Effects of baseline abdominal pain and bloating on response to lubiprostone in patients with irritable bowel syndrome with constipation

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134450/1/apt13807.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134450/2/apt13807_am.pd

International nifedipine trial on anti-atherosclerotic therapy (INTACT) - methodologic implications and results of a coronary angiographic follow-up study using computer-assisted film analysis

Animal experiments demonstrated a significant suppressive effect of various calcium channel blockers on the formation of atherosclerotic lesions. Therefore, a prospective, placebo-controlled, randomized, double blind multicenter study was performed to investigate the inhibitory influence of the calcium channel blocker nifedipine (80 mg/day) on the progression of coronary artery disease in man. Study endpoints were changes of coronary morphology documented by coronary angiography with particular respect to the formation of new coronary stenoses. In 348 out of 425 patients included in the study, coronary angiograms were repeated after three years. The angiograms were standardized by induction of a maximal coronary vasodilation with high doses of nitrates and by using absolutely identical angiographic projections. Quantitative analysis of coronary cineangiograms was performed with the computer-assisted contour detection system CAAS. Parameters were mean and minimal diameter of all segments and minimal stenosis diameter, percent diameter stenosis, length and plaque area of all stenoses. Continuous intake of study medication was registered in 282 patients, 134 on nifedipine and 148 patients on placebo. In these patients, a total of 3808 coronary segments with 893 stenoses (≥ 20% diameter reduction in at least one angiographic projection) were compared on the baseline and follow-up cineangiograms. The changes in all angiographic parameters analyzed averaged over all patients by considering all angiographic projections analyzed, indicated significant progression of the disease (p < 0.006). The average changes in all parameters were even about three times more profound, when in the individual patients only the respective projections indicating the maximal changes were considered for the calculation (p < 0.001). However, with neither of these two analysis modes, the differences in progression between the treatment groups were statistically significant. In the follow-up angiograms, a total of 196 new coronary lesions (185 stenoses, 11 occlusions) were found at previously normal arterial sites. In patients on nifedipine, an average of only 0.58 new lesions per patient were detected versus 0,80 lesions per patient on placebo (-27%; p=0.031). INTACT is the first prospective angiographic trial on the progression of coronary artery disease using computer-assisted quantitative coronary angiography in such a high number of patients. All parameters analyzed indicated significant progression of coronary artery sclerosis. Nifedipine had no influen

The Cost Effectiveness of Lubiprostone in Chronic Idiopathic Constipation

OBJECTIVE: The objective of this study was to evaluate the cost effectiveness of lubiprostone, prucalopride, placebo and immediate referral to secondary care in chronic idiopathic constipation (CIC) in an economic model that was used by the UK National Institute for Health and Care Excellence (NICE) in developing guidance. METHODS: We developed a cohort state-transition model to reflect the treatment pathway in CIC from the UK NHS and personal social services perspective. Time on treatment was determined by a treatment continuation rule using data from an indirect comparison and survival curves fitted to long-term data. Quality of life was defined by whether CIC was resolved or unresolved, using published values. Costs were determined by drug acquisition costs, invasive procedures and healthcare resource use (associated with resolved or unresolved CIC), using published UK sources. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: Over a 10-year time horizon, lubiprostone was more costly and more effective than placebo and immediate referral to secondary care, with incremental cost-effectiveness ratios (ICERs) of £58,979 and £21,152. Lubiprostone dominated prucalopride in the base case and with a time horizon of 1 year. The main sensitivity for the comparison against placebo was the assumptions around placebo cost and efficacy. The main sensitivity for the comparison against prucalopride was the endpoint used in the indirect comparison. CONCLUSION: Lubiprostone may be cost effective compared with prucalopride or immediate referral but not compared with placebo in the base case. The implementation of the guidance issued by NICE should increase quality of life for patients with CIC and provide a further treatment option

Physicians' acquaintance with a new procedure results in higher patient referral: experience of Kosovo in coronary angiography

The first coronary angiography in Kosovo was completed in 2003. We analyzed coronary angiographies performed in our center from October 2003 until October 2009 divided into two 3-year periods. The aims of our study were: to compare the number of coronary angiographies completed in the two periods; to evaluate the prevalence of normal coronary angiographies diagnosed in the first period compared to the second period; and to assess the prevalence of advanced coronary artery disease in the first three years compared to the last three years. This was a prospective angiography study that included 1,139 patients. The first group had 422 patients, who underwent the angiography procedure during the first three years, and the second group had 717 patients that went through the procedure during the last three years. In the first year, 109 coronary angiographies were completed, followed by 137, 176, 213, 218 and 286 (P<0.001) procedures in the subsequent years. In the first period, a normal or near-normal coronary artery profile was found in 27% of patients, while this figure rose to approximately 39% in the second period (P=0.004). Advanced coronary artery disease was found in 45% of the patients who underwent coronary angiography during the first three years, whereas this figure was only 24% of cases during the second period (P<0.001). We believe that the availability of specialized resources and the physicians' familiarity with coronary angiography in our country influenced their decision to refer more patients for this procedure

Chronic Delivery of Antibody Fragments Using Immunoisolated Cell Implants as a Passive Vaccination Tool

BACKGROUND: Monoclonal antibodies and antibody fragments are powerful biotherapeutics for various debilitating diseases. However, high production costs, functional limitations such as inadequate pharmacokinetics and tissue accessibility are the current principal disadvantages for broadening their use in clinic. METHODOLOGY AND PRINCIPAL FINDINGS: We report a novel method for the long-term delivery of antibody fragments. We designed an allogenous immunoisolated implant consisting of polymer encapsulated myoblasts engineered to chronically release scFv antibodies targeted against the N-terminus of the Aβ peptide. Following a 6-month intracerebral therapy we observed a significant reduction of the production and aggregation of the Aβ peptide in the APP23 transgenic mouse model of Alzheimer's disease. In addition, functional assessment showed prevention of behavioral deficits related to anxiety and memory traits. CONCLUSIONS AND SIGNIFICANCE: The chronic local release of antibodies using immunoisolated polymer cell implants represents an alternative passive vaccination strategy in Alzheimer's disease. This novel technique could potentially benefit other diseases presently treated by local and systemic antibody administration

MTF-1-Mediated Repression of the Zinc Transporter Zip10 Is Alleviated by Zinc Restriction

The regulation of cellular zinc uptake is a key process in the overall mechanism governing mammalian zinc homeostasis and how zinc participates in cellular functions. We analyzed the zinc transporters of the Zip family in both the brain and liver of zinc-deficient animals and found a large, significant increase in Zip10 expression. Additionally, Zip10 expression decreased in response to zinc repletion. Moreover, isolated mouse hepatocytes, AML12 hepatocytes, and Neuro 2A cells also respond differentially to zinc availability in vitro. Measurement of Zip10 hnRNA and actinomycin D inhibition studies indicate that Zip10 was transcriptionally regulated by zinc deficiency. Through luciferase promoter constructs and ChIP analysis, binding of MTF-1 to a metal response element located 17 bp downstream of the transcription start site was shown to be necessary for zinc-induced repression of Zip10. Furthermore, zinc-activated MTF-1 causes down-regulation of Zip10 transcription by physically blocking Pol II movement through the gene. Lastly, ZIP10 is localized to the plasma membrane of hepatocytes and neuro 2A cells. Collectively, these results reveal a novel repressive role for MTF-1 in the regulation of the Zip10 zinc transporter expression by pausing Pol II transcription. ZIP10 may have roles in control of zinc homeostasis in specific sites particularly those of the brain and liver. Within that context ZIP10 may act as an important survival mechanism during periods of zinc inadequacy

Zinc homeostasis and signaling in health and diseases: Zinc signaling

The essential trace element zinc (Zn) is widely required in cellular functions, and abnormal Zn homeostasis causes a variety of health problems that include growth retardation, immunodeficiency, hypogonadism, and neuronal and sensory dysfunctions. Zn homeostasis is regulated through Zn transporters, permeable channels, and metallothioneins. Recent studies highlight Zn’s dynamic activity and its role as a signaling mediator. Zn acts as an intracellular signaling molecule, capable of communicating between cells, converting extracellular stimuli to intracellular signals, and controlling intracellular events. We have proposed that intracellular Zn signaling falls into two classes, early and late Zn signaling. This review addresses recent findings regarding Zn signaling and its role in physiological processes and pathogenesis