Epithelial delamination is protective during pharmaceutical-induced enteropathy.

Intestinal epithelial cell (IEC) shedding is a fundamental response to intestinal damage, yet underlying mechanisms and functions have been difficult to define. Here we model chronic intestinal damage in zebrafish larvae using the nonsteroidal antiinflammatory drug (NSAID) Glafenine. Glafenine induced the unfolded protein response (UPR) and inflammatory pathways in IECs, leading to delamination. Glafenine-induced inflammation was augmented by microbial colonization and associated with changes in intestinal and environmental microbiotas. IEC shedding was a UPR-dependent protective response to Glafenine that restricts inflammation and promotes animal survival. Other NSAIDs did not induce IEC delamination; however, Glafenine also displays off-target inhibition of multidrug resistance (MDR) efflux pumps. We found a subset of MDR inhibitors also induced IEC delamination, implicating MDR efflux pumps as cellular targets underlying Glafenine-induced enteropathy. These results implicate IEC delamination as a protective UPR-mediated response to chemical injury, and uncover an essential role for MDR efflux pumps in intestinal homeostasis.

Bioactivation of glafenine by human liver microsomes and peroxidases: identification of electrophilic iminoquinone species and GSH conjugates.

Glafenine (Privadol; 2,3-dihydroxypropyl 2-[(7-chloro-4-quinolinyl) amino]benzoate) is a non-narcotic analgesic agent widely used for the treatment of pains of various origins. Severe liver toxicity and a high incidence of anaphylaxis were reported in patients treated with glafenine, eventually leading to its withdrawal from the market in most countries. It is proposed that bioactivation of glafenine and subsequent binding of reactive metabolite(s) to critical cellular proteins play a causative role. The study described herein aimed at characterizing pathways of glafenine bioactivation and the metabolic enzymes involved. Two GSH conjugates of glafenine were detected in human liver microsomal incubations using liquid chromatography tandem mass spectrometry. The structures of detected conjugates were determined as GSH adducts of 5-hydroxyglafenine (M3) and 5-hydroxy glafenic acid (M4), respectively. GSH conjugation took place with a strong preference at C6 of the benzene ring of glafenine, ortho to the carbonyl moiety. These findings are consistent with a bioactivation sequence involving initial cytochrome P450-catalyzed 5-hydroxylation of the benzene ring of glafenine, followed by two electron oxidations of M3 and M4 to form corresponding para-quinone imine intermediates that react with GSH to form GSH adducts M1 and M2, respectively. Formation of M1 and M2 was primarily catalyzed by heterologously expressed recombinant CYP3A4 and to a lesser extent, CYP2C19 and CYP2D6. We demonstrated that M3 can also be bioactivated by peroxidases, such as horseradish peroxidase and myeloperoxidase. In summary, these findings have significance in understanding the bioactivation pathways of glafenine and their potential link to mechanisms of toxicity of glafenine.

Hypersensitivity reactions to anthranilic acid derivatives.

Anthranilic acid derivatives are a group of nonsteroidal antiinflammatory drugs that include glafenine and fenamates. We report a woman who had immediate adverse reactions to glafenine and meclofenamate sodium. Skin prick and intradermal tests were performed with solutions of glafenine and meclofenamate in phosphate-buffered saline (PBS) and with the drugs bound to human serum albumin (HSA). Prick and intradermal tests with PBS solutions were negative for both drugs as were prick tests with HSA solutions. Intradermal tests with HSA-glafenine, however, were positive at 20 minutes, and at 6 and 24 hours. Intradermal tests with HSA-meclofenamate elicited a positive response at 6 and 24 hours. These tests were negative when performed in control subjects. A leukocyte histamine release test and a RAST assay were negative for both drugs. The patient was challenged following a double-blind placebo-controlled oral procedure and tolerated therapeutic doses of aspirin, indomethacin, ibuprofen, dipyrone, diclofenac, piroxicam, and acetaminophen. The oral challenge with glafenine and meclofenamate reproduced the reactions (eliciting doses: 50 mg and 15 mg, respectively), and the patient also reacted to 30 mg of mefenamic acid, an anthranilic acid derivative she had never previously received. This is an exceptional case of selective adverse reactions to glafenine and fenamates, anthranilic acid derivatives, in a patient tolerating aspirin and other cyclooxygenase inhibitors. Our study implicates an immunologic mechanism, and the existence of cross-reactivity between the drugs (or some active metabolite generated in vivo).

Glaphenine-containing gallstones.

Glaphenine is an analgesic drug derived from anthranilic acid. We report the analytical procedures for stone analysis in three cases of common bile duct stones containing glaphenic acid, which developed in arthrosic patients treated for 13.7 +/- 5 years with glaphenine. Stone analysis was performed by infrared spectroscopy, high performance thin layer chromatography, scanning electron microscopy and energy dispersive X-ray analysis. Mechanisms of lithogenesis are discussed. These observations emphasize the possibility of radiolucent gallstones mainly composed of drug compounds.

A population based case-cohort study of drug-induced anaphylaxis.

1. In order to determine the risk of anaphylaxis as an adverse reaction to drugs, a case-cohort study was performed. Cases consisted of all admissions in 1987 and 1988 to all Dutch hospitals with anaphylaxis as the principal diagnosis, and a random sample of admissions with related symptoms. Hospital discharge summaries were classified according to probability to anaphylaxis by a blinded Audit Committee. Of admissions classified as probable or possible anaphylaxis, the causative agent was assessed. The reference cohort consisted of all persons in the catchment area of a sample of pharmacies in The Netherlands, in the period between January 1, 1987 and December 31, 1988. 2. Out of 934 admissions, discharge summaries on 811 admissions were received, of which 727 contained enough clinical details. Out of 727, 391 were classified as probable or possible anaphylaxis. In 336 of these 391, anaphylaxis was reason for admission. This group consisted of 158 men and 178 women. Drug-induced anaphylaxis occurred in 107 patients. 3. Drug-induced anaphylaxis was most frequently caused by penicillins, analgesics and non-steroidal antiinflammatory drugs (NSAID) with the highest point estimate of the risk relative to all other drugs of 10.7, 6.9 and 3.7 respectively. 4. In the cases of probable anaphylaxis, the risk of anaphylaxis to glafenine relative to all other drugs was 167.7 in 1987 (95%-CI: 63.0-446.4) and 128.6 in 1988 (95%-CI: 50.4-328.5), to amoxycillin 15.2 in 1987 (95%-CI: 5.0-46.0) and 4.4 in 1988 (95%-CI: 1.03-18.9) and to diclofenac 6.1 in 1988 (95%-CI: 1.4-26.1).(ABSTRACT TRUNCATED AT 250 WORDS)

[Anaphylactic shock complicated by myocardial infarction: side effect of glaphenine?]. / Choc anaphylactique compliqué d'un infarctus du myocarde: effet indésirable de la glafénine? A propos d'un cas.

The authors report a case of anaphylactic shock complicated by coronary spasm and infarction attributed to glafenine medication in a 43-year-old male patient. The outcome was positive and coronary angiography showed healthy coronary vessels. The ergonovine maleate was negative. A review of the literature confirms the rarity of this complication of anaphylactic shock and study the ECG changes induced by this type of reaction and to analyze the mechanisms responsible for this coronary spasm in this situation. These consists basically of histamine release and prostaglandin-synthesis inhibition.

[Severe immunoallergic hemolytic anemia caused by a glafenine metabolite]. / Anémie hémolytique immuno-allergique grave provoquée par un métabolite de la glafénine.

Three weeks after a surgical operation, a 74-year old woman was admitted to hospital for severe haemolytic anaemia. A strongly positive IgG type direct Coombs test pointed to a iatrogenic origin, but a search for anti-molecule antibodies directed against all medicines taken by the patient after surgery was negative. We extended our immunological investigations and were able to demonstrate the presence of IgG type antibodies directed against an ex vivo metabolite of glafenine.

[Fatal liver cell necrosis following administration of glafenine]. / Dodelijk verlopende levercelnecrose na gebruik van glafenine.

The case is described of a patient with fulminant hepatic failure attributed to intake of glafenine 400 mg daily for 15 days. The first symptoms appeared two weeks after discontinuation of glafenine. Other causes of hepatic necrosis could be excluded. Approximately five weeks after the onset of symptoms the patient died of hepatic failure. At autopsy massive hepatic necrosis and massive pancreatic necrosis were demonstrated.

Glafenine-associated anaphylaxis as a cause of hospital admission in The Netherlands.

In 1981 generalized anaphylaxis was registered on 166 occasions in Dutch general and academic hospitals. Clinical details of 120 of those patients revealed that in 107 anaphylaxis was either probable (n = 90) or possible (n = 17), whereas in 13 cases some other reaction than anaphylaxis had occurred. The series of confirmed cases contained 46 men and 61 women, with mean ages of 47 y and 48 y, respectively. There was a complete recovery in 102 patients and two patients died. Hypotension was present in 79 cases (74%), dyspnoea in 34 cases (32%) and a skin reaction, mainly urticaria, erythema or angioedema, was mentioned in 62 cases (58%). Most cases of anaphylaxis were drug-induced (76%), the main causes being the analgesic glafenine and contrast media. Glafenine was mentioned as the cause in 36% of all admissions for drug-induced anaphylaxis. Only 3.7% of cases had been reported to the voluntary reporting scheme of the Netherlands Centre for Monitoring of Adverse Reactions to Drugs. On the basis of reimbursement data, the risk of developing severe anaphylaxis to glafenine was estimated at 11.7-19.3-fold relative to indomethacin, and 13.4-20.2-fold relative to oral penicillins.

A new approach to encapsulating nonsteroidal anti-inflammatory drugs. IV. Effect of cellulose derivatives with different functional groups on the bioavailability and gastric ulcerogenic activity of acidic as well as basic nonsteroidal anti-inflammatory drugs.

The bioavailability and gastric ulcerogenic activity of oxyphenbutazone and glafenine (acidic and basic nonsteroidal anti-inflammatory drugs), coated with different cellulose derivatives were assessed in albino rats. The cellulose derivatives chosen have different functional groups, acidic (carboxymethyl cellulose), basic (chitosan) and neutral (hydroxypropylmethyl cellulose). The bioavailability was dependent on the drug and polymers. Generally, all the cellulose derivatives chosen decreased the gastric ulcerogenic activity of the drugs studied.

[Urinary calculi caused by glaphenine. Role of radiology in diagnosis. Apropos of a case]. / Les lithiases urinaires dues à la glafénine. Place de la radiologie dans le diagnostic. A propos d'un cas.

The authors report a case of urinary calculi secondary to glafenine which posed a difficult problem in the radiological diagnosis. They review the literature of iatrogenic urinary calculi and discuss the place of radiology (Excretory Urography, Ultrasound and Computed Tomography) in the diagnosis.

[Shock caused by glafenine. Apropos of 7 complications]. / Les chocs à la glafénine. A propos de sept accidents.

Glafenine-induced shock. Seven cases. Glafenine is a widely prescribed analgesic drug, and shock is one of its severe side-effects. We report six documented and one highly probable cases of such accidents. From these seven cases and a review of the literature, we have extracted the clinical characteristics of glafenine-induced shock. Shock usually occurs about 30 minutes on average after taking one single tablet. Previous use of the drug is found in more than 50 per cent of the patients, and it was often followed by a neglected side-effect. A series of cutaneous and respiratory manifestations precedes or accompanies the shock. Two physiopathological mechanisms of glafenine-induced shock have been postulated: either anaphylaxis or idiosyncratic reaction involving the prostaglandins. In vitro tests give highly variable results and therefore are of limited value. Glafenine-induced shock is rare; its incidence, probably underestimated, is about 0.7 in 10(5) treatments. Prevention is essential, cure relies on adrenaline.