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Most cases of cystic fibrosis (CF) are caused by class 2 mutations in the cystic fibrosis transmembrane regulator (CFTR). These proteins preserve some channel function but are retained in the endoplasmic reticulum (ER). Partial rescue of the most common CFTR class 2 mutant, F508del-CFTR, has been achieved through the development of pharmacological chaperones (Tezacaftor and Elexacaftor) that bind CFTR directly. However, it is not clear whether these drugs will rescue all class 2 CFTR mutants to a medically relevant level. We have previously shown that the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen can correct F508del-CFTR trafficking. Here, we utilized RNAi and pharmacological inhibitors to determine the mechanism of action of the NSAID glafenine. Using cellular thermal stability assays (CETSAs), we show that it is a proteostasis modulator. Using medicinal chemistry, we identified a derivative with a fourfold increase in CFTR corrector potency. Furthermore, we show that these novel arachidonic acid pathway inhibitors can rescue difficult-to-correct class 2 mutants, such as G85E-CFTR > 13%, that of non-CF cells in well-differentiated HBE cells. Thus, the results suggest that targeting the arachidonic acid pathway may be a profitable way of developing correctors of certain previously hard-to-correct class 2 CFTR mutations., (© 2022. The Author(s).)

The analgesic efficacy and tolerability of diclofenac-potassium 50 mg were compared with those of glafenine 200 mg in 109 outpatients suffering from moderate to severe dental pain. Throughout the four-day trial period, patients (Diclofenac-potassium: n = 58, mean age = 32.84 +/- 12.0 yrs. Glafenine n = 51, mean age = 34.12 +/- 14.0 yrs.) were randomised, in a double-blind fashion, to receive one tablet of either medications three times daily, together with an antibiotic, ampicillin, 500 mg, 8 hourly. Half an hour following the administration of the first analgesic dose, both treatment groups showed highly statistically significant (P < 0.001) reductions in the mean pain level when compared with their baseline values. The mean decrease of pain level in diclofenac-potassium group after 1/2 hour was significantly (P < 0.01) greater than that in the glafenine group. Moreover, the percent of pain free patients after 1/2 hour in the diclofenac-potassium group was significantly higher (P = 0.05) compared with those in the glafenine group. The mean decreases in pain and tenderness on the second and fourth days, in relation to their initial values, were greater in the diclofenac-potassium treated patients than the glafenine treated ones. The overall evaluation of therapeutic effect was considered excellent in 72% of the diclofenac- potassium patients compared with 57% of the glafenine patients. Furthermore, 95% of the diclofenac-potassium patients, compared with 90% of the glafenine ones, expressed their willingness to use the trial medication again in similar conditions. None of the patients in both treatment groups discontinued the trial due to unwanted effects. Both therapies were well tolerated. Only one patient (1.72%) in the diclofenac-potassium treatment group experienced slight diarrhoea. It can be concluded from this study that both medications are effective and well tolerated in the management of dental pain. However, diclofenac-potassium with its fast onset of effect is particularly suitable in the management of acute painful conditions.

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.

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.

In a randomized, single-dose, double-blind, parallel comparative trial of analgesic efficacy, 96 adult patients received either 10 mg ketorolac tromethamine or 400 mg glafenine orally the morning after surgery if they requested pain relief medication. Each patient provided a baseline pain assessment and then received the assigned medication. Patients assessed pain intensity and pain relief and reported any adverse events in interviews held 30 minutes after drug administration and then hourly for 6 hours. The demographic characteristics, baseline pain intensity, and surgical categories of the 47 patients who received ketorolac tromethamine and the 49 who received glafenine were similar. Both drugs provided prompt, sustained pain relief throughout the 6-hour observation period, and there were no statistically significant differences between the two groups in any of the efficacy measures analyzed. The global assessment recorded by patients suggested a slight clinical advantage for ketorolac tromethamine (32.6% of 'excellent' responses) as compared to glafenine (12.5% 'excellent'). The differences in overall response were statistically significant (p = 0.017). Fourteen (30%) patients who received ketorolac tromethamine and 17 (35%) who received glafenine reported adverse experiences that began or seemed to worsen after administration of the study drugs. The most prominent were drowsiness and sleeping, both of which are common in post-surgical patients.

A double-blind multicenter cross-over study was conducted on 166 outpatients with painful chronic osteoarthritis of the hip and of the femoro-tibial joints, to compare the effectiveness of glafenine and paracetamol. Patients were randomly assigned to receive over a period of a week, either 400 mg of glafenine or 1000 mg of paracetamol twice a day at 8 a.m. and 4 p.m. in order to fill up the physical activity period during the daytime. This interval between tablet intake was chosen according to the design of the model. At the end of the week treatment period, patients crossed over. There was no wash out period between treatments. The following measurements: pain intensity (on Huskisson's visual analogue scale), functional index for hip and knee diseases, patients' overall opinion, patient preference, were evaluated at days 0, 7, 14. The results showed that both treatments produced effective analgesia but the improvement was significantly greater and observed in a larger number of cases when using glafenine rather than paracetamol. Fifty-one per cent of the nonresponsive patients to paracetamol could benefit from the glafenine treatment and 18 per cent of patients suffering from hip or knee osteoarthritis in this study showed improvement only with glafenine. Safety and biological tolerance were satisfactory with both drugs.

The action of tiapride on headaches has been studied in several neurological departments, both in hospitalized and ambulatory patients. A favourable result was obtained in 63,3% of cases (nearly 2 out of 3). A dosage of 400 mg/day is adequate for an opinion of the efficacy of the product to be made, with the average dosage is about 150 mg/day (1/2 table x 3 times a day). Tolerance is excellent. Side-effects, wich were noted in 18% of the patients, consist mainly of somnolence and more rarely akathisia. The good results obtained, and the excellent tolerance, enable its use in debilitated alcoholics, the elderly, and those with vascular disorders.

The authors report 5 cases of shock type anaphylactic reactions after the ingestion of glafenine. Up to the present, acute tubulo-interstitial nephritis had chiefly been reported. The existence of allergy to this medication remains to be proved by the wider application of allergological studies.

A double-blind study was carried out in 42 patients suffering from acute rheumatic pain to compare the analgesic effectiveness and tolerance of tiapride with that of glafenine, a widely used analgesic in Europe. Patients were allocated at random to receive either 100 mg tiapride or 200 mg glafenine 3-times daily over a period of 14 days. Pain intensity was rated daily by the patients using a visual analogue scale and an overall assessment of response to treatment was made by both patients and physician at the end of the study. The results showed that, whilst both treatments resulted in a marked reduction in mean pain scores, pain disappeared completely in 16 (76%) of the 21 patients treated with tiapride compared with 9 (43%) of the 21 receiving glafenine. There was also a significant difference in favour of tiapride in the physician's overall assessment of response which was considered as excellent in 71% of the patients on tiapride compared with 31% receiving glafenine. Both treatments were well tolerated and few side-effects were reported. Drowsiness occurred in 6 patients on tiapride but this was only mild in 5 and moderate in the other patient.

Envenomation by exotic poisonous snakes constitutes a rare emergency in Western Europe, but which in the future may be seen more frequently due to the increasing number of captive specimens in private collections. A case report of moderate envenomation by a viper is described. Diagnostic problems and therapeutic management are discussed for viper envenomation. The importance of differentiating between local and systemic poisoning is emphasized.

Seventy-eight patients, 40 suffering from cervical arthrosis and 38 from lumbar arthrosis, received for a period of two weeks paracetamol or a new preparation of glaphenine, in a double blind study. The two drugs were found to have the same efficiency on the subjective parameters but high bioavailability glaphenine seems to have an effectiveness in the range of articulatory movements, which is not found with paracetamol. The side effects were quite equivalent.