{"id":225416,"date":"2016-10-04T12:31:29","date_gmt":"2016-10-04T15:31:29","guid":{"rendered":"http:\/\/revistapesquisa.fapesp.br\/en\/?p=225416"},"modified":"2016-10-05T12:31:40","modified_gmt":"2016-10-05T15:31:40","slug":"the-ultimate-trial-of-phosphoethanolamine","status":"publish","type":"post","link":"https:\/\/revistapesquisa.fapesp.br\/en\/the-ultimate-trial-of-phosphoethanolamine\/","title":{"rendered":"Phosphoethanolamine’s ultimate trial"},"content":{"rendered":"
\"Pill

L\u00e9o Ramos<\/span>Pill of discord: the Brazilian government approved phosphoethanolamine before the drug had been adequately testedL\u00e9o Ramos<\/span><\/p><\/div>\n

In the coming weeks, two independent clinical trials will test the alleged beneficial effects of phosphoethanolamine \u2013 which has been used for over two decades with no scientific backing as an attempt to treat cancer.\u00a0 Artisanally produced since the 1990s by Gilberto Chierice, a retired full professor at the S\u00e3o Carlos Chemistry Institute of the University of S\u00e3o Paulo (IQSC-USP), the controversial chemical will undergo its first controlled human trials, based on research protocols, in the states of S\u00e3o Paulo, Cear\u00e1 and Rio de Janeiro.\u00a0 Its potential effect on different types of tumors will be thoroughly monitored for months, perhaps years if the results are promising, by medical doctors and the researchers involved in the experiments.\u00a0 \u201cWhen the trials are over, we will have left the realm of subjectivity, where some report improvements after taking phosphoethanolamine, and will have gained objective information on any true effectiveness of the drug against one or more cancers,\u201d says Roger Chammas, professor of basic oncology at the USP School of Medicine (FM-USP) and coordinator of the Center for Translational Investigation in Oncology at the S\u00e3o Paulo State Cancer Institute (ICESP).<\/p>\n

ICESP will conduct the first trial.\u00a0 For two months, the cancer drug candidate will be administered to a group of 10 patients with the illness to confirm its apparent nontoxicity.\u00a0 \u201cWe must validate this point before any further work,\u201d says Paulo Hoff, managing director of ICESP and coordinator of the trial.\u00a0 If no safety issues arise, phosphoethanolamine pills will be given to a group of 210 patients, divided into groups of 21, presenting the 10 most common types of cancer: head and neck, breast, prostate, cervical, colorectal, stomach, liver, lung, pancreatic, and melanoma.\u00a0 If the compound shows any benefits, the experiment may be expanded to include up to 1,000 patients, who will be monitored for two years.<\/p>\n

The scientific protocol to be followed by this study, funded up to a cost of R$2 million by the S\u00e3o Paulo State government, has already been approved by the National Health Council’s National Commission for Ethics in Research (CONEP-CNS) and by the Brazilian Health Surveillance Agency (ANVISA), the federal regulator that handles food and drug registrations.\u00a0 The phosphoethanolamine that will be used in the study was synthesized by PDT Pharma, a company in the city of Cravinhos, in inland S\u00e3o Paulo State, and is being encapsulated by the Popular Medicine Foundation (FURP), the state’s official pharmaceutical laboratory.\u00a0 \u201cWe can start the trial as soon as we receive the pills,\u201d says Hoff.\u00a0 Six months after testing begins, it will be possible to get a preliminary idea of whether the compound is effective against any kind of tumor, according to the ICESP managing director.<\/p>\n

The second initiative involves the Drug Research and Development Center at the Federal University of Cear\u00e1 (NPDM-UFC) and the National Cancer Institute (INCA), in the city of Rio de Janeiro.\u00a0 The NPDM plans to initiate phase 1 of the clinical trial (on humans) in August 2016, when four different dosages of phosphoethanolamine will be orally administered to a group of 60 to 120 healthy, cancer-free volunteers to check for toxicity.\u00a0 \u201cBy then, we should have all the reports from the pre-clinical trials conducted by our work group, and we will have obtained the necessary authorizations to start the trials,\u201d says physician Manoel Odorico de Moraes, professor at UFC and coordinator of the NPDM.<\/p>\n

\"Phosphoethanolamine\"<\/a>If it passes this initial test, the drug will advance to phase 2 of the clinical trial at INCA.\u00a0 At that stage, it will be tested in up to 200 patients, divided into four groups of 50, each presenting a type of tumor that does not respond well to standard treatments: melanoma, cervical cancer, lung adenocarcinoma without EGFR gene mutation, and triple-negative breast cancer (without three types of biomarkers).\u00a0 \u201cFirst, we will test phosphoethanolamine on a group of 20 patients with each type of tumor,\u201d says physician Marisa Maria Dreyer Breitenbach, research coordinator at INCA.\u00a0 If the results are positive in at least 10% of patients, the drug will be administered to the other subjects in the group.\u00a0 Finally, if it continues to show promising effects in a significant percentage of subjects, the molecule may be tested on a larger population of cancer patients.\u00a0 \u201cWe need to run all the tests.\u00a0 You can’t simply take the positive results of studies performed on animals or laboratory-grown cells and extrapolate them to human beings,\u201d says Breitenbach.\u00a0 The trials at the NPDM-UFC and INCA are among the pre-clinical and clinical studies on phosphoethanolamine being conducted by a work group created in October 2015, as a joint initiative of Brazil\u2019s Ministry of Health and Ministry of Science, Technology and Innovation.\u00a0 Up to R$10 million have been earmarked for the group’s initiatives, which may extend over a period of three years.\u00a0 However, this funding will not be sufficient to cover all expenses, if phosphoethanolamine reaches the final stages of testing.<\/p>\n

According to Chierice, who retired from USP in December 2013, the phosphoethanolamine produced in his laboratory was tested in the second half of the 1990s on cancer patients at Amaral Carvalho Hospital in the city of Ja\u00fa, with which his research group signed an agreement.\u00a0 But the hospital’s press relations office denies having administered the drug to humans at that time.<\/p>\n

Defined as the chemical molecule C2<\/sub>H8<\/sub>NO4<\/sub>P, phosphoethanolamine is produced naturally by mammals, including humans.\u00a0 It is produced in the endoplasmatic reticulum of eukaryotic cells, namely those that contain a nucleus and organelles protected by membranes, and it is found in every tissue and organ, as well as in breast milk.\u00a0 The compound is identified with a precursor of phosphatidylcholine and phosphatidylethanolamine, two molecules involved in the synthesis of phospholipids, a type of fat that is the main component in cell membranes.\u00a0 The connection between phosphoethanolamine and cancer dates back to 1936, when the molecule was isolated for the first time from bovine tumors.\u00a0 It was later synthesized in laboratories and is now sold as a chemical ingredient, appearing in the formula for some calcium supplements sold outside Brazil.<\/p>\n

Unorthodox developments <\/b><\/strong>
\nTrials on patients would be a natural stage of clinical research if phosphoethanolamine had undergone the classic legal path prescribed by Brazil’s health authorities for registering new drugs.\u00a0 But its history is peculiar and unorthodox, and the drug has had an unusual legal status since April 14, 2016.\u00a0 On that day, a federal bill proposed by the Senate and passed into law without vetoes by the Brazilian president authorized the drug’s use by patients bearing a medical document confirming a cancer diagnosis.\u00a0 The crowd-pleasing measure, overriding the authority of ANVISA (Brazil’s food and drug regulator), was taken despite an absolute lack of any published scientific evidence that phosphoethanolamine is safe and effective for humans.\u00a0 The law does not specify where the phosphoethanolamine will be produced.\u00a0 PDT Pharma is currently responsible for supplying the pills exclusively for testing at ICESP.\u00a0 USP closed Chierice’s old laboratory at IQSC in late March 2016.\u00a0 Soon after, in early April, Brazil\u2019s Federal Supreme Court gave the university the legal right to stop supplying the drug to patients upon depletion of the existing inventory of pills.\u00a0 ANVISA, medical associations, the Brazilian Academy of Science (ABC) and other scientific entities are against the law.\u00a0 After all, phosphoethanolamine is not registered as a medicinal drug anywhere in the world.<\/p>\n

Candidates for recognition as medicines are required to undergo pre-clinical trials before they are ever tested on healthy people or on patients.\u00a0 At this preliminary stage, the drug’s toxicity and potential therapeutic effects are observed in vitro<\/i><\/em> (in laboratory-grown animal or human cells) and in vivo<\/i><\/em> in animal models, usually mice with a version of the human disease targeted by the potential drug.\u00a0 About 90% of all tested molecules never make it past this stage because they fail to present any satisfactory results.\u00a0 Those that prove safe and potentially effective against a disease may move on to full-fledged clinical trials, i.e., testing on humans.\u00a0 \u201cMany compounds that produce good results in in vitro<\/i><\/em> experiments do not have the same effect when tested on people,\u201d says INCA\u2019s Breitenbach.\u00a0 If it truly proves effective against an illness, with more benefits than adverse effects, the drug candidate is approved and registered by ANVISA as a medication for a specific health condition.\u00a0 The whole process rarely takes less than 10 years, given the need to make sure that the drug will produce the desired effect without being toxic (see infographic<\/a><\/i><\/em>).<\/p>\n

\"Cells

Thomas Ried\/NCI Center for Cancer Research<\/span><\/a> Cells dividing: speed of the process increases cancer riskThomas Ried\/NCI Center for Cancer Research<\/span><\/p><\/div>\n

About a dozen studies about the use of phosphoethanolamine have been published in international journals, but they involve only administering the drug to strains of animal and human cells (in vitro<\/i><\/em>) or animal models with cancer (in vivo<\/i><\/em>).\u00a0 Overall, these studies suggest that phosphoethanolamine is not toxic to healthy, cancer-free cells and may have some effect on some types of tumors: melanoma, breast, leukemia, liver, lung, kidney, bone, and glioblastoma (brain).\u00a0 Durvanei Augusto Maria, from the Biochemistry and Biophysics Laboratory at the Butantan Institute, is the author of most of these papers in partnership with Chierice and his colleagues.<\/p>\n

In the past 10 years, Durvanei Maria has systematically focused on studying phosphoethanolamine in pre-clinical experiments.\u00a0 \u201cI work with pure, crystallized phosphoethanolamine, which is water-soluble and was supplied to me by Professor Chierice,\u201d says the researcher, who currently advises two master’s degree candidates and one PhD student, who were given grants from FAPESP to study the compound.\u00a0 \u201cI administer it to the animals intravenously or intraperitoneally, not orally through pills, as it would be given to patients.\u201d\u00a0 This is a crucial detail.\u00a0 The dissemination, absorption, deposition and elimination rates of a drug can vary widely as a result of how it is taken in.\u00a0 Particularly noteworthy among Durvanei Maria’s recent studies on phosphoethanolamine are two articles: one published in the British Journal of Cancer<\/i><\/em> in November 2013 and another published on April 18, 2016 in the electronic version of the International Journal of Nanomedicine<\/i><\/em>.<\/p>\n

According to the Butantan Institute researcher, phosphoethanolamine’s assumed mechanism of action against cancer is different from those of chemotherapy and radiotherapy treatments.\u00a0 \u201cWe believe that it has a painkilling effect and alters the lipid [fat] composition near cancer cells,\u201d says Durvanei Maria.\u00a0 This means that the compound might alter mitochondrial function and stimulate apoptosis (programmed cell death) in cancer cells, while preserving healthy ones.\u00a0 According to Chierice, phosphoethanolamine acts as a sort of marker for cancer cells, which function anaerobically, i.e., without oxygen, whereas healthy cells require oxygen to survive.\u00a0 Therefore, he continues, the compound might help the patient’s immune system fight the disease.\u00a0 \u201cDoctors say there are about 150 different types of cancer, but only these two types of cells, namely anaerobic and aerobic,\u201d says Chierice.<\/p>\n

According to Roger Chammas, the hypothetical mechanism of action for phosphoethanolamine proposed by Chierice and his group is interesting and plausible, but must be proven by further research and indicates a lack of knowledge of the complexity of biological systems.\u00a0 \u201cThey believe that the compound might be modified by the organism, generating phospholipids that would then have antitumor effects,\u201d says Chammas.\u00a0 \u201cThis hypothesis has not been tested.\u00a0 We need additional studies.\u201d<\/p>\n

\"Chemist

L\u00e9o Ramos <\/span>Chemist Gilberto Chierice: pills were produced in his former laboratory at USP in S\u00e3o CarlosL\u00e9o Ramos <\/span><\/p><\/div>\n

What’s in the pills<\/b><\/strong>
\nAs an initial activity, the work group created by the Ministry of Health and the Ministry of Science, Technology and Innovation analyzed the contents of the pills produced in S\u00e3o Carlos.\u00a0 Then, they synthesized phosphoethanolamine according to Chierice’s method and conducted some pre-clinical studies.\u00a0 Apart from confirming its nontoxicity and lack of mutagenic effect on DNA, phosphoethanolamine did not reward its advocates with encouraging results.\u00a0 The research group headed by Luiz Carlos Dias, coordinator of the Synthetic Organic Chemistry Laboratory at the University of Campinas (LQOS-Unicamp), analyzed the weight and content of 16 pills.\u00a0 None of them contained the stated amount of 500 milligrams (mg), instead ranging from 233 to 368 mg. \u201cThe manufacturing process for the pills was uncontrolled and amateurish,\u201d says pharmacist Eliezer J. Barreiro from the Federal University of Rio de Janeiro (UFRJ), coordinator of the National Institute of Science and Technology of Drugs and Medicines (INCT-Inofar), who co-signed the phosphoethanolamine pill analysis report along with Dias.<\/p>\n

On average, the composition of the pills was 32.2% phosphoethanolamine, plus four other components: 34.9% calcium, magnesium, iron, manganese, aluminum, zinc and barium phosphates; 3.6% calcium, magnesium, iron, manganese, aluminum, zinc and barium pyrophosphates; 18.2% protonated monoethanolamine; and 3.9% phosphobisethanolamine.\u00a0 \u201cWe were expecting a single compound and found five,\u201d says Dias.\u00a0 Also as part of the pre-clinical studies conducted by the work group, the Innovation Center for Pre-Clinical Trials (CIEnP), a private, nonprofit institute located in the city of Florian\u00f3polis, found that monoethanolamine, and not phosphoethanolamine, demonstrated in vitro<\/i><\/em> toxicity in skin and pancreas cancer cells.\u00a0 But monoethanolamine proved useful against tumor cells only at a high concentration, about 3,000 times higher than that used in chemotherapy drugs.\u00a0 \u201cPure phosphoethanolamine is inactive,\u201d says Jo\u00e3o Batista Calixto, retired full professor of pharmacology at the Federal University of Santa Catarina (UFSC) and CIEnP coordinator.\u00a0 In the state of Cear\u00e1, the research and development center coordinated by Manoel Odorico de Moraes, from UFC, also reported that phosphoethanolamine did not show toxicity against five different strains of in vitro <\/i><\/em>human and mouse cells, three of them tumoral and two cancer-free.<\/p>\n

Chierice and Durvanei Maria dispute most of the pre-clinical results presented by the work group set up by the federal government.\u00a0 \u201cI never said the pills contained only phosphoethanolamine,\u201d says Chierice.\u00a0 \u201cIt’s an acidic compound that needs to be neutralized with bases before it can be given to people.\u201d\u00a0 Although he admits that the weight of the pills produced in his former laboratory in S\u00e3o Carlos may vary somewhat, he was surprised when the tests conducted at Unicamp revealed the presence of barium.\u00a0 \u201cI don’t think they ran the tests on phosphoethanolamine from my pills.\u00a0 They must have synthesized the compound using a different method from mine,\u201d says Chierice.\u00a0 Dias reaffirms that the tests were conducted on material from the pills manufactured in S\u00e3o Carlos.\u00a0 Durvanei Maria also argues that the studies conducted by the work group used excessively low concentrations of phosphoethanolamine.\u00a0 This may be why their results were different from those of his research performed at the Butantan Institute.<\/p>\n

An expert in the synthesis of polymers derived from castor beans that can be used for medical applications (see Pesquisa FAPESP <\/i><\/em>Issue n\u00ba 91<\/a>), Chierice had never worked with phosphoethanolamine before the late 1980s.\u00a0 It was then that he first discovered the chemical, during an experiment using a calcium-selective electrode.\u00a0 He consulted the scientific literature and his initial impression was that phosphoethanolamine could cause cancer.\u00a0 Then, he started thinking the exact opposite.\u00a0 \u201cI thought that phosphoethanolamine is produced by the body to fight tumors,\u201d says Chierice.\u00a0 For months, he attempted to produce the compound in his laboratory.\u00a0 He successfully synthesized phosphoethanolamine by combining two substances \u2013 monoamine and phosphoric acid.\u00a0 In 2008, Chierice filed a patent request for the method he used.\u00a0 It was a low-cost, high-yield way of producing the drug, he says.<\/p>\n

\"Asking

Cec\u00edlia Bastos \/ USP Images<\/span>Asking for phosphoethanolamine at IQSC: A court order was issued forcing USP to deliver the drug to certain patients, but distribution of the pills is now forbiddenCec\u00edlia Bastos \/ USP Images<\/span><\/p><\/div>\n

Agreement with a hospital<\/b><\/strong>
\nIn 1995, Chierice signed an agreement with Amaral Carvalho Hospital to test three of his laboratory’s initiatives over a period of five years: castor bean implants, an antibacterial\/antifungal agent also extracted from this plant, and the effect of phosphoethanolamine on patients with cancer.\u00a0 It was around that time that the compound started being distributed to cancer patients.\u00a0 \u201cInitially, I supplied the phosphoethanolamine so the hospital could perform the tests,\u201d says Chierice, who has a copy of the written agreement.\u00a0 \u201cThe whole thing was approved by the hospital’s ethics committee and by the Ministry of Health.\u00a0 ANVISA did not yet exist.\u201d\u00a0 Over time, according to the chemist, the doctors at the hospital saw that the test results were good and started asking the patients themselves to pick up the pills at Chierice’s laboratory at USP.\u00a0 If they were indeed completed, the results of the tests at Amaral Carvalho Hospital were never released, and the hospital now denies having dispensed phosphoethanolamine to cancer patients.<\/p>\n

With the end of the agreement between the research group and the hospital in 2000, cancer-stricken patients from the S\u00e3o Carlos area and other parts of the state and country started flocking to Chierice’s laboratory at IQSC in search of the pills that could cure cancer, at least according to some people who had used them.\u00a0 Chierice did not turn them away, and his laboratory became a site of silent pilgrimage for often-desperate patients and relatives.\u00a0 The chemist estimates that he produced around 40,000 pills a year, enough to supply approximately 800 people.\u00a0 \u201cI never did anything in secret.\u00a0 Everyone knew about phosphoethanolamine.\u00a0 Many colleagues at USP picked up the pills,\u201d he says.<\/p>\n

The situation went on for years out of the public eye.\u00a0 In December 2013, Chierice turned 70 and was forced to retire from the university.\u00a0 In June 2014, IQSC issued an administrative act reinforcing the federal ban on university researchers producing and distributing substances not approved as pharmaceutical drugs by ANVISA and the Ministry of Health.\u00a0 Phosphoethanolamine was not specifically mentioned, but was the main target.\u00a0 \u201cWhen I was still a professor at USP, no one had the nerve to forbid its production,\u201d says Chierice.\u00a0 In early 2016, USP formally accused the chemist of \u201cwitch-doctoring\u201d and crimes against public health.<\/p>\n

Patients who had been receiving phosphoethanolamine informally (in noncompliance with ANVISA regulations) obtained court orders giving them the legal right to continue receiving the pills from USP.\u00a0 The university argued that it was not a pharmaceutical laboratory and no research had been conducted to authorize the drug’s use by humans.\u00a0 In late 2015, the discussions reached Brazil’s Chamber of Deputies and Senate, where Chierice and other researchers in his group were brought in to defend the use of the compound.<\/p>\n

The clinical trials that will soon start in Brazil are not likely to end the controversy.\u00a0 Chierice does not fully accept them and shows no intention of changing his opinion.\u00a0 \u201cI am conducting tests on phosphoethanolamine abroad to challenge their results with those obtained in Brazil,\u201d he says, without identifying the foreign laboratories.\u00a0 \u201cI am certain that I have found the cure for cancer.\u201d\u00a0 This kind of statement creates unreasonable expectations, according to most researchers.\u00a0 Oncologists do not believe that a single drug could fight all 200 different types of tumors.\u00a0 \u201cWe did not design our tests in the hope that phosphoethanolamine would be miraculous.\u00a0 This cannot reasonably be expected from the drug,\u201d says Paulo Hoff from ICESP.\u00a0 \u201cWe will analyze its potential effects, independently for each of the 10 groups of patients with different types of tumors.\u201d<\/p>\n

Projects
\n<\/b>1.<\/strong> Evaluation of the antitumor effects of the DODAC\/synthetic phosphoethanolamine liposomal formulation in a model of hepatocellular carcinoma (n\u00ba 2015\/02950-1<\/a>); Grant Mechanism <\/b><\/strong>Scholarships in Brazil \u2013 Fast-track Doctorate; Principal Investigator <\/b><\/strong>Durvanei Augusto Maria (Butantan Institute); Grantee\u00a0<\/b><\/strong>Arthur Cassio de Lima Luna; Investment<\/b><\/strong>\u00a0R$93,974.40
\n2.<\/strong> Assessment of antiproliferative and apoptosis effects of liposomal formulation DODAC associated with synthetic phosphoethanolamine in cell lines of oral squamous cell carcinoma (n\u00ba 2015\/00547-5<\/a>); Grant Mechanism\u00a0<\/b><\/strong>Scholarships in Brazil \u2013 Master’s; Principal Investigator <\/b><\/strong>Durvanei Augusto Maria (Butantan Institute); Grantee <\/b><\/strong>Larissa Kim Higashi de Carvalho; Investment<\/b><\/strong>\u00a0R$49,143.90
\n3.<\/strong> Evaluation of antitumoral liposomal formulation DODAC with synthetic compound phosphoethanolamine in human breast tumor cells (n\u00ba 2014\/02344-1<\/a>); Grant Mechanism<\/b><\/strong>\u00a0Scholarships in Brazil \u2013 Master’s; Principal Investigator<\/b><\/strong>\u00a0Durvanei Augusto Maria (Butantan Institute); Grantee<\/b><\/strong>\u00a0Manuela Garcia Laveli da Silva; Investment <\/b><\/strong>R$47,624.90<\/p>\n

Scientific articles<\/em>
\nLUNA, A. C. L. et al<\/i><\/em>. Potential antitumor activity of novel DODAC\/PHO-S liposomes<\/a>. International Journal of Nanomedicine<\/b><\/strong>. Apr. 18, 2016.
\nFERREIRA, A. K. et al<\/i><\/em>. Synthetic phosphoethanolamine has in vitro<\/i><\/em> and in vivo<\/i><\/em> anti-leukemia effects<\/a>. British Journal of Cancer<\/b><\/strong>. V. 109. No. 11, pp. 2819-28. 2013.<\/p>\n","protected":false},"excerpt":{"rendered":"Clinical trials on humans should determine if the drug could be treat cancer","protected":false},"author":13,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"_exactmetrics_skip_tracking":false,"_exactmetrics_sitenote_active":false,"_exactmetrics_sitenote_note":"","_exactmetrics_sitenote_category":0,"footnotes":""},"categories":[156],"tags":[259,247,232,260],"coauthors":[101],"class_list":["post-225416","post","type-post","status-publish","format-standard","hentry","category-cover","tag-chemistry","tag-medicine","tag-pharmacology","tag-public-health"],"acf":[],"_links":{"self":[{"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/posts\/225416","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/users\/13"}],"replies":[{"embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/comments?post=225416"}],"version-history":[{"count":0,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/posts\/225416\/revisions"}],"wp:attachment":[{"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/media?parent=225416"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/categories?post=225416"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/tags?post=225416"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/coauthors?post=225416"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}