Administration Of Folic Acid Research Articles

Role of folic acid supplementation in level of c-reactive protein in metabolic syndrome

Introduction: The prevalence of metabolic syndrome is increasing, its progression involves an inflammatory response that has an important impact on the initiation, progressivity, and complications of several diseases such as heart disease, stroke, type 2 diabetes mellitus, and cancer. C-reactive protein (CRP) is one of the inflammation markers increased in patients with metabolic syndrome. Folic acid has a role in metabolizing homocysteine and improving endothelial function. There have been many studies conducted, but the results are still inconsistent. Method: Literature searching was conducted using PubMed, Cochrane Library, and Embase databases. MeSH terms, advanced search and eligibility criteria were used for title/abstract screening before journal review. Results: One systematic review and meta-analysis (SR-MA) and one RCT met the PICO and eligibility criteria. The SR-MA found that folic acid administration can reduce CRP level (WMD -0.94 (95% CI -1.56 – 0.32; p=0.00) at a dose of 0.15 mg/day for 12 weeks to 10 mg/day for 2 weeks, while the RCT found an insignificant result. Conclusion: Folic acid supplementation has a potential benefit to decrease CRP levels in metabolic syndrome.

The Impact of Folic Acid and B12 Administration on Growth, Wool Traits and Some Hormones Concentrations of Male Arabi Lambs

This study aimed to investigate the effects of folic acid and vitamin B12 administration on the growth and wool traits in male lambs. A total of fifteen animals was used from 1st February 2015 to 30th April 2015, divided into three treatment groups. The first group served as a control, the second group received a folic acid dosage equivalent to 0.5 mg per kilogram of body weight per head, and the third group received a vitamin B12 dosage equivalent to 0.1 mg per kilogram of body weight per head. The vitamins were administered orally twice a week. The results showed a significant improvement (P<0.05) in final body weight, daily gain, and total weight gain in the vitamin B12 and folic acid groups compared to the control group. Additionally, there was a significant (P<0.05) increase in all wool characteristics, except for crimp number, in the folic acid group compared to the control group. The study demonstrated significant relationships between body weight and every aspect of wool quality except for fiber length. There was a significant (P<0.05) increase in the concentrations of growth and thyroxine hormones in the vitamin B12 and folic acid groups compared to the control group, particularly in the second and third months of the experiment. No significant difference in insulin hormone concentration among the groups was observed during the 90-day experiment. In conclusion, administering vitamin B12 and folic acid are orally administered twice a week to improve growth, increase hormone concentrations (thyroxine and growth hormone), and improve wool quality

Targeting SRD5A1 and MMP-2/NLRP3/TGF-β1 axis alleviates the amlodipine-induced gingival hyperplasia in rats: Emerging role of saw palmetto and folic acid

Saw palmetto (SAW), the herbal drug used to treat prostatic hyperplasia, exerts its antiproliferative effects by blocking steroid 5 alpha-reductase (SRD5A1) activity, that has also been involved in gingival hyperplasia (GH) pathogenesis. Concurrently, folic acid (FA) could reduce GH prevalence via its antioxidant and anti-inflammatory effects. Thus, this study tended to assess the potential therapeutic efficacy of SAW, alone and along with FA, against amlodipine-induced gingival inflammation and overgrowth in rats. Rats were grouped into (CONT, AIGH, SAW, SAW-treated, FA-treated, and SAW + FA-treated). SAW and FA were administered once daily for 4 weeks. Gingival SRD5A1, CTGF, GSK-3β, and NLRP3 expressions, as well as T, DHT, MDA, TAC, ET-1, and MMP2 levels were determined. In addition, histopathological and immunohistochemical analyses of TNF-α, IL-6, TGF-β1, and α-SMA were documented. Results declared that SAW and FA administration markedly ameliorated amlodipine-associated GH and may be presenting a novel therapeutic avenue in the future.

Role of vitamin B12 and folic acid in treatment of Alzheimer's disease: a meta-analysis of randomized control trials.

Vitamin B12 and folic acid could reduce blood homocysteine levels, which was thought to slow down the progression of Alzheimer's disease (AD), but previous studies regarding the effect of vitamin B12 and folic acid in treatment of AD have not reached conclusive results. We searched PubMed and Embase until January 12, 2023. Only randomized control trials involving participants clearly diagnosed with AD and who received vitamin B12 and folic acid were enrolled. Five studies that met the criteria were selected for inclusion in the meta-analysis. Changes in cognitive function were measured based on either the Mini-Mental State Examination (MMSE) or the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Changes in daily life function and the level of blood homocysteine were also investigated. After a 6-month treatment, administration of vitamin B12 and folic acid improved the MMSE scores more than placebo did (SMD = 0.21, 95% CI = 0.01 to 0.32, p = 0.04) but did not significantly affect ADAS-Cog scores (SMD = 0.06, 95% CI = -0.22 to 0.33, p = 0.68) or measures of daily life function. Blood homocysteine levels were significantly decreased after vitamin B12 and folic acid treatment. Participants with AD who received 6 months of vitamin B12 and folic acid supplementation had better MMSE scores but had no difference in ADAS-Cog scores. Daily life function did not improve after treatment.

The effect of methionine and folic acid administered in ovo on the blood biochemical parameters of chickens (Gallus gallus domesticus)

Methionine is one of the most frequently supplemented amino acids in raising of poultry. However, an overdose of methionine can cause hyperhomocysteinemia. Folic acid, taking part in the process of homocysteine remethylation, is a factor affecting the reduction of the concentration of this amino acid. The study was carried out in 2 stages. The experiment of step I was to investigate the effect of methionine and/or folic acid administration in ovo in the early stage of embryogenesis (E4), and the experiment of the second stage - in the late stage of embryogenesis (E17) on the following biochemical parameters of chicken blood: glucose concentration in whole blood and concentration of homocysteine and uric acid in plasma of domestic chickens (Gallus gallus domesticus). Our results confirm that methionine supplementation may increase the concentration of uric acid and homocysteine. Moreover, we demonstrated that folic acid administered during embryogenesis decreased homocysteine concentration, also in groups simultaneously supplemented with methionine, especially in the initial stage of postnatal life of the bird.

Folic Acid in Neuropsychiatric Disorders

It is known that Folic Acid (FA) plays an important role in normal brain development and functions. Interest is growing about the implications of folic acid employment in neuropsychiatric disorders. This work reviews the literature available from 2018 to 2022 on the biochemical and clinical correlates of FA administration in cognitive diseases such as Autism Spectrum Disorders (ASD), Attention Deficit-Hyperactivity Disorder (ADHD), and Obsessive-Compulsive Disorder (OCD). It was found that FA supplementation is a safe and promising therapeutic strategy to mitigate the symptoms of these diseases.

Toxic effects of triclosan on hepatic and intestinal lipid accumulation in zebrafish via regulation of m6A-RNA methylation

Triclosan (TCS), recognized as an endocrine disruptor, has raised significant concerns due to its widespread use and potential health risks. To explore the impact of TCS on lipid metabolism, both larval and adult zebrafish were subjected to acute and chronic exposure to TCS. Through analyzes of biochemical and physiological markers, as well as Oil Red O (ORO) and hematoxylin and eosin (H&E) staining, our investigation revealed that TCS exposure induced hepatic and intestinal lipid accumulation in larval and adult zebrafish, leading to structural damage and inflammatory responses in these tissues. The strong affinity of TCS with PPARγ and subsequent pathway activation indicate that PPARγ pathway plays a crucial role in TCS-induced lipid buildup. Furthermore, we observed a decrease in m6A-RNA methylation levels in the TCS-treated group, which attributed to the increased activity of the demethylase FTO and concurrent suppression of the methyltransferase METTL3 gene expression by TCS. The alteration in methylation dynamics is identified as a potential underlying mechanism behind TCS-induced lipid accumulation. To address this concern, we explored the impact of folic acid—a methyl donor for m6A-RNA methylation—on lipid accumulation in zebrafish. Remarkably, folic acid administration partially alleviated lipid accumulation by restoring m6A-RNA methylation. This restoration, in turn, contributed to a reduction in inflammatory damage observed in both the liver and intestines. Additionally, folic acid partially mitigates the up-regulation of PPARγ and related genes induced by TCS. These findings carry substantial implications for understanding the adverse effects of environmental pollutants such as TCS. They also emphasize the promising potential of folic acid as a therapeutic intervention to alleviate disturbances in lipid metabolism induced by environmental pollutants.

The mechanism of folic acid on N-methyl-N’-nitro-N-nitrosoguanidine-induced chronic atrophic gastritis through the PI3K/Akt pathway.

Chronic atrophic gastritis (CAG) is a precancerous atrophic gastritis of the stomach, which generates an urge to develop novel therapeu-tic schedules. This study aimed to investigate the effect of experimental folic acid administration on N-methyl-N’-nitro-N-nitrosoguanidine (MNNG)-induced CAG through the PI3K/Akt pathway in rats. The rats were divided into a Model Group, a Folic Acid Group and a Blank Group. Rats in the Model Group were induced by MNNG and given 10 mL/kg/d distilled water by gavage, while rats in the Folic Acid Group were induced by MNNG and given 5 mg/kg/d folic acid suspension by gavage. As a control, rats in the Blank Group were given the same amount of distilled water as MNNG and 10 mL/kg/d distilled water by gavage. The levels of gastrin (GAS) and motilin (MTL) in serum were measured by enzyme-linked immunosorbent assay (ELISA), and the mRNA and protein ex-pressions were detected by quantitative polymerase chain reaction (q-PCR) and Western blot. According to hematoxylin and eosin (H&E) pathological analysis, there were inflammatory factors infiltration and derangement of mucosal epi-thelial cells in the model group, while the gastric tissue injury in the folic acid group was improved. Folic acid could decrease the content of GAS, increase the content of MTL in the serum of the rats, and regulate the expression of PI3K and AKT signal pathways. Folic acid can have a therapeutic effect on CAG by reducing the concentration of GAS in serum and increasing the concentration of MLT in serum. Our study would lay a theoretical foundation for using folic acid to investigate new therapies for CAG in humans.

Spina Bifida Prevention: A Narrative Review of Folic Acid Supplements for Childbearing Age Women.

Neural tube defects (NTDs) are malformations that occur during embryonic development, and they account for most central nervous system birth anomalies. Genetic and environmental factors have been shown to play a role in the etiology of NTDs. The different types of NTDs are classified according to anatomic location and severity of the defect, with most of the neural axis anomalies occurring in the caudal spinal or cranial areas. Spina bifida is a type of NTD that is characterized by an opening in the vertebral arch, and the level of severity is determined by the extent to which the neural tissue protrudes through the opened arch(es). Prevention of NTDs by administration of folic acid has been studied and described in the literature, yet there are approximately 300,000 cases of NTDs that occur annually, with 88,000 deaths occurring per year worldwide. A daily intake of at least 400 μg of folic acid is recommended especially for women of childbearing age. To provide the benefits of folic acid, prenatal vitamins are recommended in pregnancy, and many countries have been fortifying foods such as cereal grain products with folic acid; however, not all countries have instituted folic acid fortification programs. The present investigation includes a description of the pharmacology of folic acid, neural tube formation, defects such as spina bifida, and the relevance of folic acid to developing spina bifida. Women's knowledge and awareness of folic acid regarding its importance in the prevention of spina bifida is a major factor in reducing incidence worldwide.

Folic Acid and Diabetic Foot Ulcers.

Diabetic foot ulcers (DFUs) remain a major cause of morbidity. This narrative mini-review aimed to investigate the potential role of folic acid (FA) in DFUs. Individuals with DFUs exhibit lower levels of FA and lower daily intake, compared to those without DFUs. There is preliminary evidence that FA administration may contribute to improved DFUs healing. In this context, regular evaluation of dietary FA intake may prove important towards reduction or even prevention of DFUs. However, data are still limited and further research is required to enable definitive conclusions and any recommendations.

Acyloxyacyl Hydrolase Protects against Kidney Injury via Inhibition of Tubular CD74-Macrophage Crosstalk.

Renal fibrosis is the common pathway in the progression of chronic kidney disease (CKD). Acyloxyacyl hydrolase (AOAH) is expressed in various phagocytes and is highly expressed in proximal tubular epithelial cells (PTECs). Research shows that AOAH plays a critical role in infections and chronic inflammatory diseases, although its role in kidney injury is unknown. Here, we found that AOAH deletion led to exacerbated kidney injury and fibrosis after folic acid (FA) administration, which was reversed by overexpression of Aoah in kidneys. ScRNA-seq revealed that Aoah-/- mice exhibited increased subpopulation of CD74+ PTECs, though the percentage of total PTECs were decreased compared to WT mice after FA treatment. Additionally, exacerbated kidney injury and fibrosis seen in Aoah-/- mice was attenuated via administration of methyl ester of (S, R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid (ISO-1), an inhibitor of macrophage inhibition factor (MIF) and CD74 binding. Finally, AOAH expression was found positively correlated with estimated glomerular filtration rate while negatively correlated with the degree of renal fibrosis in kidneys of CKD patients. Thus, our work indicates that AOAH protects against kidney injury and fibrosis by inhibiting renal tubular epithelial cells CD74 signaling pathways. Targeting kidney AOAH represents a promising strategy to prevent renal fibrosis progression.

Folic acid supplementation in women of childbearing age with epilepsy: No association with type or number of antiepileptic drugs.

For over two decades, a daily folic acid (FA) supplementation has been recommended for women of childbearing age with epilepsy. This recommendation is based on evidence that FA administration before conception and during pregnancy can decrease the risk of fetal malformations in the general population, improve cognitive development, and reduce the risk of autistic traits in children exposed in utero to antiepileptic drugs (AEDs). The aim of this study was to evaluate FA supplementation rate in nonpregnant women of childbearing age with epilepsy and its relation to AED type and number. We retrospectively reviewed the computerized database and the medical records of all the women who had a first visit to our outpatient epilepsy clinic (Shamir-Assaf Harofeh Medical Center, Zerifin, Israel) during a 10-year period (2012-2021). Only 61 (22%) of 282 nonpregnant women of childbearing age with epilepsy treated with AEDs received FA supplementation. Ninety-two (33%) of the women were treated with AED polytherapy, and 41 (15%) received valproic acid in monotherapy or polytherapy. FA supplementation rate was higher in women aged ≤40 versus >40 (25% vs. 8.5%) (p = .004). No correlation was found between FA supplementation and AED type or number. FA supplementation rate was low and was unaffected by AED treatment. Patient and physician-targeted interventions should be implemented to increase FA prescription and patient adherence.

Effect of Folic Acid in Sepsis-induced Lung Damage in Rats

Aim: Sepsis-induced lung injury remains a critical concern with significant morbidity and mortality. This study aimed to investigate the potential therapeutic role of Folic Acid in mitigating lung injury induced by sepsis while exploring its interaction with the soluble suppression of tumorigenicity 2 (sST2) protein in an experimental rat model. 
 Material and Methods: Rats were divided into three groups: a normal control group, a group induced with sepsis and treated with saline, and a group induced with sepsis and treated with Folic Acid (5 mg/kg). Biomarkers of oxidative stress, inflammation, respiratory gas exchange, and lung histopathology were assessed. 
 Results: Folic Acid administration resulted in significantly decreased Malondialdehyde (MDA) levels (p

Effect of in ovo feeding of folic acid on Disabled-1 and gga-miR-182-5p expression in the cerebral cortex of chick embryo.

Folate (vitamin B9) has been shown to reduce the prevalence of neural tube defects (NTDs). Many genes comprising Disabled-1 (DAB1) and miRNAs have been shown to play important role in normal brain development. Reelin-signalling has been shown to play key role in regulating of neuronal migration during brain development. The aim of this study was to evaluate the effects of in ovo administration of folic acid (FA) on DAB1 and gga-miR-182-5p expression in the cerebral cortex of chick embryo. A total number of 30 hatching eggs were used in this study. The number of 10 eggs were injected into the yolk sac with FA(150 µg/egg), 10 eggs by normal saline (sham group) on embryonic day 11 and 10 eggs were left without injection as control. Then the cerebral cortices were collected on E19 and the expression of DAB1 and gga-miR-182-5p was studied by Real-Time PCR. The results showed that DAB1 expression in the cerebral cortex of FA-treated, sham and control were 2.51 ± 0.13, 1.01 ± 0.04and 1.03 ± 0.04 fold changes, respectively, and this amount for gga-miR-182-5p were 0.54 ± 0.03, 1.09 ± 0.07 and 1.00 ± 0.06-fold changerespectively. Statistical analysis showed that there is a significant increase in DAB1 and a decrease in gga-miR-182-5p expression in FA injected cerebral cortex as compared either with either SHAM or control (p < 0.0001). But, no significant change in DAB1 and gga-miR-182-5p expression was observed between sham and the control group (p = 0.99 and p = 0.57respectively). It is concluded that in ovo feeding of FA increases DAB1 and decreases gga-miR-182-5p expression in the developing chick cerebral cortex.

Neurobehavioral alterations induced by third-trimester gestation-equivalent ethanol exposure are inhibited by folate administration.

Prenatal ethanol exposure (PEE) causes several neurobehavioral impairments in the fetus. Postnatal days (PDs) 4-9 in rodents are considered equivalent to the third trimester of gestation in humans. This period is characterized by high rates of synaptogenesis and myelination and the maturation of key structures and transmitter systems. Nutritional supplements, such as folate, have gained attention as putative treatments to mitigate detrimental effects of PEE. Folate is crucial for DNA synthesis and amino acid metabolism and heightens antioxidant defenses. The present study examined neurobehavioral effects of the concurrent administration of folate (20mg/kg/day) and ethanol (5g/kg/day) during PDs 4-9 in male and female Wistar rats. During PDs 16-18, the rat pups were tested for anxiety-like and exploratory activity in the light-dark box (LDB), open field (OF), and concentric square field (CSF) tests. After weaning, they were tested for sucrose preference and ethanol intake. Neonatal ethanol exposure reduced body weight in infancy but did not enhance ethanol self-administration or significantly affect performance in the OF or LDB. Neonatal ethanol exposure also reduced sucrose intake in the preference test and increased shelter-seeking in the CSF, and folate significantly inhibited these effects. The present findings suggest that folate, a treatment that is devoid of serious side effects, can ameliorate some neurobehavioral effects of PEE.

Folic acid supplementation improved nicotine withdrawal-induced of memory loss via affecting oxidative status, inflammatory response, cholinergic activity, BDNF and amyloid-B in adolescent male rat

BackgroundThe present study aimed to assess whether folic acid (FA) have potential to prevent memory impairment caused by nicotine (Nico) withdrawal in adolescent male rats. Methods and materialsThe experiments were divided into 7 groups: 1) vehicle, 2) Nico (Nico 2 mg/kg injection from 21 to 42 days of ages), 3–5) Nico FA5/10/15 mg/kg (received Nico from 21 to 42 days of ages and received FA at three doses 5, 10 and 15 mg/kg 43–63 days of ages), and 6) received normal saline from 21 to 42 days of age after that received FA 15 mg/kg by oral gavage from 43 to 63 days of age. At 64–69 days of ages, behavioral tests related to memory including Morris Water Maze (MWM) and Object Recognition Test (ORT) were performed and related biochemical analysis including the hippocampal levels of oxidative stress markers, inflammatory indices, brain-derived neurotrophic factor (BDNF), nitrite, amyloid-B and acetylcholinesterase [1] were measured. ResultsResults showed that nicotine exposure in adolescence followed by withdrawal dramatically impaired learning and memory performance along with affecting a variety of biochemical markers in the hippocampal tissues. In addition, it was observed that administration of FA significantly ameliorated Nico withdrawal-induced adverse effects through restoration of the mentioned biochemical disturbances. ConclusionThe present study and other relevant researches demonstrated that FA as a well-known, inexpensive, and safe supplement has strong potential to either prevent or ameliorate the detrimental effect of Nico withdrawal. However, further investigation is required to be more elucidated the precise mechanisms underlying memory impairment-induced by Nico withdrawal.

Folic acid supplementation rescues bladder injury in fetal rats with myelomeningocele.

Bladder dysfunction has been linked to the progression of renal failure in children with neurogenic bladder (NB) dysfunction. The purpose of this study was to determine whether bladder injuries in fetal rats with myelomeningocele (MMC) may be treated with folic acid. Pregnant Sprague-Dawley rats were randomly divided into three groups. On the 10th day of gestation, pregnant rats were intragastrically injected with all-trans retinoic acid (ATRA) (60 mg/kg) to induce MMC fetal rats. The same amount of olive oil was put into the control group to create normal fetal rats. The rats in the rescue group were given folic acid (40 mg/kg) by gavage 0.5 and 12 hr after ATRA therapy. Bladders were obtained via cesarean section on embryonic day E20.5 and examined for MMC. The histology of the fetuses was examined using hematoxylin and eosin staining, and immunohistochemistry (IHC) was utilized to determine the expression of α-smooth muscle actin (α-SMA) and neuron-specific nuclear-binding protein (NeuN). Furthermore, the levels of neuromuscular development-related and apoptotic proteins were determined by western blotting. The incidence of MMC in the model group was 60.6% (20/33) while it was much lower in the rescue group (21.4%). In comparison to the model group, the weight and crown-rump length of the fetal rats in the rescue group were significantly improved. IHC revealed that there was no significant difference in the expression of α-SMA and NeuN between the control and ATRA groups, while the expression levels decreased significantly in the MMC group. Western blot analysis showed that there was no significant difference between the model and ATRA groups, but the expression of the α-SMA protein and the β3-tubulin was much lower in the MMC group than in the control group. After the administration of folic acid, the α-SMA and β3-tubulin proteins considerably increased in the folic acid-rescued MMC group and folic acid-rescued ATRA group. Meanwhile, in the control group, the expression of cleaved caspase-3 in the bladder tissue was significantly higher, and the expression of poly (ADP-ribose) polymerase (PARP) protein was significantly lower compared to the control group. Folic acid therapy reduced cleaved caspase-3 expression while increasing PARP expression in comparison to the MMC group. NB in MMC fetal rats is associated with the reduction of bladder nerve and smooth muscle-related protein synthesis. However, folic acid therapy can help improve these functional deficiencies. Folic acid also exhibits strong anti-apoptotic properties against NB in MMC fetal rats.

TJ-17 (Goreisan) mitigates renal fibrosis in a mouse model of folic acid-induced chronic kidney disease

Background and purposeTJ-17 (Goreisan), a traditional Japanese Kampo medicine, has been generally used to treat edema, such as heart failure, due to its diuretic effect. In the present study, we investigate the effects of TJ-17 on chronic kidney disease (CKD). MethodsWe the preventive action of TJ-17 against acute kidney injury (AKI) transition to CKD in vivo using a folic acid (FA)-induced mouse model. Mice were treated with food containing TJ-17 at 48 h after FA intraperitoneal injection (AKI phase). ResultsHistological analysis, as well as renal function and renal injury markers, deteriorated in mice with FA-induced CKD and were ameliorated by TJ-17 treatment. Increased levels of inflammatory cytokines and macrophage infiltration were also alleviated in mice treated with TJ-17. Renal fibrosis, a crucial factor in CKD, was induced by FA administration and inhibited by TJ-17 treatment. Pretreatment with TJ-17 did not exert an inhibitory effect on FA-induced AKI. The increase in urinary volume in FA-induced CKD mice was ameliorated by TJ-17 treatment, with a concurrent correction of reduced aquaporins expression in the kidney. ConclusionTJ-17 may have a novel preventive effect against inflammation, oxidative stress, and fibrosis, contributing to innovation in the treatment of CKD.

EFFECT OF FOLIC ACID ON SOME PHYSIOLOGICAL PARAMETERS IN FEMALE RABBITS TREATED WITH METHOTREXATE

The present study was carried out to investigate the effect of folic acid (FA) on the hematological picture of female rabbits treated with methotrexate MTX. A total of twenty female rabbits were used in this study. They were at age 4-5 months. Their body weight ranged between 1-1,200 Kgm. All animals were kept under normal condition. its divided in to four groups and each group consist of five animals as follows ( Control group :5 rabbits were received distilled water, Folic acid group : 5 rabbits were received folic acid at 0.07mg/kg body weight daily, Methotrexate group : 5 rabbits were received methtrexate (0.03 mg/kg body weight ) three times a week , folic acid with Methotrexate group : 5 rabbits were received folic acid (0.07 mg/kg body weight) and methotrexate (0.03mg/kg body weight) three times a week. The drugs were given by intubation. The experiment was last for 9 weeks . Blood sample were collected after end of the experiment to study the following hematological parameters: RBCs count, Hb, PCV, RBCs indices (MCV, MCH, MCHC). The group treated with folic acid showed a significant increase P≤0.05 in RBCs count, Hb conc. and PCV% as compared with all other groups. The results of MTX group reveal a high significant decrease in their RBC count, Hb conc., PCV%. At the same time there is a significant increase in MCV, MCH and MCHC indices. The group of animals received FA with MTX showed a good prognosis with health improvement characterized by high significant changes in all studied parameters to return back to their normal values. It was concluded that folic acid is very important for erythropoiesis. MTX treatment induce megaloblastic anemia resulted from inhibition of DNA synthesis in RBCs mainly by folate deficiency. FA administration with MTX correct these changes and the animals return to normal conditions. More work is needed to study the effects of these drugs on other systems in the body.

Predicting the effect of different folate doses on [68Ga]Ga-PSMA-11 organ and tumor uptake using physiologically based pharmacokinetic modeling

BackgroundFolate intake might reduce [68Ga]Ga-PSMA-11 uptake in tissues due to a competitive binding to the PSMA receptor. For diagnostic imaging, this could impact decision making, while during radioligand therapy this could affect treatment efficacy. The relationship between folate dose, timing of dosing and tumor and organ uptake is not well established. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict the effect of folates on [68Ga]Ga-PSMA-11 PET/CT uptake in salivary glands, kidneys and tumors.MethodsA PBPK model was developed for [68Ga]Ga-PSMA-11 and folates (folic acid and its metabolite 5-MTHF), with compartments added that represent salivary glands and tumor. Reactions describing receptor binding, internalization and intracellular degradation were included. Model evaluation for [68Ga]Ga-PSMA-11 was performed by using patient scan data from two different studies (static and dynamic), while for folates data from the literature were used for evaluation. Simulations were performed to assess the effect of different folate doses (150 µg, 400 µg, 5 mg and 10 mg) on accumulation in salivary glands, kidney and tumor, also for patients with different tumor volumes (10, 100, 500 and 1000 mL).ResultsFinal model evaluation showed that predictions adequately described data for both [68Ga]Ga-PSMA-11 and folates. Predictions of a 5-MTFH dose of 150 µg and folic acid dose of 400 µg (in case of administration at the same time as [68Ga]Ga-PSMA-11 (t = 0)) showed no clinically relevant effect on salivary glands and kidney uptake. However, the effect of a decrease in salivary glands and kidney uptake was determined to be clinically relevant for doses of 5 mg (34% decrease for salivary glands and 32% decrease for kidney) and 10 mg (36% decrease for salivary glands and 34% decrease for kidney). Predictions showed that tumor uptake was not relevantly affected by the co-administration of folate for all different folate doses (range 150 µg–10 mg). Lastly, different tumor volumes did not impact the folate effect on [68Ga]Ga-PSMA-11 biodistribution.ConclusionUsing a PBPK model approach, high doses of folate (5 and 10 mg) were predicted to show a decrease of [68Ga]Ga-PSMA-11 salivary glands and kidney uptake, while intake by means of folate containing food or vitamin supplements showed no relevant effects. In addition, tumor uptake was not affected by folate administration in the simulated dose ranges (150 µg–10 mg). Differences in tumor volume are not expected to impact folate effects on [68Ga]Ga-PSMA-11 organ uptake.