Hypersensitivity reactions to nonsteroidal anti-inflammatory drugs: an update on pharmacogenetics studies.

Nonsteroidal anti-inflammatory drugs are the medications most frequently involved in hypersensitivity reactions to drugs. These can be induced by specific immunological and nonimmunological mechanisms, being the latter the most frequent. The nonimmunological mechanism is related to an imbalance of inflammatory mediators, which is aggravated by the cyclooxygenase inhibition. Genetic studies suggest that multiples genes and additional mechanisms might be involved. The proposals of this review is summarize the contribution of variations in genes involved in the arachidonic acid, inflammatory and immune pathways as well as the recent genome-wide association studies findings related to cross-intolerant nonsteroidal anti-inflammatory drugs hypersensitivity reactions. In addition, using integration of different genetic studies, we propose new target genes. This will help to understand the underlying mechanism of these reactions.

Allergic Reactions to Metamizole: Immediate and Delayed Responses.

BACKGROUND: Pyrazolones are the most common causes of selective nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity. We studied a large group of patients with immediate and delayed selective responses to metamizole. METHODS: Patients with suspicion of hypersensitivity to metamizole were evaluated. We verified acetylsalicylic acid tolerance and classified patients as immediate or delayed responders if they showed symptoms less or more than 24 h after metamizole administration. Skin tests were performed and if negative, a basophil activation test (BAT) was performed on immediate responders. If it was negative, we performed a drug provocation test (DPT) with metamizole. RESULTS: A total of 137 patients were included: 132 reacted within 24 h (single NSAID-induced urticaria/angioedema/anaphylaxis; SNIUAA) and 5 after 24 h (single NSAID-induced delayed hypersensitivity reaction; SNIDHR). Most SNIUAA patients developed anaphylaxis (60.60%); for SNIDHR, maculopapular exanthema was the most frequent entity (60%). Skin testing was positive in 62.04% of all cases and BAT in 28% of the SNIUAA patients with negative skin tests. In 5.1% of the cases, DPT with metamizole was needed to establish the diagnosis. In 22.62% of the cases, diagnosis was established by consistent and unequivocal history of repeated allergic episodes in spite of a negative skin test and BAT. CONCLUSIONS: SNIUAA to metamizole is the most frequent type of selective NSAID hypersensitivity, with anaphylaxis being the most common clinical entity. It may occur within 1 h after drug intake. SNIDHR occurs in a very low percentage of cases. The low sensitivity of diagnostic tests may be due to incomplete characterization of the chemical structures of metamizole and its metabolites.

Perception of the usefulness of drug/gene pairs and barriers for pharmacogenomics in Latin America.

Pharmacogenetics and Pharmacogenomics areas are currently emerging fields focused to manage pharmacotherapy that may prevent undertreatment while avoiding associated drug toxicity in patients. Large international differences in the awareness and in the use of pharmacogenomic testing are presumed, but not well assessed to date. In the present study we review the awareness of Latin American scientific community about pharmacogenomic testing and the perceived barriers for their clinical application. In order to that, we have compiled information from 9 countries of the region using a structured survey which is compared with surveys previously performed in USA and Spain. The most relevant group of barriers was related to the need for clear guidelines for the use of pharmacogenomics in clinical practice, followed by insufficient awareness about pharmacogenomics among clinicians and the absence of regulatory institutions that facilitate the use of pharmacogenetic tests. The higher ranked pairs were TPMT/thioguanine, TPMT/azathioprine, CYP2C9/warfarin, UGT1A1/irinotecan, CYP2D6/amitriptiline, CYP2C19/citalopram and CYP2D6/clozapine. The lower ranked pairs were SLCO1B1/simvastatin, CYP2D6/metoprolol and GP6D/chloroquine. Compared with USA and Spanish surveys, 25 pairs were of lower importance for Latin American respondents. Only CYP2C19/esomeprazole, CYP2C19/omeprazole, CYP2C19/celecoxib and G6PD/dapsone were ranked higher or similarly to the USA and Spanish surveys. Integration of pharmacogenomics in clinical practice needs training of healthcare professionals and citizens, but in addition legal and regulatory guidelines and safeguards will be needed. We propose that the approach offered by pharmacogenomics should be incorporated into the decision-making plans in Latin America.

Alcohol dehydrogenase 2 genotype and allelic variants are not associated with the risk for essential tremor.

OBJECTIVE: To investigate the possible association between alcohol dehydrogenase 1B, beta-polypeptide (ADH2) genotype and allelic variants and the risk for developing essential tremor (ET). METHODS: Leukocytary DNA from 204 ET patients and 200 healthy controls was studied for the genotype ADH2 and the occurrence of ADH2 allelic variants using allele-specific polymerase chain reaction amplification and MslI-restriction fragment length polymorphism's analyses. RESULTS: The frequencies of the ADH2*1/ADH2*2 genotype and of the allelic variant ADH2*2 did not differ significantly in ET patients when compared with those of the controls. The mean age at onset of ET did not differ significantly between patients with genotypes ADH2*1/ADH2*2 and ADH2*1/ADH2*1. The frequencies of the genotype ADH2*1/ADH2*2 and of the allelic variant ADH2*2 in patients with voice, tongue, and chin tremors did not differ from those of the controls, whereas patients with voice tremor showed lower frequencies of mutated genotypes and ADH2*2 alleles. The frequencies of ADH2 genotypes and ADH2 alleles did not differ significantly between patients who did not drink ethanol and those who reported improvement, no improvement, or unknown response of tremor to ethanol. CONCLUSIONS: These results suggest that ADH2 genotype and allelic variants are not associated with the risk for ET in white Spanish people.