, at a dose rate of 100 mg/kg served as experimental animals, while ten pigs administered with distilled water per os served as control, and were transported for 8 h during the hot-dry season. EDTA blood samples collected a day before (pre-transportation), immediately after 8-h transportation and 7 days post-transportation were used to determine erythrocyte osmotic fragility. The ambient temperature (AT) and relative humidity (RH) measured within the vehicle ranged between 30.5-39.0 °C and 40.0-71.0% respectively. These values were outside the thermoneutral zone for the pig, indicating that the season was thermally stressful. Results obtained showed a significant difference (p<0.05) in percent haemolysis recorded at NaCl concentrations of 0.4% and 0.6% immediately after transportation in experimental pigs and at 0.5, 0.6, 0.8 and 0.9% NaCl concentrations in experimental pigs 7 days post-transportation. In conclusion, result from the present study indicated that 8-h road transportation during the hot-dry season could induce stress resulting in haemolysis of erythrocytes and AA administration ameliorated the stress.
... One of the first studies to assess the bioavailability of liposomal versus non-liposomal ascorbate was by Hickey and colleagues in 2008 [27]. This study, however, reported data from only two cases and was not included in this scoping review. ...
Due to the essential requirement of vitamin C (ascorbate) by humans, formulation of the vitamin to increase its bioavailability is of relevance, particularly for those with higher requirements for the vitamin. In this scoping review, studies assessing the bioavailability of liposomal versus non‐liposomal ascorbate were identified through database and manual searching and relevant pharmacokinetic data were extracted. Of the 321 studies identified, 10 were included in the final review. Seven of the trials used randomised crossover designs, one used parallel groups and two were non‐randomised. Vastly different liposomal formulations, ascorbate doses (0.15–10 g) and sample collection durations (4–24 h) were used, thereby making it difficult to directly compare the studies. Nevertheless, nine of the studies showed higher bioavailability of liposomal versus non‐liposomal ascorbate: 1.2–5.4‐fold higher Cmax and 1.3–7.2‐fold higher AUC. However, none of the studies assessed ascorbate elimination; therefore, it is uncertain whether the ratios of liposomal to non‐liposomal ascorbate in urine are equivalent to those observed in plasma. Furthermore, only two of the studies assessed in vivo cellular uptake and only two assessed potential biological effects. Thus, future studies should include urinary elimination and cellular uptake kinetics, assess participants with low baseline status and investigate potential biological effects.
Summary
Due to the essential requirement of vitamin C by humans, formulations to increase its uptake into the body are of relevance, particularly in those with higher requirements for the vitamin.
In this review, studies assessing the uptake of liposomal versus non‐liposomal vitamin C were investigated; liposomal vitamin C comprising the vitamin encapsulated within lipids.
Ten studies were identified, which administered different liposomal formulations, vitamin C doses (0.15‐10 g) and sample collection durations (4–24 h).
Nine of the studies showed higher uptake of liposomal vitamin C. Future studies should assess urinary excretion, cellular uptake and biological effects of liposomal vitamin C.
... It bypasses SVCT1 transporters, potentially increasing cellular uptake, with some studies reporting 1.5-2x higher plasma levels compared to oral ascorbic acid. (84,85) This form minimizes gastrointestinal distress and is suitable for highdose therapy (3000-6000 mg/day) in chronic conditions like inflammatory arthritis. However, it is costlier than standard forms, and long-term safety data remain limited. ...
ABSTRACT
Subclinical vitamin C deficiency, while less apparent than scurvy, is increasingly recognized as a contributing factor to idiopathic musculoskeletal pain, yet it remains underdiagnosed in clinical settings. This review consolidates mechanistic and clinical evidence that links vitamin C insufficiency to dysfunction in joints, bones, and muscles, advocating for its integration into pain management protocols. A comprehensive literature analysis of peer-reviewed studies was conducted, focusing on the roles of vitamin C in collagen biosynthesis, antioxidant defense, and immunomodulation. Clinical trials, observational studies, and mechanistic research were evaluated to clarify associations with musculoskeletal symptoms and therapeutic outcomes. Vitamin C deficiency disrupts collagen stability, increases oxidative stress, and triggers pro-inflammatory cytokine cascades, leading to nonspecific myalgia, arthralgia, and delayed recovery. High-risk populations, including smokers, the elderly, bariatric surgery patients, and socioeconomically disadvantaged groups, are disproportionately affected. Repletion trials indicate that vitamin C supplementation can reduce pain and improve functional outcomes, supporting its therapeutic use. Clinicians should routinely screen for vitamin C deficiency in patients presenting with unexplained musculoskeletal pain, particularly among at-risk groups. Evidence-based supplementation, dietary modifications, and interdisciplinary collaboration are essential to address this reversible contributor to chronic pain. The prevalence of vitamin C deficiency remains a significant public health concern, with estimates suggesting that approximately 7% of the U.S. population is affected, based on NHANES data from 2003 to 2006 and 2017–2018. In India, the prevalence is notably higher, with 74% of adults in North India and 46% in South India exhibiting deficiency, with men showing a higher prevalence than women. Further research is necessary to establish causality and optimize dosing regimens to mitigate the burden of vitamin C deficiency on musculoskeletal health.
... This form of vitamin C has a neutral pH (nonacidic) and has been shown in clinical studies to have a longer retention (up to 24 h) in immune cells (leukocytes) [15][16][17]. The other alternative forms include vitamin C lipid metabolites (PureWay C ® ), a composition that combines lipid metabolites (fatty acids) and citrus bioflavonoids with ascorbic acid for improved delivery efficiency to the human body [18]; liposomal-encapsulated L-ascorbic acid forms, encompassing different modern microencapsulation techniques that have been developed, involving the encapsulation of vitamin C with biopolymers and lipids like liposomes, which are expected to reduce the degradation of vitamin C, facilitate its controlled release, and enhance its absorption [19][20][21][22]; and sustained-release oral forms, utilizing a delivery format suited for sustained release over a 12 h period, such as the novel sustained-release L ascorbic acid (C-Fence ® ) [23]. ...
Vitamin C is an antioxidant and is essential for immune function and infection resistance. Supplementation is necessary when a sufficient amount of vitamin C is not obtained through the diet. Alternative formulations of vitamin C may enhance its bioavailability and retention over traditional ascorbic acid. This systematic review consolidates the evidence on this and the effects on immunity and infection. A systematic literature search was conducted in October 2024 in Embase and Medline, focused on healthy adults (Population); oral forms of liposomal-encapsulated ascorbic acid, liposomal-encapsulated lipid metabolite ascorbic acid, calcium ascorbate, slow-release ascorbic acid, or lipid metabolite ascorbic acid (Intervention); compared to placebo/others (Comparison); in terms of bioavailability, absorption, vitamin C concentration in plasma, serum, and leukocytes, and impacts on tolerability, immunity, and infection (Outcome); and included randomized or non-randomized controlled trials, single-arm trials, and observational studies (Study design). Thirteen studies were included, several evaluating calcium ascorbate in combination with vitamin C metabolites, including L-threonate, referred to here as Calcium ascorbate EC (Ester C®; n = 7). No safety or tolerability concerns were noted with Calcium ascorbate EC vs. placebo or ascorbic acid. Calcium ascorbate EC showed better tolerability and fewer epigastric adverse events, improved quality of life, and induced favorable oxalate changes vs. ascorbic acid. Four studies reported leukocyte vitamin C concentration, some showing higher concentrations with Calcium ascorbate EC vs. ascorbic acid; seven reported more favorable plasma concentrations with the alternative forms over ascorbic acid or placebo; one reported higher serum vitamin C levels with vitamin C lipid metabolites than with Calcium ascorbate EC, calcium ascorbate, and ascorbic acid. No study reported retention in tissues. One study reported a favorable impact of Calcium ascorbate EC on immune parameters, and one found an association of Calcium ascorbate EC with fewer colds and a shorter duration of severe symptoms vs. placebo. Findings suggest that alternative vitamin C forms can improve leukocyte vitamin C, sometimes without affecting plasma levels. Most studies (77%) had a low risk of bias. In conclusion, the type and delivery modality of vitamin C can impact its bioavailability and functionality. Studies highlight the advantages of Calcium ascorbate EC over traditional ascorbic acid in terms of its tolerability and its potential to increase leukocyte vitamin C concentrations, crucial for immune function and protection against infection. However, further research is required to conclusively establish its effects on immune health.
... Another research in the late 1970s, accomplished by Creagan, shows the failure of high-dose oral VC (10 g/day) in last-stage malignancy (26) . The previous two studies have used oral VC, which shows low bioavailability due to many factors and barriers that affect absorption from the intestine (27). It is suggested that VC could act as a cytotoxic agent to cancer cells through the formation of hydrogen peroxide, so it may inhibit tumor growth. ...
... Various forms of vitamin C are used in supplement formulations (i.e., calcium ascorbate (CA), liposomal encapsulated ascorbic acid (AA), liposomal encapsulated lipid metabolite AA, slow-release AA, lipid metabolite AA) with companies making claims these forms are superior to AA in absorptive ability, bioavailability, retention in leukocytes, and tolerability. Most comparative trials assess the efficacy of CA against AA [1][2][3][4][5][6][7][8]; however, several trials have shown higher retention, greater absorption, and tolerance in liposomal encapsulated vitamin C [8][9][10][11][12][13], but equivocal findings with sustained release vitamin C in plasma vitamin C concentration compared to AA [14][15][16]. ...
Background: Previous trials have displayed augmented intracellular vitamin C concentrations in the leukocytes at 24 h after acute supplementation with 1000 mg calcium ascorbate (CA), compared to ascorbic acid (AA). Objective: The primary objective was to evaluate comparative leukocyte vitamin C accumulation kinetics over 32 h following acute 250 mg or 500 mg doses from the two sources. Secondary objectives were to evaluate neutrophil phagocytic function and lymphocyte differentiation between the two sources of vitamin C. Methods: Ninety-three healthy females (250 mg, n = 27; 500 mg, n = 24) and males (250 mg, n = 19; 500 mg, n = 23) were assigned to ingest a single dose of CA or AA providing 250 mg or 500 mg of vitamin C in two separate double-blind, randomized crossover trials. Results: There were no significant differences in the primary or secondary outcomes between the two treatments in the 250 mg low-dose study. Conversely, there was evidence that ingestion of 500 mg of CA increased DHA in plasma, increased neutrophil functionality during the first 8 h of the PK study, promoted increased natural killer cells, and altered weight-adjusted PK profiles, suggesting greater volume distribution and clearance from the blood. Conclusions: These findings indicate that 500 mg of CA may promote some immune benefits compared to 500 mg of AA ingestion.
... However, the oral administration of VC reached only 200 µM with a further increase to 400 µM by a special encapsulated formulation of VC [105,107]. Novel VC pharmaceutical formulations focus on increasing structural stability and cellular uptake [108,109]. ...
The turn-on mutations of the KRAS gene, coding a small GTPase coupling growth factor signaling, are contributing to nearly 25% of all human cancers, leading to highly malignant tumors with poor outcomes. Targeting of oncogenic KRAS remains a most challenging task in oncology. Recently, the specific G12C mutant KRAS inhibitors have been developed but with a limited clinical outcome because they acquire drug resistance. Alternatively, exploiting a metabolic breach of KRAS-mutant cancer cells related to a glucose-dependent sensitivity to oxidative stress is becoming a promising indirect cancer targeting approach. Here, we discuss the use of a vitamin C (VC) acting in high dose as an oxidative “Trojan horse” agent for KRAS-mutant cancer cells that can be potentiated with another oxidizing drug arsenic trioxide (ATO) to obtain a potent and selective cytotoxic impact. Moreover, we outline the advantages of VC’s non-natural enantiomer, D-VC, because of its distinctive pharmacokinetics and lower toxicity. Thus, the D-VC and ATO combination shows a promising path to treat KRAS-mutant cancers in clinical settings.
... Furthermore, all medications exhibited equal protection against hypoperfusion damage [247]. Because iron deficiency is a prominent cause of anemia in nondialysis chronic kidney disease (ND-CKD) patients, Pisani et al. [248] investigated whether liposomal iron improved anemia in ND-CKD patients. ...
Advanced nutritional interventions are one of the key components of elite sports performance in general. Combat sports require a high percentage of muscle mass with minimum body weight to generate the maximum power possible. An adequate level of nutrition knowledge, particularly with respect to identifying energy needs while avoiding confusion over dietary supplements and false perceptions of steroid requirement, which may compromise the health condition, is of crucial importance. In this context, the aim of our work is to highlight nutritional requirements/nutritional assessment, the importance of daily dietary intake in combat players, which increasingly includes a broad range of sports nutrition supplements, and the roles of vitamins, minerals and proteins, combined with antioxidants and strength training, in muscular performance. The main nutrients required in the daily diet of combat players, the mechanisms of action, the main outcomes and possible side effects are summarized. Special attention is paid to natural supplements and their importance and advantages over synthetic ones, along with future trends of development.
... VitC has a half-life of 30 min and thus it was assumed that HPN administered overnight would not falsely affect plasma VitC concentrations. 8 Specialist IF dietitians recorded weight, height and anthropometric measurement (mid-arm muscle circumference and tricep skinfold), for which the methods are described elsewhere. 9,10 A pragmatic approach to dietary assessment of oral/enteral intake was undertaken, whereby experienced specialist IF dietitians took detailed diet histories of atypical dietary intake across the week. ...
Background
Ascorbic acid (VitC) is an essential coenzyme to maintain health, but there are minimal data on the adequacy of VitC supply in patients requiring home parenteral nutrition (HPN).
Methods
A prospective pilot study was carried out measuring plasma VitC, serum vitamins A, D and E, and the minerals zinc, copper, selenium and magnesium in 28 adult HPN‐dependent (≥6 months) patients.
Results
Fifty‐seven percent of patients had insufficient VitC status. There was a strong, positive correlation between HPN provision of VitC and plasma VitC concentrations (rs = 0.663, p = 0.00) with an 83% insufficiency rate below a provision of 800 mg week–1. There was no association seen between plasma VitC and number of HPN days week–1 (p = 0.539), number of months on HPN (p = 0.773) or dependency on HPN (86% ± 31% of energy requirements met via HPN (77% ± 23%, p = 0.39).
Conclusions
VitC insufficiency is prevalent in HPN‐dependent patients. Our data highlight the need for regular monitoring of VitC in those living with type III intestinal failure.
... Mikirova also studied the efficacy of liposomal AA at high dosages (36 and 25 g, respectively), and the results showed the inefficiency to absorb high dose of AA to the blood even at the liposomal formulations. 43,44 Besides, the physical stability of the formulation in a powdered form estimated a negative value for ζ-potential due to electrostatic repulsion between particles, which is larger with no propensity for the particles to come together. This stability of the formulation without flocculation can be ascribed to the strengthening effect of the TNF between the phospholipids and AA. ...
l-ascorbic acid (AA) or vitamin C is a crucial nutrient needed for optimal health. However, being unable to be synthesized by the body, it is thus necessary to be included in health care products. Moreover, AA is one of the antioxidants that occur naturally, which is used in pharmaceutical and food products as an antioxidant additive. However, AA is vulnerable to environmental settings and undergoes oxidative degradation to dehydroascorbic acid and further to inactive products. Therefore, new research strategies and approaches are required to augment its stability. The objective of this study is to develop and characterize a fiber-reinforced-phospholipid (FRP) matrix-based vehicle, Zeal-AA, for the delivery of AA and optimize the oral bioavailability of the obtained AA powder using an efficacy study by open-label, randomized, single-dose, two-treatment, two-sequence, two-period, two-way crossover. The structural and surface morphologies were analyzed by Fourier transform infrared spectroscopy, transmission electron microscopy, scanning electron microscopy, and differential scanning calorimetry studies. Encapsulation efficiency, mean particle size, size distribution, ζ-potential measurements, and ADMET profiling revealed the potential delivery system for AA. AUC0–t was found to be 55.23 (mg/dL) for Zeal-AA, whereas it was 9.38 (mg/dL) for AA, and Cmax was found to be 6.69 (mg/dL) for Zeal-AA, whereas it was 1.23 (mg/dL) for AA, with a fold difference of bioavailability in terms of AUC found to be 5.9 fold. The results show that a single oral dose of Zeal-AA is capable of rising the AA levels in the body relative to the control up to 24 h.
... It should, however, be noted that recent studies have suggested that sustaining higher plasma levels of AA may be possible by using the oral infusion of liposomal AA [174]. Interestingly, recent studies have outlined the preparation of novel oral liposomal formulations of AA with increased bioavailability and improved antioxidant efficiency [175,176]. ...
Lead (Pb) neurotoxicity is a major concern, particularly in children. Developmental exposure to Pb can alter neurodevelopmental trajectory and has permanent neuropathological consequences, including an increased vulnerability to further stressors. Ascorbic acid is among most researched antioxidant nutrients and has a special role in maintaining redox homeostasis in physiological and physio-pathological brain states. Furthermore, because of its capacity to chelate metal ions, ascorbic acid may particularly serve as a potent therapeutic agent in Pb poisoning. The present review first discusses the major consequences of Pb exposure in children and then proceeds to present evidence from human and animal studies for ascorbic acid as an efficient ameliorative supplemental nutrient in Pb poisoning, with a particular focus on developmental Pb neurotoxicity. In doing so, it is hoped that there is a revitalization for further research on understanding the brain functions of this essential, safe, and readily available vitamin in physiological states, as well to justify and establish it as an effective neuroprotective and modulatory factor in the pathologies of the nervous system, including developmental neuropathologies.
... Albumin-based nanoparticle reported by Scheffel & his team [103] 2008 Vitamin C oral liposomal formulation reported [104] 1973 ...
Advanced drug delivery systems such as liposomes, niosomes, ethosomes and phytosomes significantly influence the quality of synthetic drug formulations. However, the trend is now shifting towards natural-based moieties, most probably because of their promising therapeutic responses, and considerably lower incidence of side effects and toxicity issues. The effectiveness of herbal plant formulations in nano-sized particles in the delivery of active compounds is increased since nanoparticles offer a larger surface area and promote longer contact time with the surfaces of the targeted sites. Thus, nanoparticles allow the sustained release of small amounts of active compounds and the optimization of the dosing frequency of the drug. The implementation of nanotechnology in the development of natural-based products is able to enhance the delivery of plant extracts and active phytochemicals to the targeted sites. In fact, maximum therapeutic outcomes can be achieved since the herbal formulations are more stable compared to traditional preparations. The development of herbal formulations in modern drug delivery systems will be further discussed in this review. The possible improvement of phytosomes is highlighted in order to give future insights into improvising phytosomes as a targeted drug carrier system. A compilation of evidence-based studies involving the nanotechnology of herbal formulations is summarized accordingly. The use of modern technology in herbal drug delivery systems has been growing in past decades and needs to be further explored by scientists. Hence, at the end of this review, a brief summary is given of a few success stories regarding modern nano formulations that have been commercialized by leading herbal companies and which can be considered as great achievements in this field. Thus, this review is aimed at exploring the use of nanotechnology in drug delivery systems and discusses their contribution to the design of modern herbal formulations.
... Dodatkowo, jednorazowe dawki powyżej 2 g przy podaniu doustnym mogą działać przeczyszczająco. Zwiększenie wchłaniania przy podaniu doustnym możliwe jest przy zastosowaniu liposomalnej postaci kwasu L(+)-askorbinowego [17]. Uzyskanie znacznie wyższych stężeń o potencjalnym działaniu farmakologicznym w schorzeniach typu reumatoidalnych lub nowotworowych, rzędu milimolowych, jest jednak możliwe tylko w przypadku dożylnego podawania witaminy C [15,18]. ...
Celem tej pracy jest przedstawienie obecnego stanu wiedzy na temat witaminy C, jej wła-ściwości i działania fizjologicznego. Witamina C, czyli grupa związków o biologicznej aktywności analogicznej do kwasu L(+)-askorbinowego, jest niezbędna do prawidłowego przebiegu wielu różnych procesów w ludzkim organizmie. Przyczynia się do prawidłowego działania układu krążenia, immunologicznego i nerwowego, jak również utrzymania prawidłowego stanu skóry i układu ruchu, jednak mechanizmy jej działania nie są dokładnie poznane ze względu na trudności ze znalezieniem odpowiednich układów modelowych. Jej głównym źródłem są pokarmy pochodzenia roślinnego. Zapotrzebowanie na witaminę C zależy od trybu życia, wieku i stanu zdrowia, a optymalna wysokość dziennej dawki wciąż nie została jednoznacznie ustalona. Istnieją przesłanki wskazujące na pozytywny wpływ suplementacji witaminą C w przypadku chorób związanych z zaburzeniami układu immunologicznego czy chorób układu krążenia, a także możliwości stosowania witaminy C w terapii wspomagającej leczenie nowotworów czy sepsy przy podawaniu drogą dożylną.
... The antioxidant protective effect of vitamin C was obtained at oral dose supplementation (±25 µg/ml). High doses of vitamin C administrated intravenously were shown to produce millimolar plasma concentration of ascorbate, which is toxic to many cancer cell lines, inhibiting malignant growth through different mechanisms; nevertheless, this remains a subject of investigation and controversy [10][11][12][13] . ...
Ascorbate as well as other antioxidants (urate, caffeic acid and bovine albumin) are shown to alleviate oxidative damage (hemoglobin oxidation, cell lysis) effected by cisplatin on red blood cells. While such reactivity is visible at physiological ascorbate levels, at concentrations of 1 mM and above ascorbate alone induces oxidation of hemoglobin. Moreover, at higher concentrations irreversible heme degradation is shown. The oxyhemoglobin-ascorbate interaction appears to involve redox cycling of the heme through ferryl, on a peroxidase pathway relying on peroxides accumulated upon autooxidation and comproportionation of the ascorbate. This mixed reactivity is not unique to ascorbate among antioxidants.
... In order to improve vitamin C bioavailability and thus boost its beneficial effects, researchers have started to consider liposomal formulations as a good alternative to standard oral vitamin C supplementation. The first study to describe the pharmacokinetics of different single doses (5, 20, and 36 g) of liposomal vitamin C, versus 'standard' oral vitamin C (5 g), was conducted by Hickey and colleagues [20]. The authors reported that the highest peak plasma level (~ 400 uM/L) was achieved with 36 g, peaking after ~5-6 hours post-ingestion. ...
There are many orally ingested nutrients which cannot be fully absorbed bythe human body. For this reason scientists have been experimenting with different techniques to improve nutrient bioavailability. One such technique, microencapsulation, has been extensively used in industry in recent years, especially liposomal technology. Briefly, polar lipids are used to create spherical
capsules, called liposomes, where solids, liquids or gaseous materials compoundscan be entrapped. This technique is used to stabilize certain compounds in nutritional supplements and fortified foods, which would otherwise slowly degrade and lose their nutritional value, as well as improve their bioavailability.
Although there has been limited research investigating nutrients that might impact exercise performance (e.g. liposomal vitamin C and liposomal iron), there is currently no published evidence for the use of liposomal supplementation in this context. With the potential to augment nutrient bioavailability, further research should consider the application of liposomal formulations as a strategy to improve exercise performance.
... Oral uygulamalarda lipozomla kapsüllenmiş aktif ajanın bioyararlanımının arttığı gözlemlenmiştir. Bunun nedeni olarak lipozomların hücre zarına benzerliğinin yanı sıra; lipozomlarla kapsüllenmiş ajanların sindirim sistemi içerisinde dış etkilerden korunarak kana karışana dek bozunumunun engellenmesi gösterilmiştir [25,27,28]. 16,30]. ...
Lipozomlar farmasötik uygulamalar başta olmak üzere yıllardır birçok uygulamada kapsülasyon maddesi olarak kullanılan çift katmanlı polar lipitlerden oluşan keseciklerdir. Doğal fosfolipit kompozisyonları olan lesitinlerden elde edilen bu keseciklerin gıdalarda kullanımı son yıllarda artış göstermiştir. Lipozomların gıdalarda kullanımı sonucunda kapsüllenmiş maddenin stabilitesini arttırması ve bu maddenin bulunduğu ortamdaki diğer maddelerle etkileşimini minimize etmesi gibi faydalarının yanı sıra; diğer kapsülasyon maddelerine kıyasla oluşturulma metotlarının basitliği, tamamen doğal bileşiklerden oluşturulması gibi özellikleri, lipozomları birçok enkapsülasyon sisteminden ayıran belirgin özelliklerdir. Ancak lipozomların gıda uygulamalarında kullanılan yüksek sıcaklık, basınç, pH ekstremleri ve fiziksel karıştırma gibi stres koşulları karşısında stabilitesini koruyabilmesi zordur. Bu konuda süregelen araştırmalar, lipozom stabilitesinin artırılması için uygulanabilecek metotların varlığını göstermiştir. Bu derleme, gıda bilimi konusunda çalışan araştırmacılara, lipozomların yapısı, kullanımının sağladığı avantajlar, oluşturma metotları, karakterizasyonu, stabilite sorunları ve gıdalarda uygulama alanlarıyla ilgili bilgi vermek ve lipozomları bir kapsülasyon maddesi olarak kullanmak amacında olan araştırmacılara da yol gösterecek bir kaynak olmayı hedeflemiştir.
Liposomes are polar lipid bilayers vesicles used in pharmaceutical applications for years. These spherical vesicles are manufactured from natural phospholipid compositions known as lecithins. Their utilization in foods have recently attracted some interest. Using liposomes as encapsulating agents in foods provides a number of advantages like increased stability for the active agent and minimized interaction of capsuled material with the surrounding medium. However, what sets liposomes apart from other encapsulation agents is the ease of capsulation and its natural composition. Nevertheless, the fragile nature of liposomes poses some challenges with their use under extremes of temperature, pH or pressure. Studies have shown that a number of methods could help to increase liposomes' stability. This review is written with the purpose of providing food scientists, who plan to use liposomes as an encapsulation agent, with a Turkish source covering the chemical and physical structure of liposomes, the advantages they provide, production and characterization methods, stability issues, and their use in food related applications.
... The results further demonstrated that AA began to manifest its action as early as 30 min of its administration, corresponding to the time when the transportation lasted 30 min. This finding agreed with the results of the pharmacokinetic study on vitamin C that AA exerts its effects following 30 min of its oral administration in humans (Hickey et al., 2008). The results of this study further showed that AA exerted a hypothermic effect in treated rabbits, which agree with the previous findings of Ayo et al. (2005) in pullets and Minka and Ayo (2007b) the adverse effects of road transportation stress in rabbits, and that the vitamin is beneficial when administered to the animals before the commencement of the journey. ...
This experiment was performed with the aim of investigating the effects of ascorbic acid (AA) on stress due to road transportation of rabbits. Nine rabbits administered AA served as the treated animals, while seven other given sterile water were used as the controls. All the rabbits were transported by road for 2 h under standard conditions, and their rectal temperature (RT), excitability score and liveweight values were recorded before, during and after the transportation. The results showed that road transportation was stressful to all the rabbits, as evidenced by an increase in RT values of both the treated and control animals after the transportation. Post-transportation RT value in the control rabbits (39.67 ± 0.41°C) was significantly (P < 0.05) higher than that of the treated rabbits (39.0 ± 0.16°C). The excitability scores of the rabbits decreased considerably following road transportation, especially in the control rabbits that were not administered AA. The liveweights of both the treated and control rabbits decreased on arrival. On day 1 post-transportation, the control rabbits lost 2.70% of the pre-transportation liveweight, while the treated rabbits gained 2.37% of the pre-transportation liveweight. In conclusion, the administration of AA to rabbits prior to the commencement of the journey ameliorated the adverse effects of stress due to road transportation.
The management of ascorbic acid (AA) in biological fluids is of significant importance for body functions and human health, yet challenging due to the lack of high-performance sensing catalysts. Herein, we report the design of Rh single-atom nanozymes (Rh SAzymes) by mimicking the active sites of ascorbate peroxidase toward efficient electrocatalytic oxidation and detection of AA. Benefiting from the enzyme-mimicking single-atom coordination, the Rh SAzyme exhibits an unprecedented electrocatalytic activity for AA oxidation with an onset potential as low as 0.02 V (vs. Ag/AgCl). Combined with the screen-printing technology, a miniaturized Rh SAzyme biosensor was firstly constructed for tracking dynamic trends of AA in the human subject and detecting AA content in nutritional products. The as-prepared biosensor exhibits excellent detection performances with a wide linear range of 10.0 μM-53.1 mM, a low detection limit of 0.26 μM, and a long stability of 28 days. This work opens a door for the design of artificial single-atom electrocatalysts to mimic natural enzymes and their subsequent application in biosensors.
Vitamin C is an important nutrient implicated in different physiological functions in humans. Despite its important biological functions, therapeutic applications of vitamin C are rare and its use is further impacted by low chemical stability. Several nano-encapsulation techniques have been described in the literature and yet, there are only a handful of clinical investigations dedicated to unlocking the therapeutic applications of nano-encapsulated vitamin C. Clearly, further investigations are warranted in order to affirm the promising clinical potential of nano-encapsulated vitamin C. In this review, we describe the mechanisms of vitamin C activity as a modulator of crucial therapeutic uses in biological systems. We look at key factors affecting the chemical stability of vitamin C alone and in nano-encapsulated and explore pre-clinical and clinical evidence on current vitamin C nano-formulations along with their therapeutic applications. Finally, we critically appraise the gaps and opportunities prevailing in nano-vitamin C research and its potential translation towards relevant clinical outcomes.
Vitamin C is an essential nutrient that humans must consume because, unlike most mammals, humans cannot synthesize it from glucose. It has multiple physiological functions including serving as a cofactor for many essential molecules that provide structural, immune, and metabolic functions in the cells. The mitochondria are the energy-producing organelles of the cell. Mitochondria use aerobic glycolysis to produce a very efficient set of reactions called oxidative phosphorylation that is comprised of the Krebs cycle and the electron transport system, which produces physiological energy in the form of adenosine triphosphate. The production of energy by the mitochondria produces a significant amount of reactive oxygen species (ROS) which must be neutralized to avoid membrane and cell damage. Mitochondria generate 95% of the ATP in the cell. However, because the mitochondria generate ROS as a normal part of oxidative phosphorylation, and because its mitochondrial DNA (mDNA) lack histone protection, its genetic material is more vulnerable to damage which can lead to mitochondrial damage, mitochondrial energy deficits, and the development of chronic degenerative disease. Mitochondrial diseases are a group of congenital or acquired conditions where the capacity of the mitochondria to produce ATP is significantly reduced. The acquired condition can be a mutation, an enzymatic defect, or can be caused by an exogenous toxic agent. In some conditions, vitamin C can improve mitochondrial activity. Vitamin C supplementation can be helpful in reducing excessive ROS formation and protecting the mitochondria. In addition, it can reduce inflammation in various tissues including skeletal muscle. Therefore, it has the potential to improve recuperation time and athletic performance. Taken together, the effect antioxidant supplementation has on skeletal muscle adaptation to exercise training is still equivocal. On one hand, supplementation might produce possible interference with hormesis where stressors induce ROS that act as intracellular signaling molecules to promote adaptations that equip the cell to better tolerate future stress. On the other hand, supplementation may prevent excessive exercise-induced stress sufficient to chronically elevate ROS to levels and impair function and cause damage. This does not preclude the potential for acute antioxidant supplementation to enhance the performance of certain types of exercise and in certain sports. The level of ROS required to impair muscle performance is likely to be lower than that which would hamper muscle adaption.
A poorly water soluble polar and non-polar bioactive complexes encapsulated in a nanocellulose-based polymeric network are the focus of this research. Ascorbic acid, resveratrol, holy basil extract, pomegranate extract, and niacin are all microencapsulated bioactive complexes that make up Zetalife®, a nutritional ingredient. It uses an interpenetrating polymeric network (IPN) with more dispersed nanocellulose and phospholipids to increase Zetalife® s bioavailability. Field Emission Scanning Electron Microscopic (FESEM) images were used in studying the morphology of encapsulated bioactive molecules. The average microbead size was determined to be 244.2 nm. After each month of storage, the sample’s microbial content was measured to assess stability. In vitro release followed a first-order kinetic model with high R2.
The antioxidant, anti-inflammatory, immunomodulating, anti-thrombotic, and antiviral effects along with its protective effects against respiratory infections have generated a great interest in vitamin C (vitC) as an attractive functional/nutraceutical ingredient for the management of COVID-19. However, the oral bioavailability and pharmacokinetics of vitC have been shown to be complex and exhibit dose-dependent non-linear kinetics. Though sustained-release forms and liquid liposomal formulations have been developed, only marginal enhancement was observed in bioavailability. Here we report a novel surface-engineered liposomal formulation of calcium ascorbate (CAAS), using fenugreek galactomannan hydrogel in powder form, and its pharmacokinetics following a randomized, double-blinded, single-dose, 3-way crossover study on healthy human volunteers (n = 14). The physicochemical characterization and in vitro release studies revealed the uniform impregnation of CAAS liposomes within the pockets created by the sterically hindered galactomannan network as multilaminar liposomal vesicles with good encapsulation efficiency (>90%) and their stability and sustained-release under gastrointestinal pH conditions. Further human studies demonstrated >7-fold enhancement in the oral bioavailability of ascorbate with a significant improvement in pharmacokinetic properties (C max, T max, T 1/2, and AUC), compared to the unformulated counterpart (UF-CAAS) when supplemented at an equivalent dose of 400 mg of CAAS as tablets and capsules.
La Vitamine C est essentielle au bon fonctionnement métabolique, notamment en périodes d’infections. Son innocuité et son efficacité ont été démontrées. Ses capacités prophylactiques à faibles doses, et thérapeutiques à fortes doses, méritent une attention particulière dans le cadre de la pandémie à la Covid-19. Les essais cliniques de supplémentation en Vitamine C, y compris par voie intra veineuse dans le cadre de la Covid, sont en cours dans plusieurs pays et devraient le confirmer. Contrairement à ce qui se passe à l’étranger, la galénique injectable en France est encore limitée et les indications contraintes. Ses propriétés mériteraient la mise en place d’études scientifiques à grande échelle en France. Ces dernières permettraient de valider l’intérêt de la supplémentation de vitamine C en prévention, mais aussi dans le traitement des infections au SARS-CoV-2, afin d’éviter leur évolution critique.
Nutrients are essential for the healthy development and proper maintenance of body functions in humans. For adequate nourishment, it is important to keep track of nutrients level in the body, apart from consuming sufficient nutrition that is in line with dietary guidelines. Sweat, which contains rich chemical information, is an attractive biofluid for routine non‐invasive assessment of nutrient levels. Herein, a wearable sensor that can selectively measure vitamin C concentration in biofluids, including sweat, urine, and blood is developed. Detection through an electrochemical sensor modified with Au nanostructures, LiClO4‐doped conductive polymer, and an enzymes‐immobilized membrane is utilized to achieve wide detection linearity, high selectivity, and long‐term stability. The sensor allows monitoring of temporal changes in vitamin C levels. The effect of vitamin C intake on the sweat and urine profile is explored by monitoring concentration changes upon consuming different amounts of vitamin C. A longitudinal study of sweat's and urine's vitamin C correlation with blood is performed on two individuals. The results suggest that sweat and urine analysis can be a promising method to routinely monitor nutrition through the sweat sensor and that this sensor can facilitate applications such as nutritional screening and dietary intervention.
The aim of this study was to evaluate the oral bioavailability of liposomal vitamin C and non-liposomal vitamin C in healthy, adult, human subjects under fasting conditions through an open label, randomized, single-dose, two-treatment, two-sequence, two-period, two-way crossover, study. The vitamin C loaded liposome was well characterized using transmission electron microscopy (TEM), dynamic light scattering (DLS) and zeta potential measurements for evaluating morphology, particle size and stabilities, respectively. Microscopic image shows the core-type structure that confirms the characteristic pattern of liposome. The encapsulation efficiency (EE%) and the particle size were 65.85 ± 1.84% and below 100 nm, respectively. The results of the clinical studies of liposomal vitamin C by oral delivery to be 1.77 times more bioavailable than non-liposomal vitamin C. The liposomal vitamin C demonstrated higher values of Cmax, AUC0-
t
and AUC0-∞ related to non-liposomal vitamin C due to liposomal encapsulation. No adverse events were reported. It could be concluded that liposomal encapsulated ascorbic acid (vitamin C) shows well-organized morphological pattern, uniform particle size and highly efficient, which leads to have enhanced bioavailability.
Anthocyanins are considered the largest group of bioactive molecules belonging to the flavonoids class, providing the red, purple or blue colour of different parts of the plants. Great interest has been given to the topic mainly generated by the wide range of biological activities described either for individual or mixture of anthocyanins. Most of the health benefits of anthocyanins are linked to their strong antioxidant capacity and radical scavenging activity. Chemistry and stability of anthocyanins, as well as main food plant sources and the influence of extraction and food processing conditions are discussed. Such compounds are used as excellent ingredients intended for functional foods and pharmaceutical industry, as natural colouring agents for food industry, as well as natural dyeing alternatives in textile industry. Additional technological applications of anthocyanin extracts, such as sensitisers for solar cells are also described.
A derivative spectrophotometric method has been developed for the determination of platinum(IV) in various synthetic mixtures and hydrogenation catalysts. The method is based on the reaction of platinum(IV) with new chromogenic reagent glyoxal (p-anisyl)-thiosemicarbazone (GATSC) to give coloured species. The accurate determination of these metal ions by direct and derivative spectrophotometry has been discussed. The developed methods are simple, sensitive and selective in aqueous medium without prior separation or extraction.
Products containing extracts of medicinal herbs (Crataegus sp.) and toothbrushes (Tribulus terrestris L.) are used in pharmacy as food supplements and Over the Counter (OTC) products. Their effect is due to the biologically active flavonoids and oligomeric procyanidins from Crataegus oxiacantha and furostanol saponins and flavonoids contained in Tribulus terrestris. In the present work a method for quantitative determination of lead and cadmium in tablet forms of nutritional supplements containing extracts from these medicinal plants is developed and validated by atomic absorption flame spectrometry. The analytical parameters are defined: working range, linear range, limit of detection, limit of quantification, repeatability, recovery and accuracy. The measurement uncertainty in the lead and cadmium test in the analysed tablets was calculated.
The experiment was performed with the aim of determining the effect of co-administration of antioxidant vitamins, retinol, ascorbic acid and α-tocopherol on rectal temperature (RT) fluctuations in pullets during the hot-dry season in Nigeria. Forty-eight Black Harco pullets, aged 16 weeks and weighing 1.5 ± 0.03 kg were divided by simple random sampling into two groups, consisting of 28 treated and 20 control Black Harco pullets. The RTs of 28 treated and 20 control Black Harco pullets were measured hourly for 3 days, 3 days apart, from 06:00 to 19:00 h (GMT + 1) with a standard clinical thermometer. The treated pullets were administered individually with the vitamins orally in water, while the control pullets were given only water. The lowest hourly RT of 40.9 ± 0.04 °C was obtained in treated pullets at 06:00 h, while the highest value of 41.1 ± 0.01 °C was recorded from 17:00 to 19:00 h (P < 0.001). In control pullets, the RT rose significantly from 41.0 ± 0.03 °C at 06:00 h to the maximum value of 41.6 ± 0.04 °C at 15:00 h (P < 0.001). The pullets co-administered with retinol, ascorbic acid and α-tocopherol had consistently lower RT values than those of control pullets, especially during the hot hours of the day, from 13:00 to 17:00 h. It is concluded that co-administration of retinol, ascorbic acid and α-tocopherol, by preventing a rise in body temperature, ameliorated heat stress, and may enhance productivity of pullets reared under unfavourable, thermal environment conditions.
For several decades, the role of vitamin C in the treatment of cancer has been a subject of clinical research and controversy. It has been established that ascorbate is potentially a safe and effective anti-cancer agent, able to kill cancer cells while leaving healthy cells unharmed. However, its role has been viewed in the context of existing cytotoxic chemotherapy models of medicine. Consequently, many doctors and patients have come to believe that only intravenous vitamin C administration is an effective treatment for cancer. We suggest that this view is misguided and oral intakes are preferable.
The experiment was performed to evaluate the ameliorative effect of ascorbic acid (AA) on some hematological parameters and erythrocyte osmotic fragility (EOF) in horses transported by road. A total of 14 horses, consisting of seven experimental and seven control horses, were used for the experiment. Before the transportation, blood samples were obtained by jugular venipuncture from all the horses. Experimental horses were administered with AA (200 mg/kg dissolved in 20 mL of distilled water per os), whereas the control horses were given 20 mL of distilled water per os. Thereafter, the animals were transported for 6 hours and blood samples collected after transportation. Packed cell volume and hemoglobin concentration were higher (P < .05) in experimental than the control group, whereas total leukocytes reduced significantly (P < .05) in experimental in comparison with the control horses. Lymphocyte, neutrophil counts, neutrophil/lymphocyte ratio, and total protein decreased in experimental horses in comparison with control, but they were not significant (P > .05). Erythrocyte osmotic fragility was lower in experimental than the control at 0.3% NaCl concentration (P < .05). The result of the present study revealed that AA ameliorated changes in hematological parameters and EOF induced by road transport stress, partly because of its antioxidant properties.
In the European Union (EU), interest in risk analysis as applied to micronutrients is being stimulated by the increasing availability and marketing of food (dietary) supplements, functional and fortified foods. There is also strong inter-governmental interest in harmonizing methods regionally and globally. Various models are being evaluated in the EU for the purposes of developing Community-wide, mandatory maximum (and minimum) permitted levels, as required by EC Directive 2002/46/EC and Regulation (EC) No 1925/2006 on food supplements and fortified foods, respectively. This paper provides a scientific critique of models currently proposed in the EU and demonstrates weaknesses in both the risk assessment methods used to determine upper tolerable levels (ULs) as well as the risk management approaches being considered for the determination of maximum levels, particularly as applied to food supplements. Methods for ameliorating existing models are proposed here, including a proposal for using decision science as the underlying methodology in nutrient risk analysis. Risk management approaches based on more plausible scientific methods would avoid unnecessarily restrictive policy-based levels that would adversely impact consumer choice, while contributing to a 'better regulation' approach. Scientifically robust and rational methods of nutrient risk analysis are consistent with disease risk reduction, health management and consumer protection strategies.
We tested the effect of different concentrations of ascorbic acid (AA), 50, 100, 250 mg/500 mg/dL) with copper sulfate (CS), 10 mg/dL) on human breast carcinoma (MDA-MB231) cell proliferation in vitro. Cell proliferation was measured using a colori-metric assay (Cell proliferation kit II (XTT), Boehringer, NJ). The results of the mean absorbance of the tissue culture at different AA concentrations and a constant CS concentration were as follow: 0.82 +/- 0.03 (control, mean +/- SE), 0.64 +/- 0.02 (CS above); 0.48 +/- 0.03 (50 mg/dL) AA), 0.21 +/- 0.02 (100 mg/dL), 0.08 +/- 0.01 (250 mg/dL) AA, 0.60 +/- 0.05 (500 mg/dL). These results show that a combination of AA and CS inhibits human breast carcinoma cell proliferation in vitro. This cell proliferation inhibitory effect is directly proportional to the AA concentration with the exception of the 500 mg/dL AA dose. This chemotherapeutic effect was optimally enhanced when AA was added at a concentration of 250 mg/dL. The AA concentrations of 500 mg/dL had a biphasic effect on tumor cell proliferation probably due to back and forth redox reactions between AA and dehydroascorbic acid in a closed system. This study provides preliminary evidence that AA and SC can be used as biological response modifiers (BRM) for tumor growth inhibition.
The time course of radioactivity in plasma and urine after oral administration of a single dose of (1-14C)ascorbic acid has been followed in healthy nonsmoking male volunteers. The investigation was carried out under steady state conditions with regard to ascorbic acid intake (30 to 180 mg/day). Using pharmacokinetic principles, turnover, pool size, and rates of metabolism and excretion could be calculated. It was found that the half-life of ascorbic acid was inversely related to the dosage and that the pool could be increased to about 20 mg/kg bodyweight by increasing the dosage. It was concluded that on a daily intake of about 100 mg ascorbic acid this pool size would be reached in 95% of the population.
The acute effects of contraction and insulin on the glucose transport and GLUT4 glucose transporter translocation were investigated in rat soleus muscles by using a 3-O-methylglucose transport assay and the sensitive exofacial labeling technique with the impermeant photoaffinity reagent 2-N-4-(1-azi-2,2,2-trifluoroethyl)benzoyl-1,3-bis(D-mannose-4-y loxy)-2- propylamine (ATB-BMPA), respectively. Addition of wortmannin, which inhibits phosphatidylinositol 3-kinase, reduced insulin-stimulated glucose transport (8.8 +/- 0.5 mumol per ml per h vs. 1.4 +/- 0.1 mumol per ml per h) and GLUT4 translocation [2.79 +/- 0.20 pmol/g (wet muscle weight) vs. 0.49 +/- 0.05 pmol/g (wet muscle weight)]. In contrast, even at a high concentration (1 microM), wortmannin had no effect on contraction-mediated glucose uptake (4.4 +/- 0.1 mumol per ml per h vs. 4.1 +/- 0.2 mumol per ml per h) and GLUT4 cell surface content [1.75 +/- 0.16 pmol/g (wet muscle weight) vs. 1.52 +/- 0.16 pmol/g (wet muscle weight)]. Contraction-mediated translocation of the GLUT4 transporters to the cell surface was closely correlated with the glucose transport activity and could account fully for the increment in glucose uptake after contraction. The combined effects of contraction and maximal insulin stimulation were greater than either stimulation alone on glucose transport activity (11.5 +/- 0.4 mumol per ml per h vs. 5.6 +/- 0.2 mumol per ml per h and 9.0 +/- 0.2 mumol per ml per h) and on GLUT4 translocation [4.10 +/- 0.20 pmol/g (wet muscle weight) vs. 1.75 +/- 0.25 pmol/g (wet muscle weight) and 3.15 +/- 0.18 pmol/g (wet muscle weight)]. The results provide evidence that contraction stimulates translocation of GLUT4 in skeletal muscle through a mechanism distinct from that of insulin.
Determinants of the recommended dietary allowance (RDA) for vitamin C include the relationship between vitamin C dose and steady-state plasma concentration, bioavailability, urinary excretion, cell concentration, and potential adverse effects. Because current data are inadequate, an in-hospital depletion-repletion study was conducted. Seven healthy volunteers were hospitalized for 4-6 months and consumed a diet containing <5 mg of vitamin C daily. Steady-state plasma and tissue concentrations were determined at seven daily doses of vitamin C from 30 to 2500 mg. Vitamin C steady-state plasma concentrations as a function of dose displayed sigmoid kinetics. The steep portion of the curve occurred between the 30- and 100-mg daily dose, the current RDA of 60 mg daily was on the lower third of the curve, the first dose beyond the sigmoid portion of the curve was 200 mg daily, and complete plasma saturation occurred at 1000 mg daily. Neutrophils, monocytes, and lymphocytes saturated at 100 mg daily and contained concentrations at least 14-fold higher than plasma. Bioavailability was complete for 200 mg of vitamin C as a single dose. No vitamin C was excreted in urine of six of seven volunteers until the 100-mg dose. At single doses of 500 mg and higher, bioavailability declined and the absorbed amount was excreted. Oxalate and urate excretion were elevated at 1000 mg of vitamin C daily compared to lower doses. Based on these data and Institute of Medicine criteria, the current RDA of 60 mg daily should be increased to 200 mg daily, which can be obtained from fruits and vegetables. Safe doses of vitamin C are less than 1000 mg daily, and vitamin C daily doses above 400 mg have no evident value.
Recommendations for vitamin C intake are under revision by the Food and Nutrition Board of the National Academy of Sciences. Since 1989 when the last recommended dietary allowance (RDA) of 60 mg was published, extensive biochemical, molecular, epidemiologic, and clinical data have become available. New recommendations can be based on the following 9 criteria: dietary availability, steady-state concentrations in plasma in relationship to dose, steady-state concentrations in tissues in relationship to dose, bioavailability, urine excretion, adverse effects, biochemical and molecular function in relationship to vitamin concentration, direct beneficial effects and epidemiologic observations in relationship to dose, and prevention of deficiency. We applied these criteria to the Food and Nutrition Board's new guidelines, the Dietary Reference Intakes, which include 4 reference values. The estimated average requirement (EAR) is the amount of nutrient estimated to meet the requirement of half the healthy individuals in a life-stage and gender group. Based on an EAR of 100 mg/d of vitamin C, the RDA is proposed to be 120 mg/d. If the EAR cannot be determined, an adequate intake (AI) amount is recommended instead of an RDA. The AI was estimated to be either 200 mg/d from 5 servings of fruits and vegetables or 100 mg/d of vitamin C to prevent deficiency with a margin of safety. The final classification, the tolerable upper intake level, is the highest daily level of nutrient intake that does not pose risk or adverse health effects to almost all individuals in the population. This amount is proposed to be less than 1 g of vitamin C daily. Physicians can tell patients that 5 servings of fruits and vegetables per day may be beneficial in preventing cancer and providing sufficient vitamin C intake for healthy people, and that 1 g or more of vitamin C may have adverse consequences in some people.
Vitamin C (ascorbate) is toxic to tumour cells, and has been suggested as an adjuvant cancer treatment. Our goal was to determine if ascorbate, in combination with other antioxidants, could kill cells in the SW620 hollow fibre in vitro solid tumour model at clinically achievable concentrations. Ascorbate anti-cancer efficacy, alone or in combination with lipoic acid, vitamin K3, phenyl ascorbate, or doxorubicin, was assessed using annexin V staining and standard survival assays. 2-day treatments with 10 mM ascorbate increased the percentage of apoptotic cells in SW620 hollow fibre tumours. Lipoic acid synergistically enhanced ascorbate cytotoxicity, reducing the 2-day LC(50)in hollow fibre tumours from 34 mM to 4 mM. Lipoic acid, unlike ascorbate, was equally effective against proliferating and non-proliferating cells. Ascorbate levels in human blood plasma were measured during and after intravenous ascorbate infusions. Infusions of 60 g produced peak plasma concentrations exceeding 20 mM with an area under the curve (24 h) of 76 mM h. Thus, tumoricidal concentrations may be achievable in vivo. Ascorbate efficacy was enhanced in an additive fashion by phenyl ascorbate or vitamin K3. The effect of ascorbate on doxorubicin efficacy was concentration dependent; low doses were protective while high doses increased cell killing.
The recently released Recommended Dietary Allowance of vitamin C for women, 75 mg daily, was based on data for men. We now report results of a depletion-repletion study with healthy young women hospitalized for 186 +/- 28 days, using vitamin C doses of 30-2,500 mg daily. The relationship between dose and steady-state plasma concentration was sigmoidal. Only doses above 100 mg were beyond the linear portion of the curve. Plasma and circulating cells saturated at 400 mg daily, with urinary elimination of higher doses. Biomarkers of endogenous oxidant stress, plasma and urine F(2)-isoprostanes, and urine levels of a major metabolite of F(2)-isoprostanes were unchanged by vitamin C at all doses, suggesting this vitamin does not alter endogenous lipid peroxidation in healthy young women. By using Food and Nutrition Board guidelines, the data indicate that the Recommended Dietary Allowance for young women should be increased to 90 mg daily.
We tested the effect of different concentrations of ascorbic acid (AA), 50, 100, 250 mg/500 mg/dL) with copper sulfate (CS), 10 mg/dL) on human breast carcinoma (MDA-MB231) cell proliferation in vitro. Cell proliferation was measured using a colori-metric assay (Cell proliferation kit II (XTT), Boehringer, NJ). The results of the mean absorbance of the tissue culture at different AA concentrations and a constant CS concentration were as follow: 0.82 +/- 0.03 (control, mean +/- SE), 0.64 +/- 0.02 (CS above); 0.48 +/- 0.03 (50 mg/dL) AA), 0.21 +/- 0.02 (100 mg/dL), 0.08 +/- 0.01 (250 mg/dL) AA, 0.60 +/- 0.05 (500 mg/dL). These results show that a combination of AA and CS inhibits human breast carcinoma cell proliferation in vitro. This cell proliferation inhibitory effect is directly proportional to the AA concentration with the exception of the 500 mg/dL AA dose. This chemotherapeutic effect was optimally enhanced when AA was added at a concentration of 250 mg/dL. The AA concentrations of 500 mg/dL had a biphasic effect on tumor cell proliferation probably due to back and forth redox reactions between AA and dehydroascorbic acid in a closed system. This study provides preliminary evidence that AA and SC can be used as biological response modifiers (BRM) for tumor growth inhibition.
The decision of stressed cells to die or to survive is made by integrating signals at different levels through multiple check points. However, initiation and continued progression toward cell death by apoptosis in cancer cells may be blocked by mutation of the tumor suppressor p53 or overexpression of members of the bcl-2 family of proteins. The existence of such mechanisms indicates that cancer cells lose the controls regulating their cell cycle. Therefore, the activation of their programmed cell death appears as a major therapeutic target. Oxidative stress can stimulate growth, trigger apoptosis, or cause necrosis depending upon the dose and the exposure time of the oxidizing agent. A large body of evidence supports the idea that oxidative stress induced by redox cycling of vitamins C and K(3) in association surpasses cancer cellular defense systems and results in cell death. The molecular mechanisms underlying such a process are, however, still unknown. Indeed, several types of cell death may be produced, namely autoschizis, apoptosis and necrosis. Combined vitamin C and K(3) administration in vitro and in vivo produced tumor growth inhibition and increased the life-span of tumor-bearing mice. CK(3)-treatment selectively potentiated tumor chemotherapy, produced sensitization of tumors resistant to some drugs, potentiated cancer radiotherapy and caused inhibition of the development of cancer metastases without inducing toxicity in the host. We propose the association of vitamins C and K(3) as an adjuvant cancer therapy which may be introduced into human cancer therapy without any change in the classical anticancer protocols, and without any supplementary risk for patients.
Vitamin C at high concentrations is toxic to cancer cells in vitro. Early clinical studies of vitamin C in patients with terminal cancer suggested clinical benefit, but 2 double-blind, placebo-controlled trials showed none. However, these studies used different routes of administration.
To determine whether plasma vitamin C concentrations vary substantially with the route of administration.
Dose concentration studies and pharmacokinetic modeling.
Academic medical center.
17 healthy hospitalized volunteers.
Vitamin C plasma and urine concentrations were measured after administration of oral and intravenous doses at a dose range of 0.015 to 1.25 g, and plasma concentrations were calculated for a dose range of 1 to 100 g.
Peak plasma vitamin C concentrations were higher after administration of intravenous doses than after administration of oral doses (P < 0.001), and the difference increased according to dose. Vitamin C at a dose of 1.25 g administered orally produced mean (+/-sd) peak plasma concentrations of 134.8 +/- 20.6 micromol/L compared with 885 +/- 201.2 micromol/L for intravenous administration. For the maximum tolerated oral dose of 3 g every 4 hours, pharmacokinetic modeling predicted peak plasma vitamin C concentrations of 220 micromol/L and 13 400 micromol/L for a 50-g intravenous dose. Peak predicted urine concentrations of vitamin C from intravenous administration were 140-fold higher than those from maximum oral doses.
Patient data are not available to confirm pharmacokinetic modeling at high doses and in patients with cancer.
Oral vitamin C produces plasma concentrations that are tightly controlled. Only intravenous administration of vitamin C produces high plasma and urine concentrations that might have antitumor activity. Because efficacy of vitamin C treatment cannot be judged from clinical trials that use only oral dosing, the role of vitamin C in cancer treatment should be reevaluated.
The effect of ascorbic acid on cancer has been a subject of great controversy. This is a follow-up review of the 1979 article by Cameron, Pauling, and Leibovitz published in Cancer Research. In this updated version, the authors address general aspects of ascorbic acid and cancer that have been presented before, while reviewing, analyzing, and updating new existing literature on the subject. In addition, they present and discuss their own mechanistic hypothesis on the effect of ascorbic acid on the cancer cell. The objective of this review is to provide an updated scientific basis for the use of ascorbic acid, especially intravenously as adjuvant treatment in pharmacological nutritional oncology.
Human pharmacokinetics data indicate that i.v. ascorbic acid (ascorbate) in pharmacologic concentrations could have an unanticipated role in cancer treatment. Our goals here were to test whether ascorbate killed cancer cells selectively, and if so, to determine mechanisms, using clinically relevant conditions. Cell death in 10 cancer and 4 normal cell types was measured by using 1-h exposures. Normal cells were unaffected by 20 mM ascorbate, whereas 5 cancer lines had EC(50) values of <4 mM, a concentration easily achievable i.v. Human lymphoma cells were studied in detail because of their sensitivity to ascorbate (EC(50) of 0.5 mM) and suitability for addressing mechanisms. Extracellular but not intracellular ascorbate mediated cell death, which occurred by apoptosis and pyknosis/necrosis. Cell death was independent of metal chelators and absolutely dependent on H(2)O(2) formation. Cell death from H(2)O(2) added to cells was identical to that found when H(2)O(2) was generated by ascorbate treatment. H(2)O(2) generation was dependent on ascorbate concentration, incubation time, and the presence of 0.5-10% serum, and displayed a linear relationship with ascorbate radical formation. Although ascorbate addition to medium generated H(2)O(2), ascorbate addition to blood generated no detectable H(2)O(2) and only trace detectable ascorbate radical. Taken together, these data indicate that ascorbate at concentrations achieved only by i.v. administration may be a pro-drug for formation of H(2)O(2), and that blood can be a delivery system of the pro-drug to tissues. These findings give plausibility to i.v. ascorbic acid in cancer treatment, and have unexpected implications for treatment of infections where H(2)O(2) may be beneficial.
Early clinical studies showed that high-dose vitamin C, given by intravenous and oral routes, may improve symptoms and prolong life in patients with terminal cancer. Double-blind placebo-controlled studies of oral vitamin C therapy showed no benefit. Recent evidence shows that oral administration of the maximum tolerated dose of vitamin C (18 g/d) produces peak plasma concentrations of only 220 micromol/L, whereas intravenous administration of the same dose produces plasma concentrations about 25-fold higher. Larger doses (50-100 g) given intravenously may result in plasma concentrations of about 14,000 micromol/L. At concentrations above 1000 micromol/L, vitamin C is toxic to some cancer cells but not to normal cells in vitro. We found 3 well-documented cases of advanced cancers, confirmed by histopathologic review, where patients had unexpectedly long survival times after receiving high-dose intravenous vitamin C therapy. We examined clinical details of each case in accordance with National Cancer Institute (NCI) Best Case Series guidelines. Tumour pathology was verified by pathologists at the NCI who were unaware of diagnosis or treatment. In light of recent clinical pharmacokinetic findings and in vitro evidence of anti-tumour mechanisms, these case reports indicate that the role of high-dose intravenous vitamin C therapy in cancer treatment should be reassessed.
This paper presents a new account of the action of ascorbate in humans: the dynamic flow model. The model is consistent with previous studies and with the known properties of vitamin C. Based on this model, we propose a mechanism by which human physiology can compensate for losing the ability to synthesize vitamin C. The dynamic flow approach links Linus Pauling's megadose suggestions with other reported effects of massive doses for the treatment of disease. The model also refutes the current low dose hypothesis and resulting recommendations for dietary intakes.
Do you want easy access to the latest methods in scientific computing? This greatly expanded third edition of Numerical Recipes has it, with wider coverage than ever before, many new, expanded and updated sections, and two completely new chapters. The executable C++ code, now printed in color for easy reading, adopts an object-oriented style particularly suited to scientific applications. Co-authored by four leading scientists from academia and industry, Numerical Recipes starts with basic mathematics and computer science and proceeds to complete, working routines. The whole book is presented in the informal, easy-to-read style that made earlier editions so popular. Highlights of the new material include: a new chapter on classification and inference, Gaussian mixture models, HMMs, hierarchical clustering, and SVMs; a new chapter on computational geometry, covering KD trees, quad- and octrees, Delaunay triangulation, and algorithms for lines, polygons, triangles, and spheres; interior point methods for linear programming; MCMC; an expanded treatment of ODEs with completely new routines; and many new statistical distributions.
Measurement of serum ascorbate may be useful in long-term population studies because of the possible influence of ascorbate on numerous physiological factors. We describe an automated method for determining ascorbate in serum and urine by using the reduction of ferric iron by ascorbate and the formation of a color between the resulting ferrous iron and Ferrozine [3-(2-pyridyl)-5,6-bis(4-phenylsulfonic acid)-1,2,4-triazine]. A centrifugal analyzer is used to rapidly and simultaneously measure ascorbate in the samples and standards and minimize interference from slower reacting substances in the sample. The method is highly precise and specific. Data are also presented on the stability of ascorbate in serum, urine, and aqueous solutions.
A method of utilizing vitamin C in amounts just short of the doses which produce diarrhea is described (TITRATING TO BOWEL TOLERANCE). The amount of oral ascorbic acid tolerated by a patient without producing diarrhea increase somewhat proportionately to the stress or toxicity of his disease. Bowel tolerance doses of ascorbic acid ameliorate the acute symptoms of many diseases. Lesser doses often have little effect on acute symptoms but assist the body in handling the stress of disease and may reduce the morbidity of the disease. However, if doses of ascorbate are not provided to satisfy this potential draw on the nutrient, first local tissues involved in the disease, then the blood, and then the body in general becomes deplete of ascorbate (ANASCORBEMIA and ACUTE INDUCED SCURVY). The patient is thereby put at risk for complications of metabolic processes known to be dependent upon ascorbate.
Some clinicians and alternative therapy practitioners advocate megadose intravenous and oral ascorbate treatment of cancer. Randomized control studies using oral ascorbate showed no benefit. Recent data show that intravenous but not oral administration of ascorbate can produce millimolar plasma concentrations, which are toxic to many cancer cell lines. We propose that ascorbate treatment of cancer should be reexamined by rigorous scientific scrutiny in the light of new evidence.
Exercise increases glucose transport into skeletal muscle via a pathway that is poorly understood. We investigated the role of endogenously produced reactive oxygen species (ROS) in contraction-mediated glucose transport. Repeated contractions increased 2-deoxyglucose (2-DG) uptake roughly threefold in isolated, mouse extensor digitorum longus (fast-twitch) muscle. N-Acetylcysteine (NAC), a non-specific antioxidant, inhibited contraction-mediated 2-DG uptake by approximately 50% (P < 0.05 versus control values), but did not significantly affect basal 2-DG uptake or the uptake induced by insulin, hypoxia or 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR, which mimics AMP-mediated activation of AMP-activated protein kinase, AMPK). Ebselen, a glutathione peroxidase mimetic, also inhibited contraction-mediated 2-DG uptake (by almost 60%, P < 0.001 versus control values). Muscles from mice overexpressing Mn2+-dependent superoxide dismutase, which catalyses H2O2 production from superoxide anions, exhibited a approximately 25% higher rate of contraction-mediated 2-DG uptake versus muscles from wild-type control mice (P < 0.05). Exogenous H2O2 induced oxidative stress, as judged by an increase in the [GSSG]/[GSH + GSSG] (reduced glutathione + oxidized glutathione) ratio to 2.5 times control values, and this increase was substantially blocked by NAC. Similarly, NAC significantly attenuated contraction-mediated oxidative stress as judged by measurements of glutathione status and the intracellular ROS level with the fluorescent indicator 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein (P < 0.05). Finally, contraction increased AMPK activity and phosphorylation approximately 10-fold, and NAC blocked approximately 50% of these changes. These data indicate that endogenously produced ROS, possibly H2O2 or its derivatives, play an important role in contraction-mediated activation of glucose transport in fast-twitch muscle.
How to live longer and feel better
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Methods in clinical chemistry
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Conquer cancer with redox synergy
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Hunninghake R. Conquer cancer with redox synergy. 37th Annual Conference International Society for Orthomolecular Medicine, Vancouver, May 2008, personal communication before presentation.
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González MJ, Mora EM, Miranda-Massari JR, Matta J, Riordan HD, Riordan NH. Inhibition of human breast carcinoma cell proliferation by ascorbate and copper. P R Health Sci J 2002;21(1):21–3. Pharmacokinetics of oral vitamin C 177
Ascorbate: The science of vitamin C
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Hickey S, Roberts H. Ascorbate: The science of vitamin C. Morrisville NC: Lulu Press; 2004
Contextual classification of remotely sensed data: Statistical methods and development of a system
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