2-arylpropionic Acid Derivatives Research Articles

Diagnostic evaluation of hypersensitivity reactions to arylpropionic acid derivatives: a descriptive observational study focusing on clinical characteristics and potential risk factors in children

Diagnostic evaluation of hypersensitivity reactions to arylpropionic acid derivatives: a descriptive observational study focusing on clinical characteristics and potential risk factors in children

A New Approach in Lipase-Octyl-Agarose Biocatalysis of 2-Arylpropionic Acid Derivatives.

The use of lipase immobilized on an octyl-agarose support to obtain the optically pure enantiomers of chiral drugs in reactions carried out in organic solvents is a great challenge for chemical and pharmaceutical sciences. Therefore, it is extremely important to develop optimal procedures to achieve a high enantioselectivity of the biocatalysts in the organic medium. Our paper describes a new approach to biocatalysis performed in an organic solvent with the use of CALB-octyl-agarose support including the application of a polypropylene reactor, an appropriate buffer for immobilization (Tris base-pH 9, 100 mM), a drying step, and then the storage of immobilized lipases in a climatic chamber or a refrigerator. An immobilized lipase B from Candida antarctica (CALB) was used in the kinetic resolution of (R,S)-flurbiprofen by enantioselective esterification with methanol, reaching a high enantiomeric excess (eep = 89.6 ± 2.0%). As part of the immobilization optimization, the influence of different buffers was investigated. The effect of the reactor material and the reaction medium on the lipase activity was also studied. Moreover, the stability of the immobilized lipases: lipase from Candida rugosa (CRL) and CALB during storage in various temperature and humidity conditions (climatic chamber and refrigerator) was tested. The application of the immobilized CALB in a polypropylene reactor allowed for receiving over 9-fold higher conversion values compared to the results achieved when conducting the reaction in a glass reactor, as well as approximately 30-fold higher conversion values in comparison with free lipase. The good stability of the CALB-octyl-agarose support was demonstrated. After 7 days of storage in a climatic chamber or refrigerator (with protection from humidity) approximately 60% higher conversion values were obtained compared to the results observed for the immobilized form that had not been stored. The new approach involving the application of the CALB-octyl-agarose support for reactions performed in organic solvents indicates a significant role of the polymer reactor material being used in achieving high catalytic activity.

The synergistic effect of typical chiral organic acids and solution chemistry conditions on the transport of 2-arylpropionic acid chiral derivatives in porous media

The hazards of man-made chiral compounds are of great public concern, with reports of worrying stereoselective compounds and an urgent need to assess their transport. This study evaluated the transport of 2-arylpropionic acid derivatives enantiomers (2-APA) in porous media under a variety of solution chemistry conditions via column packing assays. The results revealed the introduction of Malic acid (MA) enantiomers enhanced the mobility of 2-APA enantiomers, but the enhancement effect was different for different 2-APA enantiomers. Batch sorption experiments confirmed that the MA enantiomers occupied the sorption site of the quartz sand, thus reducing the deposition of the 2-APA enantiomer. Homo- or heterochirality between 2-APA and MA dominates the transport of 2-APA enantiomers, with homochirality between them triggering stronger retention and vice versa. Further evaluating the effect of solution chemistry conditions on the transport of 2-APA enantiomers, increased ionic strength attenuated the mobility of 2-APA enantiomers, whereas introduced coexisting cations enhanced the retention of 2-APA enantiomers in the column. The redundancy analyses corroborated these solution chemistry conditions were negatively correlated with the transport of 2-APA enantiomers. The coupling of pH and these conditions reveals electrostatic forces dominate the transport behavior and stereoselective interactions of 2-APA enantiomers. Distinguishing the transport of enantiomeric pair helps to understand the difference in stereoselectivity of enantiomers and promises to remove the more hazardous one.

Evaluation of the analgesic activity of new derivatives of aryl propionic acid on gastric male mice

This study focused on the recent synthesis of new compounds from aryl propionic acid derivatives compared to naproxen. The present study aimed to investigate the safety and efficiency of the new derivatives in improving analgesic effects and reducing adverse effects via modifying its chemical structure by adding new functional groups. The new compounds were characterized, and evaluate their pharmacodynamic effects. The analysis and characterization of new compounds were by 1HMNR and FT-IR spectrum. The investigation of the adverse effect after 5 days of remedy with 20 mg/kg daily administered with naproxen derivatives to the healthy male albino mice (25-30 g) for analgesic activity using the hot plate method. Mice were parted into 5 groups, consisting of the control group and 4 groups that administered naproxen or derivatives of aryl propionic acid (E, H, D1 and D2). The main tests are done by a hot plate, biochemical, macroscopic, and microscopic inspection. The results confirmed that the new drugs have potent analgesic activity. The results showed that mice administered with D1 expressed less ulcerative effect than parent naproxen, H, E and ethanol. Moreover, the number of lesions was significantly less in the D2 group, while D1-treated mice recorded no evidence of ulcers or hemorrhage in their stomachs after being examined under a dissecting microscope. The study concluded that the new D1 derivative is a compound worthy of research and future clinical applications due to its relatively high efficacy and low adverse effects compared to other derivatives prepared and tested in this study. Keywords: Analgesic, Aryl propionic acid, Naproxen, Acidity

Different Patterns of Response in Hypersensitivity Reactions to Arylpropionic Acid Derivatives

Ibuprofen and other arylpropionic acid derivatives (APs) are among the most consumed nonsteroidal anti-inflammatory drugs worldwide at all age ranges; however, little is known about drug hypersensitivity reactions (DHRs) they induce. To characterize in detail patients reporting DHRs to APs. We prospectively evaluated patients with symptoms suggestive of AP-DHRs and analyzed their clinical characteristics, reported reactions, and diagnostic approaches. Six hundred sixty-two patients confirmed as hypersensitive to APs were included: 489 with cross-reactive reactions (CRs) (73.86%) and 173 with selective reactions (SRs) (26.13%). The percentage of subjects reporting reactions to ibuprofen and dexketoprofen was higher in CRs (P= .005 and P= .01, respectively), whereas naproxen and ketoprofen were more frequently involved in SRs (P= .0002 and P= .00001, respectively). The most frequent symptoms induced by ibuprofen, dexketoprofen, and naproxen were isolated angioedema and urticaria, combined or not with angioedema in both CRs and SRs. The result of nasal provocation test with lysine acetylsalicylate was positive in 156 cases (77.14% in patients showing exclusively respiratory symptoms, and in 68.18% of those with both cutaneous and respiratory involvement). To confirm diagnosis, drug provocation test with acetylsalicylic acid was required in 246 CR patients (50.3%), whereas in 28 SR patients (16.18%) drug provocation test with the culprit AP was required. Skin is the organ most commonly involved in AP-DHRs, with ibuprofen and dexketoprofen inducing most frequently CRs, and naproxen and ketoprofen SRs. More studies are necessary to clarify the underlying mechanism in DHRs induced by APs.

Phytoconstituent estimation and LC-MS studies of field grown Withania somnifera (L.) Dunal root extract in Jharkhand and Bihar

Plants in either raw form or their root extracts are utilized as complementary and alternative medicine in various disorders. The present study was undertaken for phytoconstituents estimation and to evaluate chemical compositions of methanolic extract of Withania somnifera (L.) Dunal (Ashwagandha) roots collected from BAU, Ranchi, Jharkhand and Sabour, Bhagalpur, Bihar. Phytochemicals through crude methanolic extract were analyzed in Ashwagandha roots. Alcoholic extract was prepared using Soxhlet extraction apparatus. On phytochemical evaluation, total phenolic, flavonoid, total tannin and alkaloids were estimated. Presence of bioactive components in extract was determined by Liquid Chromatography-Mass Spectrophotometry (ESI positive ion) technique. Qualitative screening of extract ensured the presence of alkaloids, phenols, tannins and flavonoids. Quantitatively these phytochemicals showed TPC (66.06 mg/gm), TFC (650.0 mg/gm), TAC (102 mg/gm) and TTC (5.89 mg/gm). However, the phytochemicals and yield did not accumulate in various fractions on polarity. This result was supported by LC-MS analysis which showed 17 definite peaks in their chromatogram but only 8 peaks offer a suitable approximation. Extract revealed forty five bioactive compounds where most of them were phenolic compounds, aryl propionic acid and cinnamide derivatives. Quantitative analysis of present phytochemical showed maximum quantity of TFC followed by TAC, TPC and TTC. On the other hand, presence of various bioactive compounds in root extract showed that plant is having very high medicinal value.

Extra-thermodynamic study of the retention of anti-inflammatory 2-arylpropionic acid derivatives on a heat-resistive stationary phase: Application of HTLC approach for pharmaceutical and biological analysis

A study of the retention behavior of four frequently prescribed anti-inflammatory 2-arylpropionic acid derivatives on a reversed-phase thermostable stationary phase was conducted. Extra-thermodynamic investigations were carried out over the temperature range of 303–338 K. A modified van’t Hoff analysis was applied to assess the enthalpy, entropy, and Gibb’s free energy changes that take place during the mass transfer from the mobile phase to the stationary phase. It has been proven that enthalpy–entropy compensation exists as an extra-thermodynamic relationship. The effect of molecular structures of the investigated drugs on thermodynamic and retention behaviors was also explored. A validated high-temperature liquid chromatography method was established for the separation and analysis of ketoprofen, naproxen, diclofenac, and ibuprofen in pharmaceutical formulations and human urine with %recoveries within the range of 90.1–105.6 % and standard deviation not exceeding ±4.1% in all cases. The developed method greenness was positively assessed by the analytical eco-scale score tool.

Engineering of Saccharomyces pastorianus old yellow enzyme 1 for the synthesis of pharmacologically active (S)-profen derivatives

• Identification of the key residues for the stereo-control of ene reductase OYE1. • Engineering of OYE1 for the synthesis of active ( S )-profen derivatives. • Up to >99 % stereoselectivity was observed for the asymmetric reduction. 2-Arylpropionic acid derivatives, such as ibuprofen, constitute an important group of non-steroidal anti-inflammatory drugs (NSAIDs). Biocatalytic asymmetric reduction of 2-arylacrylic acid derivatives by ene reductases (EREDs) is a valuable approach for synthesis of these derivatives. However, previous bioreduction by EREDs resulted solely in nonpharmacological ( R )-enantiomers. Here, we present the engineering of Saccharomyces pastorianus old yellow enzyme 1 (OYE1) for the synthesis of pharmacologically active ( S )-profen derivatives. By structural comparison of substrate recognition in related EREDs and analysis of non-covalent contacts in the pro- S model of OYE1, the key residues of OYE1 were identified. Mutagenesis screening at these positions successfully provided the ( S )-stereoselective OYE1 variants, which catalyzed stereoselective bioreduction of various profen precursors to afford pharmacologically active ( S )-derivatives with up to >99 % ee values. Moreover, the key residues obtained from OYE1 successfully guided the engineering of OYE2.6 from Pichia stipites and KnOYE1 from Kazachstania naganishii for ( S )-selective reduction of 2-arylacrylic acid derivatives.

Coupling of Reformatsky Reagents with Aryl Chlorides Enabled by Ylide-Functionalized Phosphine Ligands.

The coupling of aryl chlorides with Reformatsky reagents is a desirable strategy for the construction of α‐aryl esters but has so far been substantially limited in the substrate scope due to many challenges posed by various possible side reactions. This limitation has now been overcome by the tailoring of ylide‐functionalized phosphines to fit the requirements of Negishi couplings. Record‐setting activities were achieved in palladium‐catalyzed arylations of organozinc reagents with aryl electrophiles using a cyclohexyl‐YPhos ligand bearing an ortho‐tolyl‐substituent in the backbone. This highly electron‐rich, bulky ligand enables the use of aryl chlorides in room temperature couplings of Reformatsky reagents. The reaction scope covers diversely functionalized arylacetic and arylpropionic acid derivatives. Aryl bromides and chlorides can be converted selectively over triflate electrophiles, which permits consecutive coupling strategies.

Enhancing the Mitochondrial Uptake of Phosphonium Cations by Carboxylic Acid Incorporation.

There is considerable interest in developing drugs and probes targeted to mitochondria in order to understand and treat the many pathologies associated with mitochondrial dysfunction. The large membrane potential, negative inside, across the mitochondrial inner membrane enables delivery of molecules conjugated to lipophilic phosphonium cations to the organelle. Due to their combination of charge and hydrophobicity, quaternary triarylphosphonium cations rapidly cross biological membranes without the requirement for a carrier. Their extent of uptake is determined by the magnitude of the mitochondrial membrane potential, as described by the Nernst equation. To further enhance this uptake here we explored whether incorporation of a carboxylic acid into a quaternary triarylphosphonium cation would enhance its mitochondrial uptake in response to both the membrane potential and the mitochondrial pH gradient (alkaline inside). Accumulation of arylpropionic acid derivatives depended on both the membrane potential and the pH gradient. However, acetic or benzoic derivatives did not accumulate, due to their lowered pKa. Surprisingly, despite not being taken up by mitochondria, the phenylacetic or phenylbenzoic derivatives were not retained within mitochondria when generated within the mitochondrial matrix by hydrolysis of their cognate esters. Computational studies, supported by crystallography, showed that these molecules passed through the hydrophobic core of mitochondrial inner membrane as a neutral dimer. This finding extends our understanding of the mechanisms of membrane permeation of lipophilic cations and suggests future strategies to enhance drug and probe delivery to mitochondria.

CHARACTERIZATION OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS IN TABLETS BY DIRECT ANALYSIS IN REAL TIME/TIME OF FLIGHT/MASS SPECTROMETRY (DART/TOF/MS) WITHOUT SAMPLE PREPARATION

This powerful mass spectrometric technique was used to investigate four profen drugs which are widely used as non-steroidal anti-inflammatory drugs for treating pain, fever and inflammation: Ibuprofen (M = 206), Flurbiprofen (M = 244), Naproxen (M = 230) and Ketoprofen (M = 254). The DART ion source was operated in positive ion mode with helium as the ionizing medium heated to 250°C. A solution containing a mixture of poly (ethylene glycol) standards PEG 600 and PEG 200 was used for mass calibration. A standard solution of each pure standard was manually introduced by using a small glass rod. The high resolution mass spectra of Ibuprofen, Flurbiprofen, Naproxen and Ketoprofen showed the presence of an intense protonated molecular ion [M + H]+ at 207.13860, 245.09776, 231.10632 and 255.09966 Da, respectively. Moreover, a non-protonated molecular ion M+ was also observed except for Ketoprofen. On the other hand, an intense adduct ion [M + H2O]+ was also present in the four mass spectra. Since these profens are 2-arylpropionic acid derivatives they have a known tendency to form dimers; indeed, an intense protonated ion corresponding to this dimer [2M + H]+ was present in the spectrum of Ibuprofen, Flurbiprofen, Naproxen and Ketoprofen at 413.27102, 489.19944, 461.19266 and 509.19662 Da, respectively. The presence of profens as active ingredients was then investigated in various pharmaceutical tablets collected from the local market. A small piece of each solid tablet was submitted to the DART ion source without any sample preparation. The obtained mass spectrum showed the characteristic peaks corresponding to each profen as active principle, as well as the other ingredients of the tablet.

Synthesis and Pharmacological Activity of S(-)-2-Amino-2-Methyl-3-Phenylpropanoic Acid

Taking into account the high efficacy of 2-arylpropionic acid derivatives among NSAIDs and based on their SARs, we have evaluated the anti-inflammatory, antinociceptive, and antiaggregant activity and ulcerogenic properties of a new synthesized non-protein amino acid (NPAA) derivative S(-)-2-amino-2-methyl-3-phenylpropanoic acid (NPAA-36). A new method of NPAA-36 synthesis was developed and experiments were carried out, which showed that this compound injected in a dose of 10 mg/kg (i.p.) inhibited xylene-induced ear oedema by about 31.1%, which proved its anti-inflammatory properties. The antinociceptive activity of NPAA-36 was assessed in tail-flick test by the ability to increase the tail cut-off latency by 36.78% within 60 min after injection at the same dose. Investigation of the ulcerogenic properties of NPAA-36 demonstrated that it exhibited lower gastrointestinal toxicity than a well-known arylpropionic acid derivative NSAID. Results of in vitro experiments showed the antiplatelet activity registered not in all (only in 41.2%) cases, which might imply lower bleeding. The obtained data indicate that the new NPAAderivative can be a potential basis for the development of new anti-inflammatory drugs with weak side effects.

Rapid and Efficient Approaches for Synthesis of Some New Aryl Propionic Acid Derivatives and In–Vivo Anti‐Diabetic Screening of Selected Compounds

AbstractA series of some new aryl propionic acid derivatives as 2‐(6‐(substituted phenylethynyl)‐2,3‐dihydrobenzofuran‐3‐yl)acetic acids were synthesized. The targeted molecules were prepared by using techniques such as efficient and high‐performance autoclave hydrogenation to reduce highly stable π‐electron system of furan ring and microwave‐assisted rapid Sonogashira Cross‐Coupling reaction between aryl triflate derivatives and substituted aryl acetylenes. The anti‐diabetic screening of selected compounds was performed by using alloxan‐induced diabetic model. The studies include acute and chronic toxicity, effectiveness, change in the behavioral pattern and change in glucose level of the tested animals. The compound 2‐(6‐((4‐ethylphenyl)ethynyl)‐2,3‐dihydrobenzofuran‐3‐yl)acetic acid exhibited maximum anti‐hyperglycemic properties. All the synthesized compounds were characterized by spectroscopic techniques such as 1H‐NMR, 13C‐NMR, IR, Mass spectrometry and single crystal XRD (MTS‐201).

Chromatographic and thermodynamic comparison of amylose tris(3-chloro-5-methylphenylcarbamate) coated or covalently immobilized on silica in high-performance liquid chromatographic separation of the enantiomers of select chiral weak acids

The separation of enantiomers of some chiral weak acids was studied in HPLC with chiral HPLC columns prepared by coating or covalent immobilization of the same chiral selector, namely amylose tris(3-chloro-5-methylphenylcarbamate) onto silica. After screening some representatives of arylpropionic acid derivatives, coumarins and barbiturates in hydrocarbon-alcohol type mobile phases, we studied the temperature dependence of separation parameters for ketoprofen and naproxen. Instances of reversal of the enantiomer elution order were observed function of column temperature, nature of polar modifier and its content in the mobile phase, as well as between the coated and covalently immobilized versions of the columns made with more-or-less the same chiral selector. Thermodynamic parameters such as Gibb’s free energy, the standard molar entropy and the standard molar enthalpy of analyte transfer from the mobile to the stationary phase were calculated in some cases in order to explain the differences observed in the enantiomer separation ability and pattern of coated and covalently immobilized columns.

The effect of temperature on the separation of enantiomers with coated and covalently immobilized polysaccharide-based chiral stationary phases

This article describes our attempt to re-visit the role of temperature in the separation of enantiomers with polysaccharide-based chiral columns in high-performance liquid chromatography (HPLC). Rarely observed increased retention and separation factors with increasing temperature, as well as temperature dependent reversal of enantiomer elution order are reported for several arylpropionic acid derivatives. Chiral columns with coated and covalently immobilized chiral selectors were compared from the viewpoint of effect of temperature on analyte retention, enantiomer separation and enantiomer elution order. Thermodynamic parameters were calculated for analyte transfer from the liquid phase to the chiral stationary phase and the effect of temperature on chiral selectors was investigated by using differential scanning calorimetry (DSC). DSC results along with chromatographic studies indicate that polysaccharide-based chiral selectors undergo some kind of transition at elevated temperature that is not reversible in the thermodynamic sense of this term.

Amorphisation of Free Acid Ibuprofen and Other Profens in Mixtures with Nanocellulose: Dry Powder Formulation Strategy for Enhanced Solubility.

The formulation of arylpropionic acid derivatives (profens), which are poorly soluble Biopharmaceutical Classification System (BCS) Type II drugs, has a strong impact on their therapeutic action. This article shows that heat-treated powder mixtures of free acid profens with high surface area Cladophora cellulose induces drug amorphization and results in enhanced solubility and bioavailability. Similar mixtures produced using conventional low surface area cellulose, i.e., microcrystalline cellulose, does not produce the same effect. The concept is thoroughly described and links the solid-state characterization data, such as differential scanning calorimetry, X-ray powder diffraction, and Fourier-transform infra-red spectroscopy, with in vitro dissolution in biorelevant media and in vivo pharmacokinetic analysis in rats. The concept is demonstrated for several substances from the profens group, including ibuprofen (main model drug), ketoprofen, flurbiprofen, and naproxen. The presented approach opens new ways to produce solid dosage forms of profen drugs in their free acidic form as alternatives to existing analogues, e.g., drug-salt conjugates or soft gel liquid capsules.

Enantioselective resolution of 2-arylpropionic acid derivatives employing immobilization of lipase from Bacillus subtilis strain Kakrayal_1 (BSK-L)

This work studied the enantioselective resolution of 2-arylpropionic acid derivatives employing immobilization of lipase produced by Bacillus subtilis strain Kakrayal_1 (BSK-L). The efficient immobilization of lipase on modified silica gel was confirmed by Fourier transform infrared spectroscopy. Tethering of lipase facilitated the enhancement of physiochemical properties and stability of enzyme. Covalently immobilized enzyme retained 85% of residual activity even on reuse after 10th reaction cycle. Validation of immobilized lipase for enantioselective resolution of 2-arylpropionic acid derivatives led to 47.8% conversion efficiency with 87% enantiomeric excess (ee) for ketoprofen, and 27.3% conversion efficiency with 75% ee for flurbiprofen. The enantioselective resolution using immobilized lipase (BSK-L) was superior to free and commercially procured lipase, which suggest a potential application of immobilized lipase in the pharmaceutical/chemical industry.

Metabolic chiral inversion of 2-arylpropionic acid derivatives (profens)

2-arylpropionic acid derivatives (profens) are one of the most popular anti-inflammatory, analgesic, and antipyretic drugs. They belong to a group of nonsteroidal anti-inflammatory drugs (NSAID) and exhibit metabolic chiral inversion. Enantiomers of these chiral drugs are often characterised by different pharmacological activity. It is estimated that the values of metabolic chiral inversion of ( R )-ibuprofen in humans are between 35 and 70%, depending on the condition of the liver and the intake of other medicines, while ( R )-flurbiprofen undergoes chiral metabolic inversion to its opposed ( S ) form only in small range. The described phenomenon in the case of ( R )-ketoprofen is limited to a maximum of around 10%. The metabolic chiral inversion is associated with potentially important pharmacotherapeutic and toxicological consequences, and so an attempt was made to analyse this phenomenon for the most commonly used drugs from the profens group.

STRUCTURAL MODIFICATION OF LIGNAN COMPOUNDS ISOLATED FROM NECTANDRA SPECIES (LAURACEAE)

In the genus Nectandra , the presence of certain types of secondary metabolites has been determined, including sesquiterpenes, phytosterols, polyalcohols, arylpropionic acid derivatives, flavonols, arylpropanoids, furofuran lignans, dihydrobenzofuran neolignans [1], and certain norlignans [2], alkaloids [3], tannins [4], diterpenes [5], and components of essential oils [6]. However, the chemotaxonomic characteristics are determined by the presence of lignan-type compounds [7]. The ultimate goal of structural modification of natural products is to obtain new drugs [8]. In that sense, there is a growing interest in lignans and their synthetic derivatives due to applications in cancer chemotherapy and various other pharmacological effects [9]. This work corresponds to the first report of this type of structural modification of lignan compounds (7,7’-epoxylignans and diaryldimethylbutane lignans) isolated from Nectandra species. Therefore, this work can be used as a starting point for structure-activity relationship studies.

Immediate Reactions to More Than 1 NSAID Must Not Be Considered Cross-Hypersensitivity Unless Tolerance to ASA Is Verified.

Individuals who develop drug hypersensitivity reactions (DHRs) to chemically unrelated nonsteroidal anti-inflammatory drugs (NSAIDs) are considered cross-hypersensitive. The hallmark for this classification is that the patient presents a reaction after intake of or challenge with acetylsalicylic acid (ASA). Whether patients react to 2 or more NSAIDs while tolerating ASA remains to be studied (selective reactions, SRs). Objective: To identify patients with SRs to 2 or more NSAIDs including strong COX-1 inhibitors. Patients who attended the Allergy Service of Hospital Infanta Leonor, Madrid, Spain with DHRs to NSAIDs between January 2011 and December 2014 were evaluated. Those with 2 or more immediate reactions occurring in less than 1 hour after intake were included. After confirming tolerance to ASA, the selectivity of the response to 2 or more NSAIDs was demonstrated by in vivo and/or in vitro testing or by controlled administration. From a total of 203 patients with immediate DHRs to NSAIDs, 16 (7.9%) met the inclusion criteria. The patients presented a total of 68 anaphylactic or cutaneous reactions (mean [SD], 4.2 [2.1]). Most reactions were to ibuprofen and other arylpropionic acid derivatives and to metamizole. Two different NSAIDs were involved in 11 patients and 3 in 5 patients. Patients with NSAID-induced anaphylaxis or urticaria/angioedema should not be considered cross-hypersensitive unless tolerance to ASA is verified.