TY - JOUR T1 - 5-Aminoimidazole-4-carboxamide ribonucleotide-transformylase and inosine-triphosphate-pyrophosphatase genes variants predict remission rate during methotrexate therapy in patients with juvenile idiopathic arthritis. JF - Rheumatol Int Y1 - 2015 A1 - Pastore, Serena A1 - Stocco, Gabriele A1 - Moressa, Valentina A1 - Zandonà, Luigi A1 - Favretto, Diego A1 - Malusà, Noelia A1 - Decorti, Giuliana A1 - Lepore, Loredana A1 - Ventura, Alessandro AB -

For children with juvenile idiopathic arthritis (JIA) who fail to respond to methotrexate, the delay in identifying the optimal treatment at an early stage of disease can lead to long-term joint damage. Recent studies indicate that relevant variants to predict methotrexate response in JIA are those in 5-aminoimidazole-4-carboxamide ribonucleotide-transformylase (ATIC), inosine-triphosphate-pyrophosphatase (ITPA) and solute-liquid-carrier-19A1 genes. The purpose of the study was, therefore, to explore the role of these candidate genetic factors on methotrexate response in an Italian cohort of children with JIA. Clinical response to methotrexate was evaluated as clinical remission stable for a 6-month period, as ACRPed score and as change in Juvenile Arthritis Disease score. The most relevant SNPs for each gene considered were assayed on patients' DNA. ITPA activity was measured in patients' erythrocytes. Sixty-nine patients with JIA were analyzed: 52.2 % responded to therapy (ACRPed70 score), while 37.7 % reached clinical remission stable for 6 months. ATIC rs2372536 GG genotype was associated with improved clinical remission (adjusted p value = 0.0090). For ITPA, rs1127354 A variant was associated with reduced clinical remission: (adjusted p value = 0.028); this association was present even for patients with wild-type ITPA and low ITPA activity. These preliminary results indicate that genotyping of ATIC rs2372536 and ITPA rs1127354 variants or measuring ITPA activity could be useful to predict methotrexate response in children with JIA after validation by further prospective studies on a larger patient cohort.

VL - 35 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25240429?dopt=Abstract ER - TY - JOUR T1 - Genetic determinants for methotrexate response in juvenile idiopathic arthritis. JF - Front Pharmacol Y1 - 2015 A1 - Pastore, Serena A1 - Stocco, Gabriele A1 - Favretto, Diego A1 - De Iudicibus, Sara A1 - Taddio, Andrea A1 - d'Adamo, Pio A1 - Malusà, Noelia A1 - Addobbati, Riccardo A1 - Decorti, Giuliana A1 - Lepore, Loredana A1 - Ventura, Alessandro AB -

Juvenile idiopathic arthritis (JIAs) is the most common chronic rheumatic disease of childhood and is an important cause of disability. The folic acid analog methotrexate is the first choice disease-modifying anti-rheumatic drug in this disease, however, 35-45% of patients fail to respond. Molecular elements, such as variants in genes of pharmacological relevance, influencing response to methotrexate in JIA, would be important to individualize treatment strategies. Several studies have evaluated the effects of candidate genetic variants in the complex pathway of genes involved in methotrexate pharmacodynamics and pharmacokinetics, however, results are still contrasting and no definitive genetic marker of methotrexate response useful for the clinician to tailor therapy of children with JIA has been identified. Recently, genome-wide approaches have been applied, identifying new potential biological processes involved in methotrexate response in JIA such as TGF-beta signaling and calcium channels. If these genomic results are properly validated and integrated with innovative analyses comprising deep sequencing, epigenetics, and pharmacokinetics, they will greatly contribute to personalize therapy with methotrexate in children with JIA.

VL - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25852556?dopt=Abstract ER - TY - JOUR T1 - Fasting increases tobramycin oral absorption in mice. JF - Antimicrob Agents Chemother Y1 - 2010 A1 - De Leo, Luigina A1 - Di Toro, Nicola A1 - Decorti, Giuliana A1 - Malusà, Noelia A1 - Ventura, Alessandro A1 - Not, Tarcisio KW - Administration, Oral KW - Animals KW - Anti-Bacterial Agents KW - Biological Availability KW - Fasting KW - Injections, Intramuscular KW - Injections, Intravenous KW - Intestinal Absorption KW - Lactulose KW - Male KW - Mice KW - Mice, Inbred BALB C KW - Rhamnose KW - Tobramycin AB -

The pharmacokinetics of the aminoglycoside tobramycin was evaluated after oral administration to fed or fasting (15 h) mice. As expected, under normal feeding conditions, oral absorption was negligible; however, fasting induced a dramatic increase in tobramycin bioavailability. The dual-sugar test with lactulose and l-rhamnose confirmed increased small bowel permeability via the paracellular route in fasting animals. When experiments aimed at increasing the oral bioavailability of hydrophilic compounds are performed, timing of fasting should be extremely accurate.

VL - 54 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20086144?dopt=Abstract ER - TY - JOUR T1 - Usefulness of the measurement of azathioprine metabolites in the assessment of non-adherence. JF - J Crohns Colitis Y1 - 2010 A1 - Stocco, Gabriele A1 - Londero, Margherita A1 - Campanozzi, Angelo A1 - Martelossi, Stefano A1 - Marino, Sara A1 - Malusà, Noelia A1 - Bartoli, Fiora A1 - Decorti, Giuliana A1 - Ventura, Alessandro KW - 6-Mercaptopurine KW - Adolescent KW - Azathioprine KW - Child KW - Child, Preschool KW - Female KW - Guanine Nucleotides KW - Hepatitis, Autoimmune KW - Humans KW - Immunosuppressive Agents KW - Inflammatory Bowel Diseases KW - Male KW - Medication Adherence KW - Thionucleotides KW - Young Adult AB -

Azathioprine is a thiopurine immunosuppressive antimetabolite used to chronically treat inflammatory bowel disease and autoimmune hepatitis. Azathioprine treatment is a long-term therapy and therefore it is at risk for non-adherence, which is considered an important determinant of treatment inefficacy. Measurement of 6-thioguanine and 6-methylmercaptopurine nucleotides has been recently suggested as a screener for non-adherence detection. We describe four young patients in which non-adherence to azathioprine therapy was detected only through the measurement of drug metabolite concentrations, and the criterion for non-adherence was undetectable metabolite levels. After the identification of non-adherence, patients and their families were approached and the importance of a correct drug administration was thoroughly enlightened and discussed; this allowed obtaining a full remission in all subjects. Our observations support the use of undetectable metabolite levels as indicators of non-adherence to therapy in azathioprine treated patients. The additional level of medical supervision given by this assay allows getting a better adherence to medical treatment, which results in an improvement in the response to therapy; these benefits may justify the costs associated with the assay.

VL - 4 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21122567?dopt=Abstract ER -