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Revision as of 10:17, 21 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 461581603 of page Benoxaprofen for the Chem/Drugbox validation project (updated: 'DrugBank', 'CAS_number').  Latest revision as of 12:39, 31 October 2024 edit Marbletan (talk | contribs)Extended confirmed users5,461 editsNo edit summary 
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{{Short description|Withdrawn NSAID analgesic medication}}
{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}}
{{Use dmy dates|date=February 2022}}{{Use British English|date=February 2022}}
{{Drugbox
{{Infobox drug
| verifiedrevid = 461580650
|Verifiedfields=changed
| IUPAC_name = 2-propanoic acid
|verifiedrevid =461745146
| image = benoxaprofen structure.png
|drug_name=

|INN =
|type =
|IUPAC_name=2-propanoic acid
|image =Benoxaprofen structure.png
|alt =Two-dimensional monochrome diagram showing the structure of the molecule of benoxaprofen, using the hexagonal style to depict a chemical compound.
|caption =Benoxaprofen molecule
<!--Clinical data--> <!--Clinical data-->
| tradename = |tradename=Opren, Oraflex
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |legal_AU= <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| pregnancy_US = <!-- A / B / C / D / X --> |legal_CA= <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->
|legal_UK= <!-- GSL / P / POM / CD / Class A, B, C -->
| pregnancy_category =
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 --> |legal_US= <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
|legal_status=Withdrawn
| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->
|routes_of_administration=
| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| legal_status =
| routes_of_administration =

<!--Pharmacokinetic data--> <!--Pharmacokinetic data-->
| bioavailability = |bioavailability=
| protein_bound = |protein_bound=
| metabolism = |metabolism=
| elimination_half-life = |elimination_half-life=
| excretion = |excretion=

<!--Identifiers--> <!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|??}} |CAS_number_Ref={{Cascite|changed|??}}
| CAS_number = <!-- blanked - oldvalue: 67434-14-4 --> |CAS_number =51234-28-7
| ATC_prefix = M01 |ATC_prefix=M01
| ATC_suffix = AE06 |ATC_suffix=AE06
| PubChem = 39941 |PubChem=39941
| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |DrugBank_Ref={{Drugbankcite|correct|drugbank}}
| DrugBank = DB04812 |DrugBank =DB04812
| UNII_Ref = {{fdacite|correct|FDA}} |ChEBI_Ref={{Ebicite|changed|EBI}}
|ChEBI =76114
| UNII = 17SZX404IM
| ChEMBL_Ref = {{ebicite|correct|EBI}} |UNII_Ref={{Fdacite|correct|FDA}}
|UNII =17SZX404IM
| ChEMBL = 340978
|ChEMBL_Ref={{Ebicite|correct|EBI}}
| PubChem = 39941
|ChEMBL =340978
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
|ChemSpiderID_Ref={{Chemspidercite|correct|chemspider}}
| ChemSpiderID = 36518
|ChemSpiderID =36518
| smiles = O=C(O)C(c1cc2nc(oc2cc1)c3ccc(Cl)cc3)C
|smiles= O=C(O)C(c1cc2nc(oc2cc1)c3ccc(Cl)cc3)C
| InChI = 1/C16H12ClNO3/c1-9(16(19)20)11-4-7-14-13(8-11)18-15(21-14)10-2-5-12(17)6-3-10/h2-9H,1H3,(H,19,20)
|StdInChI_Ref={{Stdinchicite|correct|chemspider}}
| InChIKey = MITFXPHMIHQXPI-UHFFFAOYAL
|StdInChI=1S/C16H12ClNO3/c1-9(16(19)20)11-4-7-14-13(8-11)18-15(21-14)10-2-5-12(17)6-3-10/h2-9H,1H3,(H,19,20)
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
|StdInChIKey_Ref={{Stdinchicite|correct|chemspider}}
| StdInChI = 1S/C16H12ClNO3/c1-9(16(19)20)11-4-7-14-13(8-11)18-15(21-14)10-2-5-12(17)6-3-10/h2-9H,1H3,(H,19,20)
|StdInChIKey =MITFXPHMIHQXPI-UHFFFAOYSA-N
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = MITFXPHMIHQXPI-UHFFFAOYSA-N

<!--Chemical data--> <!--Chemical data-->
| C=16 | H=12 | Cl=1 | N=1 | O=3 |C=16|H=12|Cl=1|N=1|O=3
| molecular_weight = 301.72438 g/mol
}} }}
'''Benoxaprofen''', also known as '''benoxaphen''', is a chemical compound with the formula C<sub>16</sub>H<sub>12</sub>ClNO<sub>3</sub>. It is a ] (NSAID) of the ] class, and was marketed under the brand name Opren in the United Kingdom and Europe by ] (commonly referred to as Lilly), and as Oraflex in the United States of America (USA). Lilly suspended sales of Oraflex in 1982 after reports from the ] and the United States ] (US FDA) of adverse effects and deaths linked to the drug.

==History==
Benoxaprofen was discovered by a team of research chemists at the British ] of ] . This laboratory was assigned to explore new ] in 1966. Lilly applied for ]s on its then named new drug 'benoxaprofen' seven years later. It also filed for permission from the U.S. Food and Drug Administration to start testing benoxaprofen on ]. It had to undergo the three-step ] procedure required by the United States Federal Government.<ref name="At Lilly">{{Cite web|last=Lueck|first=Thomas J.|name-list-style=vanc|date=15 August 1982|title=At Lilly, the side-effects of Oraflex|url=https://query.NYTimes.com/gst/fullpage.html?sec=health&res=9804E7D91E39F936A2575BC0A964948260|website=]}}</ref>

Lilly began Phase I of the benoxaprofen clinical trials by testing a selection of healthy human volunteers. These tests had to prove that their new drug posed no clear and immediate safety hazards. In Phase II, a larger number of human subjects, including some with minor illnesses, was tested; the drug's effectiveness and safety was the major target of these tests. Phase III was the largest test, and began in 1976. More than 2,000 ] patients were administered benoxaprofen by more than 100 physicians. The physicians then reported the results to the Lilly Company.<ref name="At Lilly"/>

When Lilly formally requested to begin marketing benoxaprofen in January 1980 with the US FDA, the document consisted of more than 100,000 pages of test results and patients records. However, benoxaprofen was first marketed abroad: in 1980, it was released for marketing in the United Kingdom. It subsequently came on the market in May 1982 in the USA.<ref name="RG_1982">{{cite journal | vauthors = Grahame R | title = The Rise And Fall of Benoxaprofen | journal = Rheumatol Rehabil | pages = 191–193 | date = November 1982| volume = 21 | issue = 4 | pmid = | doi = 10.1093/rheumatology/21.4.191| doi-access = free }}</ref>

When benoxaprofen was on the market as Oraflex in the USA, the first sign of trouble came for the Lilly Company. The '']'' reported in May 1982 that physicians in the United Kingdom believed that the drug was responsible for at least twelve deaths, mainly caused by ] and ]. A petition was filed to have Oraflex removed from the market.<ref name="At Lilly"/>

On 4 August 1982, the British government temporarily suspended sales of the drug in UK 'on grounds of safety'. The ] declared, in a ] to the FDA, that it had received reports of more than 3,500 adverse ]s among patients who had used Oraflex. There were also 61 deaths, most of which were of elderly people. Almost simultaneously, the FDA said it had reports of 11 deaths in the USA among Oraflex users, most of which were caused by kidney and liver damage.<ref name="At Lilly"/> The Eli Lilly Company suspended sales of benoxaprofen that afternoon.<ref name="At Lilly"/>

==Structure and reactivity==
The ] of benoxaprofen is C<sub>16</sub>H<sub>12</sub>ClNO<sub>3</sub> and the systematic (]) name is 2-propionic acid. The molecule has a ] of 301.050568&nbsp;]/].<ref>{{Cite web|url=http://www.ChemSpider.com/Chemical-Structure.36518.html|title=Benoxaprofen|website=www.ChemSpider.com|publisher=]}}</ref>

Benoxaprofen is essentially a ]. This is due to the co-planarity of the ] and ], but the molecule also has a non-planar side chain consisting of the ] moiety which acts as a carrier group. These findings were obtained from ] measurements made at the Lilly Research Centre.<ref name="Lewis_1990">{{Cite journal|vauthors=Lewis DF, Ioannides C, Parke DV|date=December 1990|title=A retrospective study of the molecular toxicology of benoxaprofen|journal=]|volume=65|issue=1–2|pages=33–47|pmid=2274968|doi=10.1016/0300-483x(90)90077-t|bibcode=1990Toxgy..65...33L }}</ref>

Benoxaprofen is highly ]. The free radical decarboxylated derivative of the drug is the ] which, in the presence of oxygen, yields ] and superoxide anion. ] of benoxaprofen in an ] causes photochemical ] via a radical mechanism and in single-strand breaks of ]. This also happens to ] and ], other NSAIDs, which are even more active in this respect than benoxaprofen.<ref name="Lewis_1990"/>

==Available forms==
Benoxaprofen is a ], (''R''/''S'')-2-(''p''-chlorophenyl-α-methyl-5-benzoxazoleacetic acid. The two ]s are (''R'')-(&minus;) and (''S'')-(+).<ref name="Bopp_1979">{{Cite journal|vauthors=Bopp RJ, Nash JF, Ridolfo AS, Shepard ER|date=1979|title=Stereoselective inversion of (R)-(-)-benoxaprofen to the (S)-(+)-enantiomer in humans|journal=Drug Metabolism and Disposition: The Biological Fate of Chemicals|volume=7|issue=6|pages=356–359|pmid=43219}}</ref>

The inversion of the (''R'')-(&minus;)-enantiomer and ] conjugation the results of ] of benoxaprofen. However, benoxaprofen will not readily undergo oxidative metabolism.<ref name="Lewis_1990"/>

It is however possible that, when ] is the catalyst, oxygenation of the 4-chlorophyll ring occurs. With the (''S'')-(+)-enantiomer, it is more likely that oxygenation of the aromatic ring of the 2-phenylpropionic acid moiety occurs, also with the catalyst as cytochrome P4501.<ref name="Lewis_1990"/>

==Toxicokinetics==
Benoxaprofen is absorbed well after oral intake of doses ranging from 1 up to 10&nbsp;]/]. Only the unchanged drug is detected in the ], mostly bound to plasma proteins. The plasma levels of benoxaprofen in eleven subjects have been accurately predicted, based on the two-compartment open model. The mean ] of absorption was 0.4&nbsp;hours. This means that within 25&nbsp;minutes, half of the dose is absorbed in the system. The mean half-life of distribution was 4.8&nbsp;hours. This means that within 5&nbsp;hours, half of the dose is distributed throughout the entire system. The mean half-life of elimination was 37.8&nbsp;hours. This means that within 40&nbsp;hours, half of the dose is excreted out of the system.<ref name="pmid303114">{{Cite journal|vauthors=Chatfield DH, Tarrant ME, Smith GL, Speirs CF|date=October 1977|title=Pharmacokinetic studies with benoxaprofen in man: prediction of steady-state levels from single-dose data|journal=]|volume=4|issue=5|pages=579–583|pmid=303114|pmc=1429156|doi=10.1111/j.1365-2125.1977.tb00789.x}}</ref>

In female ]s, after oral dose of 20&nbsp;mg/kg, the tissue concentration of benoxaprofen was the highest in liver, kidney, lungs, adrenals, and ovaries. The distribution in pregnant females is the same, while it can also be found, in lower concentrations, in the foetus. There is a big difference between species in the route of excretion. In man, ], and ], it is mostly excreted via the ], while in rat and dog it was excreted via ]-]. In man and dog, the compound was excreted as the ester glucuronide, and in the other species as the unchanged compound. This means no major metabolic transformation of benoxaprofen takes place.<ref name="Chatfield_1978">{{Cite journal|vauthors=Chatfield DH, Green JN|date=March 1978|title=Disposition and metabolism of benoxaprofen in laboratory animals and man|journal=Xenobiotica; the Fate of Foreign Compounds in Biological Systems|volume=8|issue=3|pages=133–144|pmid=418580|doi=10.3109/00498257809060392}}</ref>

==Toxicodynamics==
Unlike other ]s, benoxaprofen acts directly on ]. It inhibits their ] response by inhibiting the ] enzyme.<ref>{{Cite journal|title=Benoxaprofen|journal=]|edition=Clinical Research|volume=285|issue=6340|pages=459–460|date=14 August 1982|doi=10.1136/bmj.285.6340.459|pmid=6809122|pmc=1499290}}</ref>

==Efficacy and side effects==
===Efficacy===
Benoxaprofen is an ], ], and ] drug.<ref name="pmid6762531">{{Cite journal|vauthors=Dahl SL, Ward JR|date=1982|title=Pharmacology, clinical efficacy, and adverse effects of the non-steroidal anti-inflammatory agent benoxaprofen|journal=]|volume=2|issue=6|pages=354–366|pmid=6762531|doi=10.1002/j.1875-9114.1982.tb03212.x|s2cid=647085 }}</ref> Benoxaprofen was given to patients with ] and ] because of its anti-inflammatory effect. Patients with the ], ], ], a painful shoulder, the mixed connective-tissue disease, ], ], and the ] also received benoxaprofen. A daily dose of 300–600&nbsp;] is effective for many patients.<ref name="Halsey_1982">{{Cite journal|vauthors=Halsey JP, Cardoe N|date=May 1982|title=Benoxaprofen: side-effect profile in 300 patients|journal=]|edition=Clinical Research|volume=284|issue=6326|pages=1365–1368|pmid=6803978|pmc=1498268|doi=10.1136/bmj.284.6326.1365}}</ref>

===Adverse effects===
There are different types of ]s. Most of them were ] or ]. Side effects appear rarely in the ], and miscellaneous side effects were not often observed. A study shows that most side effects appear in patients with rheumatoid arthritis<ref name="Halsey_1982"/>

====Cutaneous side effects====
] side effects of benoxaprofen are ], ], ], ], increased nail growth, pruritus (]), and ].<ref name="Halsey_1982"/> Photosensitivity leads to burning, itching, or redness when patients are exposed to sunlight.<ref name="pmid6803979">{{Cite journal|vauthors=Hindson C, Daymond T, Diffey B, Lawlor F|date=May 1982|title=Side effects of benoxaprofen|journal=]|edition=Clinical Research|volume=284|issue=6326|pages=1368–1369|pmid=6803979|pmc=1498237|doi=10.1136/bmj.284.6326.1368}}</ref> A study shows that benoxaprofen, or other ]-inhibiting agents, might be helpful in the treatment of ] because the migration inhibition of the inflammatory cells (]) into the skin.<ref name="pmid6812822">{{Cite journal|vauthors=Allen BR, Littlewood SM|date=October 1982|title=Benoxaprofen: effect on cutaneous lesions in psoriasis|journal=]|edition=Clinical Research|volume=285|issue=6350|pages=1241|pmid=6812822|pmc=1499777|doi=10.1136/bmj.285.6350.1241}}</ref>

====Gastrointestinal side effects====
] side effects of benoxaprofen are bleeding, diarrhoea, abdominal pain, ], ]s, and taste change.<ref name="Halsey_1982"/><ref name="pmid3540919">{{Cite journal|vauthors=Somerville KW, Hawkey CJ|date=January 1986|title=Non-steroidal anti-inflammatory agents and the gastrointestinal tract|journal=Postgraduate Medical Journal|volume=62|issue=723|pages=23–28|pmid=3540919|pmc=2418576|doi=10.1136/pgmj.62.723.23}}</ref> According to a study, the most appearing gastric side effects are ], ], and ].<ref name="Halsey_1982"/>

====Side effects in the central nervous system====
For a small number of people, taking benoxaprofen might result in ], ], and feeling ill.<ref name="Halsey_1982"/>

====Miscellaneous side effects====
Faintness, dizziness, headache, ], ], blurred vision, ], and ] rarely appear in patients who take benoxaprofen.<ref name="Halsey_1982"/>

Benoxaprofen can also cause ], which led to death of some elderly patients.<ref name="pmid2200358">{{Cite journal|vauthors=Doube A|date=July 1990|title=Hepatitis and non-steroidal anti-inflammatory drugs|journal=]|volume=49|issue=7|pages=489–490|pmid=2200358|pmc=1004125|doi=10.1136/ard.49.7.489}}</ref><ref name="pmid6462187">{{Cite journal|vauthors=Taggart HM, Alderdice JM|date=May 1982|title=Fatal cholestatic jaundice in elderly patients taking benoxaprofen|journal=]|edition=Clinical Research|volume=284|issue=6326|pages=1372|pmid=6462187|pmc=1498289|doi=10.1136/bmj.284.6326.1372}}</ref> That was the main reason why benoxaprofen was withdrawn from the market.

==Toxicity==
After the suspension of sales in 1982, the toxic effects which benoxaprofen could have on humans were looked into more deeply. The fairly planar compound of benoxaprofen seems to be ] and ] in the human body.<ref name="Lewis_1990"/>

Benoxaprofen has a rather long ] in man (t<sub>1/2</sub>= 20-30&nbsp;hours), undergoes ] ] and ], and is also known to have a slow ] clearance (CL p=4.5&nbsp;] per minute). The half-life may be further increased in elderly patients (>80&nbsp;years of age), and in patients which already have an renal impairment; increasing to figures as high as 148&nbsp;hours.<ref name="Lewis_1990"/>

The fetal hepatotoxicity of benoxaprofen can be attributed to the accumulation of the drug after a repeated dosage, and also associated with the slow ]. The hepatic accumulation of the drug is presumably the cause for an increase in the activity of the hepatic cytochrome P450I, which will oxygenate benaxoprofen and produce reactive intermediates. Benoxaprofen is very likely a substrate, and weak inducer of cytochrome P450I and its enzyme family. Normally, it is not metabolised by oxidative reactions, but with the S(+) enantiomer of benoxaprofen and cytochrome P450I as a catalyst, the oxygenation of the 4-chlorophenyl ring and of the aromatic ring of 2-phenyl propionic acid seems to be possible. Therefore, the induction of a minor metabolic pathway leads to the formation of toxic metabolites in considerable amounts. The toxic metabolites may bind to vital intracellular macromolecules, and may generate reactive oxygens by ] if ] is formed.<ref name="Lewis_1990"/> This could also lead to a depletion of protective ], which is responsible for the detoxification of reactive oxygens.<ref name="pmid2069584">{{Cite journal|vauthors=Ayrton AD, Ioannides C, Parke DV|date=June 1991|title=Induction of the cytochrome P450 I and IV families and peroxisomal proliferation in the liver of rats treated with benoxaprofen; possible implications in its hepatotoxicity|journal=]|volume=42|issue=1|pages=109–115|pmid=2069584|doi=10.1016/0006-2952(91)90688-2}}</ref>

The observed skin phototoxicity of patients treated with benoxaprofen can be explained with a look at the structure of the compound. There are significant structural similarities between the benzoxazole ring of benoxaprofen and the ] ring of ], a compound known to be phototoxic. The free decarboxylated derivate of the drug can produce singlet oxygen and ] ] in the presence of oxygen. Furthermore, possible explanations for the photochemical decarboxylation and oxygen radical formation may be the accumulation of repeated dosage, the induction of cytochrome P450I, and the emergence of reactive intermediates with covalent binding. The photochemical character of the compound can cause inflammation and severe tissue damage.<ref name="Lewis_1990"/>
:] (left) and the structure of benoxaprofen (right); the benzofuran ring and the benoxazole ring are indicated in red.<ref name="Lewis_1990"/>]]{{clear-left}}

In animals, peroxisomal proliferation is also observed, but does not seem to be significant in man.<ref name="Lewis_1990"/>

==Effects on animals==
The effects of benoxaprofen on animals were tested in a series of experiments.<ref name="Chatfield_1978"/><ref name="Knights_1986">{{Cite journal|vauthors=Knights KM, Cassidy MR, Drew R|date=September 1986|title=Benoxaprofen induced toxicity in isolated rat hepatocytes|journal=]|volume=40|issue=3|pages=327–339|pmid=3750332|doi=10.1016/0300-483x(86)90064-8|bibcode=1986Toxgy..40..327K }}</ref> Benoxaprofen had a considerable ], ], and also ] activity in those tests.<ref name="Chatfield_1978"/> In all six animals tested, which included rats, dogs, ], rabbits, guinea pigs, and mice, the drug was well absorbed orally. In three of the six species, benoxaprofen was then effectively taken up from the ] (after oral doses of 1–10&nbsp;]/]).<ref name="Chatfield_1978"/> The ] ] was found to be different, being less than 13&nbsp;hours in the dog, rabbit, and monkey, it was notable longer in mice. Furthermore, there were species differences found in the rate and route of excretion of the compound. Whereas benoxaprofen was excreted into the urine by the rabbit and guinea pig, ] ] was the way of clearance found in rats and dogs. In all species, only unchanged benoxaprofen was found in the plasma mostly extensively bound to proteins.<ref name="Chatfield_1978"/>

The excretion of the unchanged compound into the ] did occur more slowly in rats. This is interpreted by the authors as evidence that no ] takes place.<ref name="Chatfield_1978"/> Another research in rats showed that the plasma membrane of ]s begun to form ] after administration of benoxaprofen. This is suggested to be due to disturbances in the ] concentration, which is possibly a result of an altered cellular redox state which can have an effect on ] function, and therefore cause disturbances in the calcium concentration.<ref name="Knights_1986"/> In none of the species, significant levels of metabolism of benoxaprofen were found to have happened. Only in dogs, ] could be found in the bile, which is a sure sign of ] in that species. Also, no differences in distribution of the compound in normal and pregnant rats were found. It was shown in rats that benoxaprofen was distributed into the ] but with a notable lower concentration than in the maternal tissue.<ref name="Chatfield_1978"/>

==Synthesis==
:]
A ] by ] of 2-(4-aminophenyl)propanenitrile (1) followed by acid hydrolysis leads to the phenol (2), which is nitrated and reduced by ] to give the aminophenol (3). Hydrolysis of the nitrile and esterification produces ester (4), which is converted to benoxaprofen by ] with ''p''-chlorobenzoyl chloride, followed by ] and then ] of the ethyl ester.<ref>{{Cite patent|country=DE|number=2324443|pubdate=1973-11-29|title=Benzoxazol-Derivate und Verfahren zu ihrer Herstellung |assign=]|inventor1-last=Evans|inventor1-first=Delme|inventor2-last=Dunwell|inventor2-first=David William|inventor3-last=Hicks|inventor3-first=Terence Alan}}</ref><ref>D. Evans et al., {{US patent|3912748}} (1975 to ]).</ref><ref>{{Cite journal|vauthors=Dunwell DW, Evans D, Hicks TA|date=January 1975|title=2-aryl-5-benzoxazolealkanoic acid derivatives with notable antiinflammatory activity|journal=]|volume=18|issue=1|pages=53–58|pmid=1109576|doi=10.1021/jm00235a012}}</ref>

==References==
{{Reflist}}

{{Anti-inflammatory products}}
{{Prostanoid signaling modulators}}
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