In May 2008, the Department of Health and Human Services announced the launch of the Sentinel Initiative by the US Food and Drug Administration (FDA) to create the Sentinel System, a national electronic system for medical product safety surveillance. This system complements existing FDA surveillance capabilities that track adverse events reported after the use of FDA regulated products by allowing the FDA to proactively assess the safety of these products.

Summary Background:  Thioguanine nucleotides (TGNs) are the active product of thiopurine metabolism. Levels have been correlated with effective clinical response. Nonetheless, the value of TGN monitoring in clinical practice is debated. We report the influence of introducing TGN monitoring into a large adult inflammatory bowel disease (IBD) clinic. Patients and methods:  Patients with IBD undergoing TGN monitoring were identified from Purine Research Laboratory records. Whole blood TGNs and methylated mercaptopurine nucleotides were hydrolysed to the base and measured using HPLC. Clinical and laboratory data were obtained retrospectively. Results:  One hundred and eighty‐nine patients with 608 available TGN results were identified. In non‐responders, TGNs directed treatment change in 39/53 patients. When treatment was changed as directed by TGN, 18/20 (90%) improved vs. 7/21 (33%) where the treatment decision was not TGN‐directed, p < 0.001. Where treatment change was directed at optimisation of thiopurine therapy, 14/20 achieved steroid‐free remission at 6 months vs. 3/10 where the TGN was ignored, (p = 0.037). Six per cent of patients were non‐adherent, 25% under‐dosed and 29% over‐dosed by TGN. Twelve per cent of patients predominantly methylated thiopurines, this group had low TGN levels and high risk of hepatotoxicity. In responders, adherence and dosing issues were identified and TGN‐guided dose‐reduction was possible without precipitating relapse. Mean cell volume (MCV), white blood cell count (WBC) and lymphocyte counts were not adequate surrogate markers. MCV/WBC ratio correlated with clinical response, but was less useful than TGN for guiding clinical decisions. Conclusions:  Monitoring TGNs enables thiopurine therapy to be optimised and individualised, guiding effective treatment decisions and improving clinical outcomes.

One hundred thirty-eight patients with hairy cell leukemia were randomized to receive either a dose of 2.0 megaunits (MU)/m2 or a 10- fold lower dose of 0.2 MU/m2 of a highly purified natural alpha- interferon, administered daily for 28 days followed by a three times a week schedule. Ninety-seven of these patients had previously undergone splenectomy, but otherwise none of the patients had received prior therapy for their leukemia. The two doses were comparable in their effect on improving the neutrophil and platelet count, whereas the higher dose had a greater beneficial effect on the hemoglobin level and a greater antileukemic effect on the marrow. Acute toxicity in the form of a flu-like syndrome, neurologic side effects, neutropenia, and the need for platelet transfusions was observed less frequently in the low- dose group, as was the chronic fatigue syndrome. No neutralizing antibody activity was seen in the sera from 61 patients examined. Because of its beneficial effect on the neutrophil and platelet count and a lower degree of toxicity (ie, a superior therapeutic/toxicity ratio), the low dose is recommended as initial therapy in patients with hairy cell leukemia. This therapy may be followed by dose escalation once clinical improvement is observed.

IntroductionDietary restriction of fermentable oligo-, di-, mono -saccharides and polyols (low FODMAP diet, LFD) is widely used for the management of irritable bowel syndrome (IBS), however it reduces gastrointestinal (GI) bifidobacteria. B-galacto-oligosaccharide (B-GOS; HOST-G904) are prebiotics that reduce symptoms and increase bifidobacteria in IBS however the combination of the two therapies has not previously been investigated.MethodThis randomised controlled trial aimed to investigate whether: 1) IBS symptoms improved on LFD supplemented with B-GOS compared to control; and 2) B-GOS could prevent the reduction of GI bifidobacteria seen in patients following the LFD. Adults fulfilling Rome criteria for IBS were screened (n=130). Sixty-nine patients were recruited to a multicentre 3-arm parallel RCT and were randomised to: control (sham diet/placebo), LFD only (LFD/placebo) or LFD plus B-GOS (LFD/B-GOS) for four weeks. Validated questionnaires were used to assess GI symptoms at week 0 and week 4 and a stool sample collected for analysis at week 0, week 1 and week 4. Stool were analysed for bifidobacteria using fluorescent in situ hybridisation, and short-chain fatty acids (SCFA) and pH were measured using gas chromatography and pH probe respectively. Logistic regression, and ANOVA/ANCOVA (with post-hoc correction) were used to determine differences across the three groups.ResultsAt week 4 adequate relief of IBS symptoms differed significantly between control (30.4%), LFD (50%) and LFD/B-GOS (66.7%) (p=0.046), with post-hoc differences specifically between control and LFD/B-GOS (p=0.015). Individual IBS symptoms were more markedly improved in the LFD/B-GOS group compared to control. Bifidobacteria (log10/g dry weight) also differed across the groups (control 9.8, LFD 9.6, LFD/B-GOS 9.5; p=0.009), with post-hoc differences between the LFD/B-GOS and control at week 4 (p=0.009) Higher stool pH, and lower butyrate at week 1 and week 4 were observed in the LFD vs control diet group. Similar differences were observed in the LFD/B-GOS vs control diet group although pH was not higher than control until week 4.ConclusionSymptoms of IBS markedly improved during LFD supplemented with B-GOS prebiotic, suggesting a synergy between the two therapies. The LFD significantly impacts the GI luminal environment within the first seven days and these changes persist with diet restriction, however addition of a low dose prebiotic does not overcome the effect of diet on bifidobacteria.Disclosure of InterestB. Wilson Conflict with: BW is the recipient of a PhD fellowship awarded by Clasado BioSciences., M. Rossi: None Declared, G. Parkes: None Declared, Q. Aziz: None Declared, S. Anderson: None Declared, P. Irving: None Declared, M. Lomer: None Declared, K. Whelan: None Declared

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