Adherence to guidelines and the Screening Tool of Older Persons' potentially inappropriate Prescriptions criteria for colchicine dosing for gout treatment in beneficiaries of the Nova Scotia Seniors' Pharmacare Program Clinical Therapeutics

Purpose: Colchicine is commonly used in the management of gout; however, older persons have higher risks of toxicity. Accordingly, the Screening Tool of Older Person’s potentially inappropriate Prescriptions (STOPP) criteria for colchicine consider 43 months of treatment as potentially inappropriate in older persons. Recent evidence also suggests lower dosing of colchicine is as effective and results in fewer toxicities than high-dose colchicine. The objectives of this study were to determine the dose, duration, and prescribers of colchicine and to evaluate adherence to the STOPP criteria and international guidelines for colchicine in older persons. Methods: A retrospective, observational study was conducted from April 1, 2006 to March 31, 2011 to evaluate colchicine use. Nova Scotia Seniors’ Pharmacare Program beneficiaries who met inclusion criteria for an incident case of gout and who filled at least 1prescription for colchicine during the study period were included. Colchicine dose and duration were reported descriptively. Multivariate logistic regression was used to identify predictors of the study population in making a claim for colchicine 490 and 4180 days. Findings: A total of 518 persons were dispensed 1327 courses of colchicine during the study period. The mean daily dose of colchicine ranged from 1.39 to 1.50 mg. Colchicine doses 41.2 mg were prescribed in approximately one-third of the study population. Colchicine was prescribed for 490 days in 14.2% of treatment courses and for 4180 days in 8.1% of treatment courses. Female sex was the only predictor of treatment duration 490 days. Implications: This study is the first to report on colchicine dose and duration using STOPP criteria in a specific cohort of older persons with incident gout. Strategies to improve colchicine prescribing in older persons are needed

DAPSONE AS AN ALTERNATIVE THERAPY IN CHILDREN WITH FAMILIAL MEDITERRANEAN FEVER

Objective: Familial Mediterranan Fever is an hereditary autoinflammatory disease that presents with recurrent febrile attacks and poly serositis. Colchicine is the only known treatment in this diease. However, nearly 5-10% of patients are resistant to colchicines. There are many different modalities in colchicine resistant patients, biologic and immunosupressive drugs being the known ones. We studied the efficacy of Dapsone as an anti inflammatory drug in children with FMF who did not tolerate colchicine well. Methods: This is a case series study in 10 patients who had FMF on the base of Tel-Hashomer criteria and did not tolerate colchicine or did not respond to it well. Patients took 2mg/kg dapsone in single dose, during 6 months. Findings In four patients episodic attacks returned after 27 days, so the drug was discontinued. One patient refused to continue the study; in five patients dapsone was taken in average for 8 months and 6 days, at least for 6 months. These five patients had no episodes of attack during the following observation. Conclusion: Dapsone could control episodic attacks of FMF in 50% of cases. It might be considered as an alternative therapy in FMF cases not responding to colchicine

The inflammatory process of gout and its treatment.

Gouty arthritis is a characteristically intense acute inflammatory reaction that erupts in response to articular deposits of monosodium urate (MSU) crystals. Important recent molecular biologic advances in this field have given us a clear picture of the mechanistic basis of gouty inflammation. The innate immune inflammatory response is critically involved in the pathology of gout. Specifically, MSU crystals promote inflammation directly by stimulating cells via Toll-like receptor signaling and by providing a surface for cleavage of C5 and formation of complement membrane attack complex (C5b-9), culminating in secretion of cytokines, chemokines, and other inflammatory mediators with a dramatic influx of neutrophils into the joint. Despite the detailed mechanistic picture for gouty inflammation, there are no placebo-controlled, randomized clinical studies for any of the therapies commonly used, although comparative studies have demonstrated that many nonsteroidal anti-inflammatory drugs are equivalent to indomethacin with respect to controlling acute gouty attacks. In general, the first line of anti-inflammatory therapy for acute gout is nonsteroidal anti-inflammatory drugs, and the selective cyclo-oxygenase-2 inhibitor celecoxib can be used where appropriate. The second line of treatment is glucocorticosteroids, given systemically (oral, intravenous, or intramuscular) or intra-articularly. Alternatively, synthetic adrenocorticotropic hormone is effective, partly via induction of adrenal glucocorticosteroids and partly via rapid peripheral suppression of leukocyte activation by melatonin receptor 3 signaling. The third line of treatment is oral colchicine, which is highly effective when given early in an acute gouty attack, but it is poorly tolerated because of predictable gastrointestinal side effects

Colchicine therapy in acute coronary syndrome patients acts on caspase-1 to suppress NLRP3 inflammasome monocyte activation

Inflammasome activation, with subsequent release of pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18, has recently been implicated in atherosclerosis-associated inflammation. This study aims to assess in acute coronary syndrome (ACS) patients (1) inflammasome activation in circulating monocytes and (2) whether short-term oral colchicine, a recognized anti-inflammatory agent that has been shown to be cardio-protective in clinical studies, might acutely suppress inflammasome-dependent inflammation. ACS patients (n=21) were randomized to oral colchicine (1 mg followed by 0.5 mg 1 h later) or no treatment, and compared with untreated healthy controls (n=9). Peripheral venous blood was sampled pre- (day 1) and 24 h post- (day 2) treatment. Monocytes were cultured and stimulated with ATP. Analysis of key inflammasome markers was performed by ELISA. IL-1β secretion increased by 580.4% (P<0.01) in ACS patients compared with controls but only with ATP stimulation. Untreated ACS patients secreted significantly higher levels of IL-18 compared with healthy controls independent of ATP stimulation (P<0.05). Colchicine treatment in ACS patients markedly reduced intracellular and secreted levels of IL-1β compared with pre-treatment levels (P<0.05 for both), as well as significantly reducing pro-caspase-1 mRNA levels by 57.7% and secreted caspase-1 protein levels by 30.2% compared with untreated patients (P<0.05 for both). Monocytes from ACS patients are ‘primed’ to secrete inflammasome-related cytokines and short-term colchicine acutely and markedly suppresses monocyte caspase-1 activity, thereby reducing monocyte secretion of IL-1β

Gout

INTRODUCTION: Gout affects about 5% of men and 1% of women, with up to 80% of people experiencing a recurrent attack within 3 years. METHODS AND OUTCOMES:We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for acute gout? What are the effects of treatments to prevent gout in people with prior acute episodes? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 21 systematic reviews, RCTs, or observational studies that met our inclusion criteria.We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: colchicine, corticosteroids, corticotrophin (ACTH), non-steroidal anti-inflammatory drugs (NSAIDs), sulfinpyrazone, xanthine oxidase inhibitors, advice to lose weight, advice to reduce alcohol intake, advice to reduce dietary intake of purines

Formation of viable cell fragments by treatment with colchicine

Time-lapse cinematography of human fibroblasts revealed that mitotic cells separated into numerous cell fragments containing varying amounts of chromatin and cytoplasm when treated with colchicine. As cell fragments were very loosely attached to the surface of the culture vessel during their formation, they could be easily detached like mitotic cells by gently shaking the vessel and thus separated from normal interphase cells. Fragments obtained by this procedure were able to exclude trypan blue indicating, therefore, an intact cell membrane. When placed into Petri dishes many of them attached to and even spread out on the surface. Five hours later the majority of the attached fragments incorporated [3H]leucine. Time-lapse films showed that fragments were able to extend and retract pseudopodia at least for several hours after their formation. Although the fragments degenerated within a few days, in the present experiments the possibility was not excluded that fragments which had lost only a very small amount of chromatin and cytoplasm survived for longer periods of time. The observations clearly indicate viability of many newly formed fragments

Gouty arthritis of the spine in a renal transplant patient : a clinical case report: an unusual presentation of a common disease

Axial gout is a well-documented but uncommon manifestation of gout. Its mimicking nature and the impracticality of axial joint aspiration might considerably delay its diagnosis. We report a case in a normouricemic renal transplant recipient, whereby the primary symptom of severe neck pain suggested pyogenic spondylodiscitis as an initial tentative diagnosis. Clinical findings included a high C-reactive protein concentration and elevated body temperature. The patient did not respond to empiric antibiotic treatment and suffered consecutive attacks of severe wrist and ankle pain in conjunction with a persistent fever. Blood and joint cultures were negative, but analysis of aspirated ankle joint fluid revealed monosodium urate crystals. A dual-energy computed tomography scan confirmed the presence of monosodium urate crystals in the costovertebral joints. Colchicine treatment dramatically improved the patient's clinical condition. Axial gout should be considered in transplant recipients with severe neck or back pain, fever, and increased inflammatory parameters with a high likelihood of an infectious etiology, despite the presence of paradoxically normal or even decreased serum urate concentrations. Dual-energy computed tomography is a noninvasive technique of possible benefit in the detection of axial gout when joint fluid aspiration is not deemed safe

Actin-dependent cell elongation in teleost retinal rods: requirement for actin filament assembly.

Teleost retinal rods elongate when exposed to light. Elongation is mediated by a narrow necklike region called the myoid. In the cichlid Sarotherodon mossambicus, the rod inner segment (composed of the myoid with adjacent ellipsoid) increases in length from 12 micrometers in the dark to 41 micrometers in the light. Long light-adapted myoids contain longitudinally oriented microtubules and bundles of parallel 60-A filaments that we have identified as actin by their ability to bind myosin subfragment 1. In short dark-adapted myoids, only microtubules are recognizable. Colchicine experiments reveal that light-induced rod elongation can occur in the absence of myoid microtubules. Intraocular injections of colchicine at concentrations that disrupt virtually all rod myoid microtubules do not block rod elongation. However, rod elongation is blocked by intraocular injections of cytochalasin B or cytochalasin D. The hierarchy of effectiveness of these drugs is consistent with their effectiveness in inhibiting actin assembly and in disrupting other actin-dependent motile processes. On the basis of ultrastructural observations and the results of these inhibitor studies, we propose that the forces responsible for rod elongation are dependent not on microtubules but on actin filament assembly

Genetic variability of anther donor versus spontaneous doubled haploid descendents and colchicine induced doubled haploid sweet pepper (Capsicum annuum L.) lines

Haploid (n) and doubled haploid (DH) plants were developed in anther culture of sweet pepper (Capsicum annuum L.). Regenerants were analyzed by flow cytometry for haploid (n = 12) and spontaneous doubled haploid (2n = 24) genomes. Haploid plants were forwarded to colchicine-treatment for induced doubled haploid (2n·) plant production. Molecular polymorphism of anther donor plants (2n), the haploid regenerants (n), the spontaneous (2n) and induced (2n·)-DH plants were analysed by RAPD-, SSR- and ISSR-PCR. The analysis of anther-donor plants compared to DH-descendents showed an unexpectedly wide range of molecular polymorphism. Our results suggest that genetic changes occurring during meiotic recombination is higher than those of occurring during colchicine-induced genomic duplication