The information on this website is exactly that, for information purposes only. This information is not intended to be a substitute for sound medical advice or for seeing a physician. Patients should always consult with their physician before starting any medical treatment. These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.
Protocatechuic Acid (PCA)
The following information represents full disclosure and complete transparency for potential purchasers for the various applications of protocatechuic acid (PCA). It may be more than you need or want to know, but the following provides a summary of all the information we have to the extent of our present knowledge.
Frankly, the many and varied health benefits documented for protocatechuic acid (PCA) reported in the literature and discovered in our studies are unbelievable. (See: PCA in the Literature). That would be so except for the fact they have been proven true by multiple credible publications and independent laboratory evidence.
Executive Summary: Protocatechuic acid is a natural substance found throughout nature; rivers, soil, trees, fruits, and vegetables. It is common to the human diet. It is safe, having been determined such by the FDA as a food flavoring additive. You can and do eat it. There are many health benefits reported in the literature. Specific benefits have been reported in the literature and determined by our research; i.e. a powerful antioxidant, broad-spectrum antibiotic, biofilm destroyer, and anti-viral properties including COVID19.
PCA is a phytochemical, classified as a benzoic acid. It is in the category of a nutraceutical. However, all the R&D by PCABioScience has been in anticipation of PCA meeting the regulation as a drug.
The potential health applications are many and varied as listed with associated websites:
- An antioxidant capsule for general health; 4whatAilsU.com.
- An antioxidant capsule for bone health: bonemakar.com
- A serum for skin health: A-Cosmetic.com
- A spray solution as an adjunct to present mitigation procedures for COVID19. sprayawaydoa.com.
PCA is non-toxic, non-allergenic, and non-mutagenic. The supporting credible scientific evidence is abundant from the literature and more importantly from our studies at independent contract laboratories. The mode of action is well understood and supporting evidence is presented.
Multiple US patents have been granted and importantly demonstrate the novel nature and many convincing proofs supporting the unique claims. (See: Intellectual Property)
Health Benefits from Literature: The medical literature has abundant evidence of its health benefits. (See: PCA in the Literature)
Pronunciation: Protocatechuic is difficult to pronounce. Therefore, it may be easier in conversation to say PCA (pee-see-A). See https://www.youtube.com/watch?v=DibgrUXH6CI
Natural Product: Protocatechuic acid is a natural product. It is found everywhere in nature; rivers and lakes, soil, trees, plants, vegetables, and fruits. It is common to the human diet. Chemically is classified as a nutraceutical and phytochemical. Recent advances have moved from plant extract methods of production to one that is biochemically produced. This advancement removed the trace metals of lead and arsenic that accompanied the extracts methods.
Isolated, PCA is naturally a tan or grey/white crystal of 177 microns or 80 mesh size. Protocatechuic acid is a phenolic acid. It is categorized as a benzoic acid as seen in the literature.
Chemical structure: The chemical structure for PCA is similar to benzoic acid, phenol, aspirin, and salicylic acid.
Note: Benzoic acid sodium benzoate are considered G.R.A.S. by FDA for human food ingredients. You can safely eat it. Aspirin is designated G.R.A.S. by FDA.
Safety: PCA has been recognized as safe for ingestion by FDA as a food flavoring additive. PCA has an existing FDA G.R.A.S. designation as Generally Recognized As Safe.
Its FEMA number is 4430 as PCA is chemically listed by is chemical designation: 3,4 dihydroxybenzoic acid.
PCA has not been evaluated by the FDA for the health benefits mentioned herein.
PCA is Common to the Human Diet: You can and do eat it. In fact, you consume it every day in your diet. PCA is ingested daily in various amounts and foods. The following is a list and amounts of PCA in common foods.
Biochemically, PCA comes from the dyes that make cherries red and blueberries blue; Cyanidin-3-Glucoside.
The benefits and properties of PCA are many and as follows.
Health Benefits from Literature: The medical literature has abundant evidence of its health benefits.
Jiao Song, Yanan He, Chuanhong Luo, Bi Feng, Fei Ran, Hong Xu, Zhimin Ci, Runchun Xu, Li Han, Dingkun Zhang, New progress in the pharmacology of protocatechuic acid: A compound ingested in daily foods and herbs frequently and heavily, Pharmacological Research, Volume 161, 2020, 105109, ISSN 1043-6618,
Anti-Oxidant: PCA is a powerful anti-oxidant; 10 times more powerful than vitamin E.
Li X, Wang X, Chen D, Chen S. Antioxidant Activity and Mechanism of Protocatechuic Acid in vitro. Functional Foods in Health and Disease 2011; 7:232-244 Page 232 of 244 Research Open Access. http://www.functionalfoodscenter.net/files/46832219.pdf
Antioxidants are fundamental to health.
Anti-Inflammatory: PCA is a powerful anti-inflammatory reagent.
Lin CY, Huang CS, Huang CY, Yin MC. Anticoagulatory, anti-inflammatory, and antioxidative effects of protocatechuic acid in diabetic mice. J Agric Food Chem. 2009;57(15):6661-6667. doi:10.1021/jf9015202
Lende AB, Kshirsagar AD, Deshpande AD, et al. Anti-inflammatory and analgesic activity of protocatechuic acid in rats and mice. Inflammopharmacol.12 July 2011. DOI 10.1007/s10787-011-0086-4
Inflammation is known to be the common denominator of all disease.
Increases Expression of Growth Factors: PCA has demonstrated to have a potential to cause enhancement of the local growth hormone, IGF-1 and growth factors related to health and or regenerative cells and or tissue. This has been demonstrated in human and animal synovium to produce IGF-1. It has been shown in rodent taped stripped skin wounds to heal in 2 days with a collagen layer regenerated in the skin with evidence of increase in local growth factors. This growth factor has been shown in dose related amounts to cause human osteoblasts and mesenchymal stem cells to make bone. US patents listed below were granted based upon this independent laboratory evidence.
Broad Spectrum Antibiotic: Basic science studies at WuXiapptec Laboratories in Marietta, GA established PCA properties as a broad-spectrum antibiotic by the Kirby-Bauer disc diffusion method. The following study established that PCA was a broad-spectrum antibiotic; including by not limited to MRSA, Pseudomonas, E. Coli, C. difficile, C. acnes and Legionella.
These studies were reported related to further investigation of PCA as a potential surgical skin disinfectant.
Jalali, Omid; Best, Molly; Wong, Alison; Schaeffer, Brett; Bauer, Brendon; Johnson, Lanny. Protocatechuic Acid as a Topical Antimicrobial for Surgical Skin Antisepsis. Preclinical Investigations. JBJS Open Access: July-September 2020 – Volume 5 – Issue 3 – p e19.00079 doi: 10.2106/JBJS.OA.19.00079
Subsequently the US patent 9,498,413 was issued concerning the antibiotic and wound healing properties.
Human Skin Disinfectant: The safety and effectiveness for controlling potential bacterial pathogens on human volunteer’s skin was studied concerning the potential for PCA formulation as a topical surgical disinfectant.
The study at Loma Linda Medical School established that a skin penetration formulation including PCA was effective in controlling potential bacterial pathogens on the human skin, specifically C. acnes which resides below the surface in the hair follicles and sebaceous glands. There were no adverse reactions.
The study was published in Journal of Bone and Joint Open Access.
Jalali, Omid; Best, Molly; Wong, Alison; Schaeffer, Brett; Bauer, Brendon; Johnson, Lanny. Reduced Bacterial Burden of the Skin Surrounding the Shoulder Joint Following Topical Protocatechuic Acid Application Results of a Pilot Study. JBJS Open Access d 2020:e19.00078. http://dx.doi.org/10.2106/JBJS.OA.19.00078
PCA Biofilm Destroying Properties: Since the introduction of antibiotics bacterial pathogens that formally existed independently in planktonic form have mutated and/or formed biofilm colonies for survival. These changes resulted in the resistance to present day antibiotics.
A second study at WuXiAppTec tested the biofilm destroying properties of the PCA crystalline coating on stainless steel and polyester cloth. PCA as a physical crystal possessrs biofilm destroying properties when in solution and or in a dry state coating on a physical article; metal and cloth.
The results of these studies by ASTM E-2647 Drip Flow Biofilm Reactor method are as follows:
This evidence supported the granting of US patent 10,004,705 cited below.
Anti-Microbial Mode of Action: The mode of action from WuXiAppTec was understood to the extent that the 99.999% of the biofilms that flowed for 24 hours across the PCA coated articles of metal and polyester cloth died upon contact.
The mode of action was subsequently understood when explained by the experts at MRIGlobal who did the antiviral studies. They explained that the sharp crystalline shapes disrupted the vulnerable coating of the SARS CoV 2 virus.
Physical Sharp Crystals: PCA’s anti-microbial function is initiated by the physical shape of the crystal; sharp edges and projections, shown to be needle-like in solution.
In recent years the recognition of these the physical properties of the PCA crystal with sharp protrusions have been reported to disrupt the coating of microbes.
Ajiboye TO, Habibu RS, Saidu K, et al. Involvement of oxidative stress in protocatechuic acid-mediated bacterial lethality. Microbiologyopen. 2017;6(4):e00472. doi:10.1002/mbo3.472
However, the study of the crystalline properties of PCA goes back to 1949. The significance in health matters is the recognition that PCA’s crystalline sharp physical shapes exist in both dry and liquid environment with potential to act as an anti-microbial.
The crystalline physical nature is constantly changing in aqueous solution.
Copied from https://royalsocietypublishing.org/doi/10.1098/rspa.1949.0064
Published:22 June 1949. https://doi.org/10.1098/rspa.1949.0064
Abstract: In this paper an extensive study is reported of the very remarkable, and thus far apparently unique, case of the deformation in three dimensions of protocatechuic acid, to which attention was drawn many years ago by Otto Lehmann. The deformations are spontaneous, and are probably due to progressive gliding of the lattice planes, which exist in two configurations, one stable and the other unstable, the latter being the condition of the long prismatic rods when they first form. Such a prism presently deforms into a zigzag crystal, with stable and unstable sections in alternation which, with continuation of the deformation, becomes again straight, but now in the stable configuration. The bending is progressive, like that of an umbrella case, pendant from the end of an oblique cane pointed down, when the latter is pushed into it. The movements are so rapid that motion pictures, made with a microscope, were necessary for the observation of certain stages of the deformation. The deformations have been shown to many chemists and physicists during the past decade or more, none of whom had ever seen or heard of this remarkable type of crystal movement. The deformations are usually observed as the warm saturated solution cools, but they also occur after the crystal has been dried for many hours.
In 1983 Agmon, et al supported Wood’s work and showed that some crystalline shapes were stable in form and others were rapidly changing.
Agmon I, Herbstein FH, Thomas JM. Spontaneous deformation of protocatechuic acid monohydrate crystals: crystallographic aspects. Proc. R. Soc. Lond. 1983. A387311–330. http://doi.org/10.1098/rspa.1983.0062
The following illustrations were taken from Agmon, et al. 1983
The clinical importance is the fact that PCA in a liquid (water, alcohol or other vehicles) retains various crystalline shapes, all with sharp edges. This PCA crystalline antimicrobial factor exists whether in a liquid vehicle or dried on a hard surface.
Therefore, the anti-microbial property would exist for the dry crystalline PCA on a surface. For instance, the SARS CoV2 virus in the liquid droplet would engage the dry crystal, immediately changing the environment to liquid. The PCA crystal is only slowly 1.24% soluble in water and its transition if the PCA crystal to the fluid state would be slow and the virus would have been inactivated before the PCA in any significant amount was in solution. In the SARS CoV2 study outlined below, the virus was inactivated upon engagement with the PCA crystal in both states.
Additional studies verified the crystalline nature of PCA in alcohol and water. The following photomicrographs show by polarized light microscopy the PCA crystals appearance while in in water and or alcohol before drying.
This photomicrograph on the left in water shows the needle physical shapes of PCA in early phase of going into solution. Note the prism shapes not yet converted to needle shapes in interval of 30 minutes. On the right the PCA is already needle shaped in alcohol solution in the same time frame due to increased solubility in alcohol as compared to water.
The associated in vitro studies reported below replicated the clinical environment in reducing transmission. The PCA crystal coating on a hard or cloth article was viricidal for SARS CoV2 virus.
The initial antimicrobial effect is the direct contact of the irregular sharp projections of the crystal that physically disrupt a bacterial biofilm and/or any other bacteria or virus including the prongs and coating of SARS CoV2 virus upon contact as described below. Following the physical disruption, the other antimicrobial properties of PCA become active.
The crystal structure of the reagent causes physical disruption of bacterial and viral coating resulting in microbe death.
PCA Anti-Viral History: PCA is known in the literature to have an antiviral effect in a variety of diseases; avian influenza, hepatitis and influenza.
Ou C, Shi N, Yang Q, Zhang Y, Wu Z, et al. (2014) Protocatechuic Acid, a Novel Active Substance against Avian Influenza Virus H9N2 Infection. PLoS ONE 9(10): e111004. doi:10.1371/journal.pone.0111004.
Guo Y, Zhang Q, Zuo Z, et al. Protocatechuic acid (PCA) induced a better antiviral effect by immune enhancement in SPF chickens. Microb Pathog. 2018; 114:233-238. doi: 10.1016/j.micpath.2017.11.068
Infectious Bursal Disease Virus
Ou CB, Pan Q, Chen X, Hou N, He C. Protocatechuic acid, a new active substance against the challenge of avian infectious bursal disease virus [published correction appears in Poult Sci. 2012 Oct;91(10):2722. Pang, Q [corrected to Pan, Q]]. Poult Sci. 2012;91(7):1604-1609. doi:10.3382/ps.2011-02069
Jiyang Li1, Hai Huang1, Meiqing Feng, Wei Zhou, Xun long, ShiPei Zhou. In vitro and in vivo anti-hepatitis B virus activities of a plant extract from Geranium carolinianum L.
Avian Influenza virus
Ou C, Shi N, Yang Q, Zhang Y, Wu Z, et al. (2014) Protocatechuic Acid, a Novel Active Substance against Avian Influenza Virus H9N2 Infection. PLoS ONE 9(10): e111004. doi:10.1371/journal.pone.0111004
Influenza A and B:
Hils J, May A, Sperber M, Klocking R, Helbig B, et al. (1986) Inhibition of several strains of influenza virus type A and B by phenolic polymers. Biomed Biochim Acta 45: 1173–1179.
Xiao-Qing Dai 1 , Wen-Tao Cai 1 , Xiao Wu, Yong Chen ⁎, Feng-Mei Han. Protocatechuic acid inhibits hepatitis B virus replication by activating ERK1/2 pathway and down-regulating HNF4α and HNF1α in vitro. Life Sciences Volume 180, 1 July 2017, Pages 68-74.
Lu, F., Tseng, S., Li, M. et al. In vitro anti-influenza virus activity of synthetic humate analogues derived from protocatechuic acid. Arch. Virol. 147, 273–284 (2002). https://doi-org.proxy1.cl.msu.edu/10.1007/s705-002-8319-5
Hassan, Sherif T. S.; Švajdlenka, Emil; Berchová-Bímová, Kateřina. Hibiscus sabdariffa L. and Its Bioactive Constituents Exhibit Antiviral Activity against HSV-2 and Anti-enzymatic Properties against Urease by an ESI-MS Based Assay. Molecules. Vol. 22 Issue 5, p. 722, 2017.
Anti-Viral Properties: The medical literature substantiates the following known antiviral properties are found in PCA.
- Physical; crystal sharp crystals for physical disruption followed by:
- low pH
- blocking agent
- cellular and hormonal immunity
- tyrosinase inhibitor
- anti-thrombosis factors.
SARS CoV2 Independent Contract Laboratory Testing:
Although PCA is a nutraceutical it has been subject to investigation as though it was to be a drug-seeking FDA approval. Studies were performed at two independent contract laboratories; Illinois Institute of Technology in Chicago, IL, and MRIGlobal, Inc. in Kansas City, MO.
The experimental method replicated the transmission of the virus in the clinical environment of a sanitizer coating of skin, masks, hard objects, and ventilation filters. The hypothesis was confirmed at both laboratories. The PCA crystalline coating on an article of metal, plastic, and/or cloth would kill the COVID19 virus on contact.
This evidence would support a hypothesis that protocatechuic acid (PCA) has the potential to disrupt the transmission and/or treat Severe Acute Respiratory Syndrome Coronavirus 2 of the genus Betacoronavirus.
The Summary of the results from IIT was as follows: The Log reduction is the scientific measure of reduction and is converted to a percentage for clearer understanding. The word reduction is used scientifically based on the condition of the experiment, but represents in lay terms “kill”.
Table 4, below, compares the Day 1 results with the Confirmatory.
Table 4: Comparison between Day 1 and Day 2 Runs
|Test Article/substrate||Incubation time||Day 1: Log difference||Day 2: Log difference|
“From both the Day 1 and the Day 2 runs, the log reduction varied between a 0.63 to a 2.38 log reduction.
These results show that PCA. when coated approximately 24 hours prior to virus exposure, can reduce infectious virus performance on treated (PCA) substrates in both the drier and more aqueous test conditions of the Day 1 and Day 2 runs, respectively. Additionally, it appears that a longer incubation time may be slightly more effective than the shorter 10-minute time. For your reference, a 1 to 2 log reduction/difference corresponds to a 90 to 99% inactivation while a 3 log reduction corresponds to a 99.9% inactivation.”
In other words, the results varied as is common in research, but results measured by Log differences converts to a no less than 90% and up to 99% inactivation or “kill” in 10 and 60 minutes after contact.
The summary from MRIGlobal were as follows:
The Key to the abbreviations:
SS: stainless steel.
K95: mask material
Table 1. Results of PCA-coated coupon testing of SARS-CoV-2 in vitro
|Sample Name||Replicate No.||TCID50||Log10 TCID50||Average TCID50||Average Log10 TCID50||Log Reduction to Virus Controls||Percent Log Reduction|
Additionally, the same PCA-coated surfaces were tested for a 2-hour contact time with similar results. These are listed in Table 2.
Table 2. Results of 2 hour PCA-coated coupon testing of SARS-CoV-2 in vitro
|Sample Name||Replicate No.||TCID50||Log10 TCID50||Average TCID50||Average Log10 TCID50||Log Reduction to Virus Controls||Percent Log Reduction|
“Based on this experiment, we conclude that PCA is able to inhibit SARS-CoV-2 infection of Vero cells. It is important to note that the virus was in contact with PCA in liquid and dried forms, thus making it impossible to determine the exact mechanism of inhibition.
PCA coating on various articles resulted in the inactivation of the live SARS Vo2 virus. The earliest time of effectiveness was time zero upon drying of the coating and at 24 hours after the sprayed crystals had dried on the articles.
The second factor was that the PCA crystal coating was effective at various time intervals; 10, 60 and 120 minutes after the coating had dried.
Most importantly was the evidence to support labeling of PCA as a viricidal reagent based upon the up to 99.99% or 4-log reduction on the plastic article in liquid environment.”
In other words, the results were stronger at this laboratory with the results measured by Log differences converts to a 99% plus inactivation or “kill” in 10, 60 and 120 minutes after contact.
Human Metabolism: The studies on metabolism of PCA are in the abundant literature from the studies seeking the bioactivity of anthocyanidins. The bioactivity of these food nutrients remained a mystery for many years since they were not identified in large amounts after ingestion. Subsequently the reason was shown by carbon labeling that these parent anthocyanins and anthocyanidins were rapidly metabolized to protocatechuic acid and beyond.
Vitaglione, P., Donnarumma, G., Napolitano, A., Galvano, F. et al., Protocatechuic acid is the major human metabolite of cyanidin-glucoside. J. Nutr. 2007, 137, 2043–2048.
Galvano F, La Fauci L, Lazzarino G, Fogliano V, Ritieni A, Cappellano S, Battistini NC, Gavazzi B, Galvano G. Cyanidins: metabolism and biological properties. J Nutr Biochem. 2004;15:2–11.
Czank C, Cassidy A, Zhang Q, Morrison DJ, Preston T, Kroon PA, Botting NP, Kay CD. Human metabolism and elimination of the anthocyanin, cyanidin-3-glucoside: a (13)C-tracer study. Am J Clin Nutr. 2013 May;97(5):995-1003. doi: 10.3945/ajcn.112.049247.
In vitro testing found PCA to be stable in human plasma during 24-h incubation.
Chen W, Wang D, Wang LS, et al. Pharmacokinetics of protocatechuic acid in mouse and its quantification in human plasma using LC-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2012;908:39-44. doi:10.1016/j.jchromb.2012.09.032
In the mouse after oral administration of 50 mg/kg PCA, it was reported that PCA was absorbed rapidly. Note this would be equivalent to 3500 milligrams for a 70-kilo human which far exceeds what would be common dose in the human. However, the reported half-life of 2.9 min a peak plasma level at 5 minutes lends understanding to PCA metabolism. The initial elimination half-life was 3 min and a terminal half-life of 16 min. PCA remained detectable up to 8 hours.
A biologically effective plasma level of PCA can be reached in mice following oral administration. Oral ingestion of 50 mg/kg PCA aqueous solution can deliver in vivo pharmacological effective concentration of PCA at 5 min, possible through gastric absorption.
De Ferrars, et al showed PCA and metabolites have short life or duration in the body. Therefore, there needs to be more than single dose to have health benefit.
De Ferrars, R.M., Czank, C., Zhang, Q., Botting, N.P., Kroon, P.A., Cassidy, A. and Kay, C.D. 2014. The pharmacokinetics of anthocyanins and their metabolites in humans. British Journal of Pharmacology171: 3268–3282.
In a report by Zheng, et al showed that after human ingestion, the maximum serum concentrations of protocatechuic acid in the free form was 3,273 nmol/L. The recovery of total protocatechuic acid in blood circulation, urine, and feces was 23.79%, 12.17%, and 12.79% of the ingested dose, respectively. Moreover, glucuronide and sulfate metabolite conjugates of protocatechuic acid made up 34.79%, 60.15%, and 72.70% of its total recovery in blood circulation, urine, and feces, respectively. Collectively, protocatechuic acid from chicory is bioavailable and undergoes partial glucuronidation and sulfation in human adults, and its regular consumption may exert health‐promoting effects.
Zheng J, Xiong H, Li Q, et al. Protocatechuic acid from chicory is bioavailable and undergoes partial glucuronidation and sulfation in healthy humans. Food Sci Nutr. 2019;7(9):3071-3080. Published 2019 Aug 14. doi:10.1002/fsn3.1168
PCA is readily absorbed even when a constituent of a food substance. It will initially be in a free form and subsequently metabolized. It is excreted via the urine and feces.
Tissues of Residence: Upon ingestion PCA via the blood stream bathe all the cells, tissues and organs of the body.
Lin C.-Y., Tsai S.-J., Huang C.-S., Yin M.-C. Antiglycative effects of protocatechuic acid in the kidneys of diabetic mice. Journal of Agricultural and Food Chemistry. 2011;59(9):5117–5124. doi: 10.1021/jf200103f.
In our experiments at an independent laboratory in Maryland showed that control rabbits on a normal vegetable diet had small amounts PCA in the synovial fluid of their knee joints.
PCA’s metabolic pathway via the intestine and kidney is now established. The down-stream metabolites are now identified. The major metabolites in addition to PCA are phloroglucinaldehyde (2,4,6 trihydroxybenzadehyde), hippuric acid, and vanillic acids. Their excretion via further metabolic change is via the urine and feces.
It should be noted that our basic science studies showed that the metabolites of hippuric and vanillic acid had little or no antibiotic properties. The antibiotic metabolites were PCA and phloroglucinaldehyde.
Normal Metabolite in Human Bowel. PCA is manufactured in small amounts by the bacteria in the human large bowel.
Aura AM, Martin-Lopez P, O’Leary KA, Williamson G, Oksman-Caldentey KM, Poutanen K, Santos-Buelga C. In vitro metabolism of anthocyanins by human gut microflora. Eur J Nutr. 2005 Mar;44(3):133-42. Epub 2004 Apr 28.
Kay C.D., Kroon P.A., Cassidy A. The bioactivity of dietary anthocyanins is likely to be mediated by their degradation products. Mol. Nutr. Food Res. 2009;53: S92–S101. doi:
Non-mutagenic: No mutagenic reports in the literature.
Tanaka T., Kojima T., Kawamori T.: Cancer Res. 53, 2775 (1993).
Chao C.-Y., Yin M.-C.: Foodborne Pathog. Dis. 1, 6 (2008).
Vitaglione P., Donnarumma G., Napolitano A., Galvano F., Gallo A., Scalfi L.,
Fogliano V.: J. Nutr. 137, 2043 (2007).
Link K.P., Angell H.R., Walker J.C.: J. Biol. Chem. 81, 369 (1929).
Stanier R.Y., Ingraham J.L.: J. Biol. Chem. 210, 799 (1954)
Non-allergenic: No known allergy.
Manufacture: Presently the PCA raw material is only available in small quantities in US; i.e. 25 to 250 milligrams by research orientated companies. Large quantities are available Internationally from China, India and Germany. Multiple sources have been evaluated from which three have been selected based upon quality of the product for including in our products. All shipments to US manufacturers are accompanied by Certificate of Analysis. The products have been independently verified as to purity, percentage confirmation of 98%+, absent of toxins and trace metals. Manufacture of these commercial end products are by American FDA certified companies.
Dose: The proposed oral dose is one or two 500 milligram capsules daily. The liquid formulations for sanitizing delivery to masks, skin, hard objects and or ventilator filters contain 1% PCA. However, when the residual crystals are dried on the surface the concentration of the coating is 100%.
Non-toxic: Toxicity is an important concern so the following reports are summarized to support the unlikelihood of toxicity.
The literature supports that PCA is non-toxic.
Morán A, Gutiérrez S, Martínez-Blanco H, Ferrero MA, Monteagudo-Mera A, RodríguezAparicio LB. Non-toxic plant metabolites regulate Staphylococcus viability and biofilm formation: a natural therapeutic strategy useful in the treatment and prevention of skin infections. Biofouling. 2014;30(10):1175-82. doi: 10.1080/08927014.2014.976207.
There are no human studies on toxicity. Animal studies have provided sufficient evidence concerning toxicity. Conversion of animal studies to a human application indicate that even a single 350,000 milligrams dose in humans would not be toxic. A human would have to ingest 700 of the 500 capsules or tablets which is not likely possible and would still not be toxic.
In conjunction of our EPA application, studies performed at Product Safety Laboratory on 9/27/2017 with a dose level of 5000 mg/kilogram PCA on rodents. It was reported in Laboratory study number 41068 that the LD50 following a single oral delivery was greater than 5000 mg/kg body weight in female rats.
The conversion to a comparable human dose would still be safe at 350,000 milligrams per day for a 70-kilogram human. This amount is obviously unlikely since the recommended dose for humans would be 500-1000 milligrams per day.
Conversion of Animal Dose to Human: The following factors and calculation are necessary to determine the comparable human dose. This is taken from the FDA regulations concerning such:
Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J. 2008 Mar;22(3):659-61. Epub 2007 Oct 17.
ABSTRACT: As new drugs are developed, it is essential to appropriately translate the drug dosage from one animal species to another. A misunderstanding appears to exist regarding the appropriate method for allometric dose translations, especially when starting new animal or clinical studies. The need for education regarding appropriate translation is evident from the media response regarding some recent studies where authors have shown that resveratrol, a compound found in grapes and red wine, improves the health and life span of mice. Immediately after the online publication of these papers, the scientific community and popular press voiced concerns regarding the relevance of the dose of resveratrol used by the authors. The animal dose should not be extrapolated to a human equivalent dose (HED) by a simple conversion based on body weight, as was reported. For the more appropriate conversion of drug doses from animal studies to human studies, we suggest using the body surface area (BSA) normalization method. BSA correlates well across several mammalian species with several parameters of biology, including oxygen utilization, caloric expenditure, basal metabolism, blood volume, circulating plasma proteins, and renal function. We advocate the use of BSA as a factor when converting a dose for translation from animals to humans, especially for phase I and phase II clinical trials.—Reagan-Shaw, S., Nihal, M., Ahmad, N. Dose translation from animal to human studies revisited. FASEB J. 22, 659–661 (2007)
TABLE 1. Conversion of animal doses to HED based on BSA via FDA regulations
|Species Human||Weight (kg)||BSA (m2)||Km factor|
Values based on data from FDA Draft Guidelines (7). To convert dose in mg/kg to dose in mg/m2, multiply by Km value.
Example calculation: The human dose equivalent can be more appropriately calculated by using the formula shown in the figure above. To convert the dose used in a mouse to a dose based on surface area for humans, multiply 22.4 mg/kg (Baur’s mouse dose) by the Km factor (3) for a mouse and then divide by the Km factor (37) for a human. This calculation results in a human equivalent dose for resveratrol of 1.82 mg/kg, which equates to a 109 mg dose of resveratrol for a 60 kg person.
In another report: http://www.hindawi.com/journals/isrn/2014/952943/
The following was stated:
Toxicity Profile of PCA is summarized as follows:
The LD50 of PCA was found to be 800 mg/kg by intra peritoneal route and 3.5 g/kg by intravenous route in mice. Due to low absorption by oral route, PCA is a nontoxic and a relatively safe compound for oral administration.
The above paper reveals that the PCA is safer at its therapeutic dose of 100 mg/kg. The compound was found to be potent antioxidant, antibacterial, anticancer, anti-hyperlipidemic, anti-diabetic, and anti-inflammatory.
We are anticipating giving 500 mg per mouth daily to subjects over 150 kilograms or 3.33 mg per kilo.
Nakamura et al reported the dose of 500 mg/kg caused significant hepatic and nephritic glutathione level depletion in mice. This dose far exceeds any anticipated or probable therapeutic dose for humans or animals. A 70-kilogram human would have to take 35,000 milligrams dose which is not likely possible. The recommended daily dose for oral intake is 500 milligrams per day or 70 times less.
Abstract: It has previously been reported that a toxic dose of protocatechuic acid (PA), a naturally occurring simple phenolic antioxidant in dietary plant foodstuff, has a potential to enhance tumorigenesis and induce contact hypersensitivity in mouse skin. In this study, the modifying effect of a toxic dose of PA on the glutathione (GSH) level in mouse liver and kidney was examined. Intraperitoneal administration of PA (500 mg/kg which would be 350,000 mg in human) caused significant hepatic and nephrotic GSH depletion. Interestingly, slight but significant hepatotoxicity and nephrotoxicity, characterized by the enhancement of plasmic alanine aminotrasferase (ALT) activity and urea level, respectively, were also observed. The subchronic administration of PA (0.1% in drinking water) for 60 days showed not only a significant decrease in the GSH level in kidney but also a significant enhancement of ALT activity in plasma. The protective role of GSH for acute hepatotoxicity using GSH-depleted mice administered a GSH synthesis inhibitor buthionine sulfoximine was also demonstrated. Thus, it is suggested that overdoses of PA can disturb the detoxification of other electrophilic toxicants including ultimate carcinogens.
Note: This again would convert to 35,000 milligrams for a 70-kilo human. Not likely.
Nakamura Y, Torikai K, Ohigashi H. Toxic dose of a simple phenolic le, protocatechuic acid, attenuates the glutathione level in ICR Mouse liver and kidney. J. Agric Food Chem. 2001 Nov;49(11):5674-8.
Expert Opinion: A personal communication from Ronald Prior, PhD, an international expert, is as follows:
“I have attached 3 manuscripts where PCA was given orally at a dose of 250 mg/kg for 3 days, 100 mg/kg for 12 weeks and 100 mg/kg for 4 weeks with no toxicity and with protective effects in cardiac, diabetetic and cognitive animal models.
Tang X-L, Lui J-X, Dong W, Lil P, Lil P, Lil L, Lin C-R, Zheng Y-Q, Cong W-H, Hou, J-C. The
Cardioprotective Effect of Protocatechuic Acid on Myocardial Ischemia/Reperfusion Injury. J Pharmacol Sci 125, 176 – 183 (2014)
Semaning Y, Kumful S, Pannangpetch P, Chattipakorn SC, Chattipakorn N. Protocatechuic acid exerts a cardioprotective effect in type 1 diabetic rats. J Endocrinol 2014 223. 13-23.
Song Y, Cui T, Xie N, Zhang X, Zianb Z, Liua J. Protocatechuic acid improves cognitive deficits and attenuates amyloid deposits, inflammatory response in aged AβPP/PS1 double transgenic mice. J Endocrino Oct 2014. 223: 13-23. Published online before print July 29, 2014. doi: 10.1530/JOE-14-0273.
“I would not expect any toxicity effects with oral doses less than 10 mg/kg BW in humans.” Ronald Prior, PhD. (700 mg for 70 kilo human)
Literature Evidence of Safety by Dose: PCA is safe at its therapeutic oral dose of 100 mg/kg. That would be 7000 mg per 70-kilogram person. This would be 14 500 mg capsules or tablets at once.
Kakkar S, Bais S. A Review on Protocatechuic Acid and Its Pharmacological Potential. ISRN Pharmacology. Volume 2014 (2014), Article ID 952943, 9 pages.
The issue of dose and safety is reported by Liu, et al. They were studying rodents. They gave 12 grams of the parent anthocyanidin, cyanidin-3-glucoside per kilogram body weight. The rodents weighed as much as 200 grams. The dose was given daily for 7 days.
They reported “no abnormalities heart, liver, spleen, lung, kidney and other organs”. There were no deaths of animals in the 8 days as reported and copied below from the machine translation of their filing CN101306003.
Safe with Prolonged use: In experimental animals protocatechuic acid did not significantly disturb the wellness of rats, even after prolonged exposure. These studies included body weight, histology of the liver,
Szumilo J, Fraczek M, Kelepaz R, Szumilo M, Budan F. Diet supplements, resveratrol and protocatechuic acid, do not disturb wellness and liver morphology in rats. Med. Weter. 2015, 71 (5), 298-302.
US Patents: These all have supporting evidence published above has resulted in the following patents easily review in full on the US patent web site; https://www.uspto.gov/patents/search.
September 11, 2012. This patent showed that the dyes of plants (anthocyanins and anthocyanins) the precursor of the metabolite protocatechuic acid turned on the gene for growth hormone IGF-1 in human synovium.
November 8, 2016. This patent secured the intra articular injection route not previously included in the granted patent claims for cyanidin-3-glucoside.
November 22, 2016. This was the parent patent showing broad spectrum antibiotic properties and wound healing acceleration. See the illustrations above.
March 27, 2018.This was a continuation of the parent application that adds 2,4,6 trihydroxybenzaldehyde to the broad-spectrum antibiotic, plus collagen proliferation (i.e. wrinkle treatment) and reduction in scar formation.
March 27, 2018.This was a continuation of the parent application that adds 2,4,6 trihydroxybenzaldehyde to the broad-spectrum antibiotic, plus collagen proliferation (i.e. wrinkle treatment) and reduction in scar formation.
May 15, 2018. This patent secures that protocatechuic acid can only be manufactured and delivered to an end user by the owner of this patent.
June 5, 2018. This patent was a continuation of 9,925,152 that now allowed for intra-articular injection.
July 26, 2018. This patent included the metabolites of protocatechuic acid and 2,4,6 trihydroxybenzaldehyde for the destruction of biofilms of MRSA and Pseudomonas on metal, cloth and ceramic.
July 26, 2018. This was an expansion of 10,004,705 applications.
July 10, 2018. This patent expanded the formulation for treatment of implants to include protocatechuic acid, 70% isopropyl alcohol, propylene glycol, and an essential oil.
July 31, 2018. This patent includes the chemical formulation of 10,016,380 for medical and surgical implants, dental implants and instrumentation. The later for spaying or soaking in solution.
December 4, 2018. This patent secures the use of PCA to coat a bandage or dressing at time or treatment and or a commercial preparation for as stated in claim #22 if a wound is a burn, skin break, bone break, muscle tear, puncture, surgical incision site, microdermabrasion site, skin graft site, a wound associated with diabetes, a bed sore, a pressure sore, skin defoliation, or a laceration, and wherein the protocatechuic acid becomes activated by contact with moisture from the wound.
April 23, 2019. An extension of prior claims that specifically cite PCA as an antibacterial for Propionibacterium acnes. This for the treatment of skin acne.
May 21, 2019. This patent extends the use of PCA to the food industry.
September 3, 2019. This is a non-surgical method of loosening biofilms from an implant via ultrasound and then treating without surgery. The treatment would be repeated needle aspirations for infection status and then injection of protocatechuic acid crystals to destroy the biofilms attached to the implant.
October 1, 2019. This is an extension and further specification of the skin penetration formulation claims for pre-operative skin disinfection and facial acne with concentration above 10%.
September 5, 2020. This is an extension that includes the disinfectant and sanitizer use emphasizing the residual anti-microbial protocatechuic acid coating the remains on the article and or person after the evaporation of the liquid vehicle.
March 30, 2021. The treatment of COVID19 virus with protocatechuic acid. This patent is for treating the patient; oral, intravenous, injection, etc.
1. A method of treating Covid-19 in a mammal comprising: administering to the mammal in need thereof a composition comprising protocatechuic acid.
2. The method of claim 1, wherein the mammal is a human.
August 31, 2021. Anti-microbials and the Methods and Use thereof. This patent is for mitigation of bacteria and virus (COVID 19) by coating of personal protective equipment; masks, gowns, hats, shoes, etc.
3/8/2022. Anti-microbials and the Methods and Use thereof. This patent for the mitigation of SARS Co-2 virus on skin, protective equipment and hard surfaces.
1. A method of interrupting the transmission of SARS CoV2 virus comprising: spraying, coating, fogging, and/or infusing a subject’s skin or personal protective equipment, room and/or facility, with a composition comprising protocatechuic acid, a liquid vehicle comprising an alcohol, and a stabilizer, the composition disinfecting SARS CoV2 virus on the subject’s skin or personal protective equipment, room and/or facility, upon contact; and forming a solid coating of protocathechuic acid on the subject’s skin or personal protective equipment, room and/or facility upon evaporation of the liquid vehicle, and disinfecting SARS CoV2 virus with the solid coating of protocatechuic acid for up to 24 hours.
May 24, 2022. Candida auris disinfectant.
May 24, 2022. Compositions including combination of cannabinoid (CBS) and protocatechuic acid.
The coating on the skin is not usually visualized following a spray application. In order to illustrate what it would look like if you could visualize we staged these photographs with heavy concentration of crystals so you could appreciate the coating including into penetration into the finger prints.
On Hair: Body hair is common to the human body and also is in the nose as a filter or particles and or microbes.
A proof of principle study on skin hairs showed that PCA crystals intimately attached to the dry body hairs.
Normal Skin Hair: Normal skin hair differs from nasal hair in that it is dry.
Photomicrographs of normal skin hair in water medium and polarized light.
The normal body hair illuminates under polarized light microscopy, but is very homogenous and no crystalline shapes.
Normal Hair shaft under polarized light shows a uniform homogenous polarization in distilled water without PCA.
A 70% denatured ethanol solution of 1% PCA applied to the normal body hair show adherence of the PCA crystals to the hair shaft. Note the intimacy of crystals to the hair shaft, but no crystals within as seen with nasal hair, but not impregnated as with nasal hair.
A proof of principle study was performed concerning nasal hair. PCA crystals are easily identified under microscopic polarized lighting.
Normal nasal hair photomicrograph shows no birefringence of crystals.
The PCA crystal delivered to nasal hairs show the impregnation of these hairs. This is likely due to the natural aqueous environment in the nose.
Higher power polarize light photomicrograph in water shows crystals within the hair shaft.
On Hard Surface: The crystals have a minimum of 2-year shelf life. They have been shown to remain unchanged for at least one year following coating of a hard surface.
Photograph of residual protocatechuate crystals on top of a filing cabinet at one year. The coating was scraped with fingernail to show the pileup of crystals to the right of the bare scraped are area. For reference, the scraped bare area is 2X4 millimeters in size.
On Masks and Personal Protective Equipment:
Governing Regulations: Although PCA is classified as a nutraceutical it was researched as though it was to be a drug.
PCA is a nutraceutical and as such for oral or topical use does not require prior FDA approval to market and sell with labeling disclaimers; not evaluated by FDA and not intended to make a diagnosis or to mitigate or treat any disease.
Therefore, it is labeled for sale to support health.
FDA Applications: There are FDA applications planned for skin, masks, room filters, nebulizer, hard surfaces, nasal and oral use.
EPA Application: EPA application submitted in JAN 2020 and last review in June 2021. Still pending.
Lanny L. Johnson, M.D.