Benoxaprofen

Last updated

Benoxaprofen
Benoxaprofen structure.png
Benoxaprofen molecule
Clinical data
Trade names Opren, Oraflex
ATC code
Legal status
Legal status
  • Withdrawn
Identifiers
  • 2-[2-(4-chlorophenyl)-1,3-benzoxazol-5-yl]propanoic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.051.864 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C16H12ClNO3
Molar mass 301.73 g·mol−1
3D model (JSmol)
  • O=C(O)C(c1cc2nc(oc2cc1)c3ccc(Cl)cc3)C
  • InChI=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) Yes check.svgY
  • Key:MITFXPHMIHQXPI-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Benoxaprofen, also known as benoxaphen, is a chemical compound with the formula C16H12ClNO3. It is a non-steroidal anti-inflammatory drug (NSAID) of the arylpropionic acid class, and was marketed under the brand name Opren in the United Kingdom and Europe by Eli Lilly and Company (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 British government and the United States Food and Drug Administration (US FDA) of adverse effects and deaths linked to the drug.

Contents

History

Benoxaprofen was discovered by a team of research chemists at the British Lilly Research Centre of Eli Lilly and Company . This laboratory was assigned to explore new anti-arthritic compounds in 1966. Lilly applied for patents 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 humans. It had to undergo the three-step clinical testing procedure required by the United States Federal Government. [1]

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 arthritis patients were administered benoxaprofen by more than 100 physicians. The physicians then reported the results to the Lilly Company. [1]

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. [2]

When benoxaprofen was on the market as Oraflex in the USA, the first sign of trouble came for the Lilly Company. The British Medical Journal reported in May 1982 that physicians in the United Kingdom believed that the drug was responsible for at least twelve deaths, mainly caused by kidney and liver failure. A petition was filed to have Oraflex removed from the market. [1]

On 4 August 1982, the British government temporarily suspended sales of the drug in UK 'on grounds of safety'. The British Committee on the Safety of Medicines declared, in a telegram to the FDA, that it had received reports of more than 3,500 adverse side effects 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. [1] The Eli Lilly Company suspended sales of benoxaprofen that afternoon. [1]

Structure and reactivity

The molecular formula of benoxaprofen is C16H12ClNO3 and the systematic (IUPAC) name is 2-[2-(4-chlorophenyl)-1,3-benzoxazol-5-yl]propionic acid. The molecule has a molecular mass of 301.050568  g/mol. [3]

Benoxaprofen is essentially a planar molecule. This is due to the co-planarity of the benzoxazole and phenyl rings, but the molecule also has a non-planar side chain consisting of the propanoic acid moiety which acts as a carrier group. These findings were obtained from X-ray crystallographic measurements made at the Lilly Research Centre. [4]

Benoxaprofen is highly phototoxic. The free radical decarboxylated derivative of the drug is the toxic agent which, in the presence of oxygen, yields singlet oxygen and superoxide anion. Irradiation of benoxaprofen in an aqueous solution causes photochemical decarboxylation via a radical mechanism and in single-strand breaks of DNA. This also happens to ketoprofen and naproxen, other NSAIDs, which are even more active in this respect than benoxaprofen. [4]

Available forms

Benoxaprofen is a racemic mixture, (R/S)-2-(p-chlorophenyl-α-methyl-5-benzoxazoleacetic acid. The two enantiomers are (R)-(−) and (S)-(+). [5]

The inversion of the (R)-(−)-enantiomer and glucuronide conjugation the results of metabolism of benoxaprofen. However, benoxaprofen will not readily undergo oxidative metabolism. [4]

It is however possible that, when cytochrome P4501 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. [4]

Toxicokinetics

Benoxaprofen is absorbed well after oral intake of doses ranging from 1 up to 10  mg/kg. Only the unchanged drug is detected in the plasma, 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 half-life of absorption was 0.4 hours. This means that within 25 minutes, half of the dose is absorbed in the system. The mean half-life of distribution was 4.8 hours. This means that within 5 hours, half of the dose is distributed throughout the entire system. The mean half-life of elimination was 37.8 hours. This means that within 40 hours, half of the dose is excreted out of the system. [6]

In female rats, after oral dose of 20 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, rhesus monkey, and rabbit, it is mostly excreted via the urine, while in rat and dog it was excreted via biliary-faecal excretion. 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. [7]

Toxicodynamics

Unlike other non-steroidal anti-inflammatory drugs, benoxaprofen acts directly on mononuclear cells. It inhibits their chemotactic response by inhibiting the lipoxygenase enzyme. [8]

Efficacy and side effects

Efficacy

Benoxaprofen is an analgesic, antipyretic, and anti-inflammatory drug. [9] Benoxaprofen was given to patients with rheumatoid arthritis and osteoarthritis because of its anti-inflammatory effect. Patients with the Paget's disease, psoriatic arthritis, ankylosing spondylitis, a painful shoulder, the mixed connective-tissue disease, polymyalgia rheumatica, back pain, and the Behçet's disease also received benoxaprofen. A daily dose of 300–600  mg is effective for many patients. [10]

Adverse effects

There are different types of side effects. Most of them were cutaneous or gastrointestinal. Side effects appear rarely in the central nervous system, and miscellaneous side effects were not often observed. A study shows that most side effects appear in patients with rheumatoid arthritis [10]

Cutaneous side effects

Cutaneous side effects of benoxaprofen are photosensitivity, onycholysis, rash, milia, increased nail growth, pruritus (itch), and hypertrichosis. [10] Photosensitivity leads to burning, itching, or redness when patients are exposed to sunlight. [11] A study shows that benoxaprofen, or other lipoxygenase-inhibiting agents, might be helpful in the treatment of psoriasis because the migration inhibition of the inflammatory cells (leukocytes) into the skin. [12]

Gastrointestinal side effects

Gastrointestinal side effects of benoxaprofen are bleeding, diarrhoea, abdominal pain, anorexia, mouth ulcers, and taste change. [10] [13] According to a study, the most appearing gastric side effects are vomiting, heartburn, and epigastric pain. [10]

Side effects in the central nervous system

For a small number of people, taking benoxaprofen might result in depression, lethargy, and feeling ill. [10]

Miscellaneous side effects

Faintness, dizziness, headache, palpitations, epistaxis, blurred vision, urinary urgency, and gynaecomastia rarely appear in patients who take benoxaprofen. [10]

Benoxaprofen can also cause hepatotoxicity, which led to death of some elderly patients. [14] [15] 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 hepa- and phototoxic in the human body. [4]

Benoxaprofen has a rather long half-life in man (t1/2= 20-30 hours), undergoes biliary excretion and enterohepatic circulation, and is also known to have a slow plasma clearance (CL p=4.5  millilitre per minute). The half-life may be further increased in elderly patients (>80 years of age), and in patients which already have an renal impairment; increasing to figures as high as 148 hours. [4]

The fetal hepatotoxicity of benoxaprofen can be attributed to the accumulation of the drug after a repeated dosage, and also associated with the slow plasma clearance. 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 redox cycling if quinone is formed. [4] This could also lead to a depletion of protective glutathione, which is responsible for the detoxification of reactive oxygens. [16]

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 benzofuran ring of psoralen, a compound known to be phototoxic. The free decarboxylated derivate of the drug can produce singlet oxygen and superoxide anions 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. [4]

The structure of psoralen (left) and the structure of benoxaprofen (right); the benzofuran ring and the benoxazole ring are indicated in red. Structures benoxaprofen and psoralen.png
The structure of psoralen (left) and the structure of benoxaprofen (right); the benzofuran ring and the benoxazole ring are indicated in red.

In animals, peroxisomal proliferation is also observed, but does not seem to be significant in man. [4]

Effects on animals

The effects of benoxaprofen on animals were tested in a series of experiments. [7] [17] Benoxaprofen had a considerable anti-inflammatory, analgesic, and also anti-pyretic activity in those tests. [7] In all six animals tested, which included rats, dogs, rhesus monkeys, 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 gastrointestinal tract (after oral doses of 1–10  mg/kg). [7] The plasma half-life was found to be different, being less than 13 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, biliary excretion 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. [7]

The excretion of the unchanged compound into the bile did occur more slowly in rats. This is interpreted by the authors as evidence that no enterohepatic circulation takes place. [7] Another research in rats showed that the plasma membrane of hepatocytes begun to form blebs after administration of benoxaprofen. This is suggested to be due to disturbances in the calcium concentration, which is possibly a result of an altered cellular redox state which can have an effect on mitochondrial function, and therefore cause disturbances in the calcium concentration. [17] In none of the species, significant levels of metabolism of benoxaprofen were found to have happened. Only in dogs, glucuronide could be found in the bile, which is a sure sign of metabolism 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 foetus but with a notable lower concentration than in the maternal tissue. [7]

Synthesis

Benoxaprofen synthesis.svg

A Sandmeyer reaction by diazotisation of 2-(4-aminophenyl)propanenitrile (1) followed by acid hydrolysis leads to the phenol (2), which is nitrated and reduced by catalytic hydrogenation to give the aminophenol (3). Hydrolysis of the nitrile and esterification produces ester (4), which is converted to benoxaprofen by acylation with p-chlorobenzoyl chloride, followed by cyclisation and then saponification of the ethyl ester. [18] [19] [20]

Related Research Articles

<span class="mw-page-title-main">Nonsteroidal anti-inflammatory drug</span> Class of therapeutic drug for relieving pain and inflammation

Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of use, but largely include an increased risk of gastrointestinal ulcers and bleeds, heart attack, and kidney disease.

<span class="mw-page-title-main">Ibuprofen</span> Medication treating pain, fever, and inflammation

Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used to relieve pain, fever, and inflammation. This includes painful menstrual periods, migraines, and rheumatoid arthritis. It may also be used to close a patent ductus arteriosus in a premature baby. It can be taken orally or intravenously. It typically begins working within an hour.

<span class="mw-page-title-main">Hepatotoxicity</span> Liver damage caused by a drug or chemical

Hepatotoxicity implies chemical-driven liver damage. Drug-induced liver injury (DILI) is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn from the market after approval.

<span class="mw-page-title-main">Duloxetine</span> Antidepressant medication used also for treatment of anxiety and chronic pain

Duloxetine, sold under the brand name Cymbalta among others, is a medication used to treat major depressive disorder, generalized anxiety disorder, obsessive-compulsive disorder, fibromyalgia, neuropathic pain and central sensitization. It is taken by mouth.

<span class="mw-page-title-main">Amiodarone</span> Antiarrhythmic medication used for various types of irregular heartbeats

Amiodarone is an antiarrhythmic medication used to treat and prevent a number of types of cardiac dysrhythmias. This includes ventricular tachycardia, ventricular fibrillation, and wide complex tachycardia, atrial fibrillation, and paroxysmal supraventricular tachycardia. Evidence in cardiac arrest, however, is poor. It can be given by mouth, intravenously, or intraosseously. When used by mouth, it can take a few weeks for effects to begin.

<span class="mw-page-title-main">Atenolol</span> Beta blocker medication

Atenolol is a beta blocker medication primarily used to treat high blood pressure and heart-associated chest pain. Although used to treat high blood pressure, it does not seem to improve mortality in those with the condition. Other uses include the prevention of migraines and treatment of certain irregular heart beats. It is taken orally or by intravenous injection. It can also be used with other blood pressure medications.

<span class="mw-page-title-main">Drug interaction</span> Change in the action or side effects of a drug caused

In pharmaceutical sciences, drug interactions occur when a drug's mechanism of action is affected by the concomitant administration of substances such as foods, beverages, or other drugs. A popular example of drug–food interaction is the effect of grapefruit on the metabolism of drugs.

<span class="mw-page-title-main">Zopiclone</span> Hypnotic medication

Zopiclone, sold under the brand name Imovane among others, is a nonbenzodiazepine, specifically a cyclopyrrolone, used to treat difficulty sleeping. Zopiclone is molecularly distinct from benzodiazepine drugs and is classed as a cyclopyrrolone. However, zopiclone increases the normal transmission of the neurotransmitter gamma-aminobutyric acid (GABA) in the central nervous system, via modulating GABAA receptors similarly to the way benzodiazepine drugs do inducing sedation but not with the anti-anxiety properties of the benzodiazepines.

<span class="mw-page-title-main">Acecainide</span> Antiarrythmic drug

Acecainide is an antiarrhythmic drug. Chemically, it is the N-acetylated metabolite of procainamide. It is a Class III antiarrhythmic agent, whereas procainamide is a Class Ia antiarrhythmic drug. It is only partially as active as procainamide; when checking levels, both must be included in the final calculation.

<span class="mw-page-title-main">Cholesterol 7 alpha-hydroxylase</span> Protein-coding gene in the species Homo sapiens

Cholesterol 7 alpha-hydroxylase also known as cholesterol 7-alpha-monooxygenase or cytochrome P450 7A1 (CYP7A1) is an enzyme that in humans is encoded by the CYP7A1 gene which has an important role in cholesterol metabolism. It is a cytochrome P450 enzyme, which belongs to the oxidoreductase class, and converts cholesterol to 7-alpha-hydroxycholesterol, the first and rate limiting step in bile acid synthesis.

<span class="mw-page-title-main">Erdosteine</span> Chemical to treat chronic bronchitis

Erdosteine is a molecule with mucolytic activity. Structurally it is a thioether derivative with two thioether groups. These two functional organosulfur groups contained in the molecule are released following first-pass metabolism with the conversion of erdosteine into its pharmacologically active metabolite Met-I.

<span class="mw-page-title-main">Bornaprine</span> Chemical compound

Bornaprine is a synthetic anticholinergic medication that is primarily used to treat Parkinson's disease. Additionally, bornaprine has been used to treat other disorders, including hyperhidrosis.

<span class="mw-page-title-main">Flunoxaprofen</span> Chemical compound

Flunoxaprofen, also known as Priaxim, is a chiral nonsteroidal anti-inflammatory drug (NSAID). It is closely related to naproxen, which is also an NSAID. Flunoxaprofen has been shown to significantly improve the symptoms of osteoarthritis and rheumatoid arthritis. The clinical use of flunoxaprofen has ceased due to concerns of potential hepatotoxicity.

Etomoxir, or rac-Ethyl 2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate, in form of the dextrorotatory (R)-(+)- enantiomer, is an irreversible inhibitor of carnitine palmitoyltransferase-1 on the inner face of the outer mitochondrial membrane. The actual inhibitor – (R)-(+)-etomoxir-Coenzym A ester – is formed in an intracellular process. The middle inhibitor concentration for the inhibition of the CPT-1 in the liver, heart, and muscle mitochondria of rats lies in between 5 and 20 nmol/l, depending on the animal's state of metabolism. (+)-Etomoxir is a colourness solid with a melting point of 38 °C (311 K). The sodium salt of (+)-Etomoxir is water-soluble. The (S)-(-)-enantiomer of Etomoxir does not block CPT-1.

<span class="mw-page-title-main">4-Ipomeanol</span> Chemical compound

4-Ipomeanol (4-IPO) is a pulmonary pre-toxin isolated from sweet potatoes infected with the fungus Fusarium solani. One of the 4-IPO metabolites is toxic to the lungs, liver and kidney in humans and animals. This metabolite can covalently bind to proteins, thereby interfering with normal cell processes.

<span class="mw-page-title-main">Proxicromil</span> Chemical compound

Proxicromil is a detergent-like, lipophilic oral medication developed in the late 1970s that was not admitted on the market because of its possible carcinogenic effects. It suppresses allergic reactions by binding to FcεRI receptor in mast cells, thereby inhibiting production of histamines. It is absorbed through the gastrointestinal tract, and has been proven hepatotoxic for dogs as a result of its accumulation in biliary canaliculi.

Selective norepinephrine reuptake inhibitors (sNRIs) are a class of drugs that have been marketed as antidepressants and are used for various mental disorders, mainly depression and attention-deficit hyperactivity disorder (ADHD). The norepinephrine transporter (NET) serves as the fundamental mechanism for the inactivation of noradrenergic signaling because of the NET termination in the reuptake of norepinephrine (NE). The selectivity and mechanism of action for the NRI drugs remain mostly unresolved and, to date, only a limited number of NRI-selective inhibitors are available. The first commercially available selective NRI was the drug reboxetine (Edronax), developed as a first-line therapy for major depressive disorder. Atomoxetine (Strattera) is another potent and selective NRI which is also effective and well tolerated for the treatment of ADHD in adults; it may also be a new treatment option for adults with ADHD, particularly for those patients at risk of substance abuse.

Chiral inversion is the process of conversion of one enantiomer of a chiral molecule to its mirror-image version with no other change in the molecule.

<span class="mw-page-title-main">Furegrelate</span> Chemical compound

Furegrelate, also known as 5-(3-pyridinylmethyl)benzofurancarboxylic acid, is a chemical compound with thromboxane enzyme inhibiting properties that was originally developed by Pharmacia Corporation as a drug to treat arrhythmias, ischaemic heart disorders, and thrombosis but was discontinued. It is commercially available in the form furegrelate sodium salt.

<span class="mw-page-title-main">Sonlicromanol</span> Chemical compound

Sonlicromanol (KH176) is a clinical-stage oral drug compound developed by Khondrion as a potential treatment for inherited mitochondrial diseases, such as Leigh's Disease, MELAS and LHON. Due to dysfunctional mitochondria, an increased level of cellular reactive oxygen species (ROS) is observed in these patients, causing a wide range of symptoms. The active metabolite of Sonlicromanol has several mechanisms of action, acting both as antioxidant and as reactive oxygen species (ROS)-redox modulator. Through selective suppression of microsomal prostaglandin E synthase-1 (mPGES-1), Sonlicromanol even has potency as anti-cancer drug for mPGES-1 overexpressing cancer like prostate cancer. Currently, Sonlicromanol is in phase II clinical trial in the KHENERGYZE, KHENEREXT and KHENERGYC studies as potent candidate in treatment for mitochondrial diseases.

References

  1. 1 2 3 4 5 Lueck TJ (15 August 1982). "At Lilly, the side-effects of Oraflex". The New York Times .
  2. ↑ Grahame R (November 1982). "The Rise And Fall of Benoxaprofen". Rheumatol Rehabil. 21 (4): 191–193. doi: 10.1093/rheumatology/21.4.191 .
  3. ↑ "Benoxaprofen". www.ChemSpider.com. ChemSpider.
  4. 1 2 3 4 5 6 7 8 9 10 Lewis DF, Ioannides C, Parke DV (December 1990). "A retrospective study of the molecular toxicology of benoxaprofen". Toxicology . 65 (1–2): 33–47. Bibcode:1990Toxgy..65...33L. doi:10.1016/0300-483x(90)90077-t. PMID   2274968.
  5. ↑ Bopp RJ, Nash JF, Ridolfo AS, Shepard ER (1979). "Stereoselective inversion of (R)-(-)-benoxaprofen to the (S)-(+)-enantiomer in humans". Drug Metabolism and Disposition: The Biological Fate of Chemicals. 7 (6): 356–359. PMID   43219.
  6. ↑ Chatfield DH, Tarrant ME, Smith GL, Speirs CF (October 1977). "Pharmacokinetic studies with benoxaprofen in man: prediction of steady-state levels from single-dose data". British Journal of Clinical Pharmacology . 4 (5): 579–583. doi:10.1111/j.1365-2125.1977.tb00789.x. PMC   1429156 . PMID   303114.
  7. 1 2 3 4 5 6 7 Chatfield DH, Green JN (March 1978). "Disposition and metabolism of benoxaprofen in laboratory animals and man". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 8 (3): 133–144. doi:10.3109/00498257809060392. PMID   418580.
  8. ↑ "Benoxaprofen". British Medical Journal . 285 (6340) (Clinical Research ed.): 459–460. 14 August 1982. doi:10.1136/bmj.285.6340.459. PMC   1499290 . PMID   6809122.
  9. ↑ Dahl SL, Ward JR (1982). "Pharmacology, clinical efficacy, and adverse effects of the non-steroidal anti-inflammatory agent benoxaprofen". Pharmacotherapy . 2 (6): 354–366. doi:10.1002/j.1875-9114.1982.tb03212.x. PMID   6762531. S2CID   647085.
  10. 1 2 3 4 5 6 7 Halsey JP, Cardoe N (May 1982). "Benoxaprofen: side-effect profile in 300 patients". British Medical Journal . 284 (6326) (Clinical Research ed.): 1365–1368. doi:10.1136/bmj.284.6326.1365. PMC   1498268 . PMID   6803978.
  11. ↑ Hindson C, Daymond T, Diffey B, Lawlor F (May 1982). "Side effects of benoxaprofen". British Medical Journal . 284 (6326) (Clinical Research ed.): 1368–1369. doi:10.1136/bmj.284.6326.1368. PMC   1498237 . PMID   6803979.
  12. ↑ Allen BR, Littlewood SM (October 1982). "Benoxaprofen: effect on cutaneous lesions in psoriasis". British Medical Journal . 285 (6350) (Clinical Research ed.): 1241. doi:10.1136/bmj.285.6350.1241. PMC   1499777 . PMID   6812822.
  13. ↑ Somerville KW, Hawkey CJ (January 1986). "Non-steroidal anti-inflammatory agents and the gastrointestinal tract". Postgraduate Medical Journal. 62 (723): 23–28. doi:10.1136/pgmj.62.723.23. PMC   2418576 . PMID   3540919.
  14. ↑ Doube A (July 1990). "Hepatitis and non-steroidal anti-inflammatory drugs". Annals of the Rheumatic Diseases . 49 (7): 489–490. doi:10.1136/ard.49.7.489. PMC   1004125 . PMID   2200358.
  15. ↑ Taggart HM, Alderdice JM (May 1982). "Fatal cholestatic jaundice in elderly patients taking benoxaprofen". British Medical Journal . 284 (6326) (Clinical Research ed.): 1372. doi:10.1136/bmj.284.6326.1372. PMC   1498289 . PMID   6462187.
  16. ↑ Ayrton AD, Ioannides C, Parke DV (June 1991). "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". Biochemical Pharmacology . 42 (1): 109–115. doi:10.1016/0006-2952(91)90688-2. PMID   2069584.
  17. 1 2 Knights KM, Cassidy MR, Drew R (September 1986). "Benoxaprofen induced toxicity in isolated rat hepatocytes". Toxicology . 40 (3): 327–339. Bibcode:1986Toxgy..40..327K. doi:10.1016/0300-483x(86)90064-8. PMID   3750332.
  18. ↑ DE 2324443,Evans, Delme; Dunwell, David William& Hicks, Terence Alan,"Benzoxazol-Derivate und Verfahren zu ihrer Herstellung [Benzoxazole Derivatives and processes for their production]",published 1973-11-29, assigned to Lilly Industries Ltd.
  19. ↑ D. Evans et al., U.S. patent 3,912,748 (1975 to Eli Lilly).
  20. ↑ Dunwell DW, Evans D, Hicks TA (January 1975). "2-aryl-5-benzoxazolealkanoic acid derivatives with notable antiinflammatory activity". Journal of Medicinal Chemistry . 18 (1): 53–58. doi:10.1021/jm00235a012. PMID   1109576.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.