A prospective study of incidence of medication-related problems in general medicine ward of a tertiary care hospital

The study is aimed to assess the incidence of drug-related problems (DRPs) and provide pharmacist interventions for identified DRPs. A prospective, observational study was conducted among 189 patients with cardiovascular disease who were aged 18 years or older and admitted to the general medicine in-patient ward. During the 6 months study period, the incidence of DRPs was identified using Pharmaceutical Care Network Europe Foundation classification system version 6.2. A total of 189 patients were screened for DRPs. Among them, 130 patients have at least one DRP. A total of 416 DRPs were identified (on average, 2.2 DRPs per each patient). Of the 416 DRPs, 125 (30.04%) interventions were accepted, 7 (1.68%) interventions were not accepted, while remaining (68.26%) accepted but no action taken. The results of the study indicate that incidence of DRPs is substantial and pharmacist-led interventions resulted in resolution of DRPs. This represents the need for the active role of the clinical pharmacist in the developing countries like India

Critical assessment of thioguanine treatment for inflammatory bowel diseases: Is it time to rehabilitate this treatment?

OBJECTIVE: The potential therapeutic effect of thioguanine in the management of inflammatory bowel disease (IBD) is hindered due to association with vascular hepatotoxicity. The study aimed to assess the evidence for efficacy of thioguanine in IBD management and the association with nodular regenerative hyperplasia (NRH) and other thioguanine-related hepatotoxicities. METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used for literature search. Due to the lack of randomized controlled trials (RCTs), the search was extended to observational studies. Quality of the included studies were graded A to C based on evaluation tools used to determine efficacy (subjective and objective grading tools) and nodular regenerative hyperplasia safety (liver biopsy and imaging tools). RESULTS: Two hundred and ninety studies were identified, but following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines only 13 studies were evaluated for efficacy and safety of thioguanine. Outcome measures were consistent across the included studies. Thioguanine appeared efficacious and well-tolerated in patients who were intolerant/non-responsive to existing immunomodulators. There was a trend toward a positive association between dose of thioguanine and NRH but not with other adverse events such as liver biochemical abnormalities or with portal hypertension. CONCLUSIONS: The evidence to support thioguanine treatment is limited to observational studies. While encouraging, there is a need for prospective RCTs to determine the role of thioguanine in the management of IBD

Colonic thioguanine pro-drug: investigation of microbiome and novel host metabolism

Thiopurines are analogues of endogenous purines. They are pro-drugs which require the purine salvage pathway to convert them to the active drug nucleotides (TGN). These drugs are used to maintain clinical remission in patients with inflammatory bowel diseases. In our recent Gut paper, we showed that thioguanine worked quickly to improve colitis in the absence in the host animal of the key guanine salvage enzyme, hypoxanthine-guanine-phosphoribosyltransferase (HPRT). Current evidence favours the proposition that active drug delivery to the host lacking HPRT requires translocation of TGN-loaded bacteria across the inflamed mucosal barrier, and most likely delivery by phagocytosis. Alternatively, the efficacy of thioguanine in treating colitis could be mediated by modulation of the community of the microbiota in the intestine, or there are novel host pathways for conversion of the thioguanine pro-drug to TGN

Microbial metabolism of thiopurines: a method to measure thioguanine nucleotides

Thiopurines are anti-inflammatory prodrugs. We hypothesised that bacteria may contribute to conversion to active drug. Escherichia coli strain DH5α was evaluated to determine whether it could metabolise the thiopurine drugs, thioguanine or mercaptopurine, to thioguanine nucleotides. A rapid and reliable high performance liquid chromatography (ultraviolet detection) method was developed to quantify indirectly thioguanine nucleotides, by measuring thioguanine nucleoside

A nucleotide analog prevents colitis associated cancer via Β-catenin independently of inflammation and autophagy

Chronic bowel inflammation increases the risk of colon cancer: colitis associated cancer (CAC). Thiopurine use is associated with a reduction in dysplasia and CAC in inflammatory bowel disease (IBD). Abnormal Wnt/β-catenin signalling is characteristic of >90% of colorectal cancers. Immunosuppression by thiopurines is via Rac1 GTPase, which also affects Wnt/β-catenin signalling. Autophagy is implicated in colonic tumours, and topical delivery of the thiopurine thioguanine (TG) is known to alleviate colitis and augment autophagy. This study investigated the effects of TG in a murine model of CAC and potential mechanisms.Colonic dysplasia was induced by exposure to azoxymethane (AOM) and dextran sodium sulfate (DSS) in wild-type (WT) mice and mice harbouring intestinal epithelial cell (IEC)-specific deletion of autophagy related 7 gene (Atg7). TG or vehicle were administered intrarectally, and the effect on tumour burden and β-catenin activity assessed. The mechanisms of action of TG were investigated in vitro and in vivo.TG ameliorated DSS colitis in wild type (WT) but not Atg7 mice, demonstrating that anti-inflammatory effects of locally delivered TG are autophagy-dependent. However, TG inhibited CAC in both WT and Atg7 mice. This was associated with decreased β-catenin activation/nuclear translocation demonstrating that TG's inhibition of tumorigenesis occurred independently of anti-inflammatory and pro-autophagic actions. These results were confirmed in cell lines and the dependency on Rac1 GTPase demonstrated by siRNA knock-down and overexpression of constitutively active Rac1.Our findings provide evidence for a new mechanism that could be exploited to improve CAC chemoprophylactic approaches