Chemotherapy of Chagas’ disease: the how and the why

Current developments in experimental chemotherapy of Chagas’ disease are reviewed, in particular the demonstration that fourth-generation azole derivatives (inhibitors of sterol C14α demethylase), with particular selectivity against Trypanosoma cruzi and special pharmacokinetic properties, are capable of inducing radical parasitological cures in murine models of both acute and chronic disease. These are the first reports of parasitological cure of this disease in its chronic phase. We also discuss the relevance of etiological treatment in the clinical outcome of patients with chronic Chagas’ disease. Although previous studies have suggested an important autoimmune component in the pathogenesis of this disease, recent results obtained using highly sensitive polymerase chain reaction based detection methods and detailed immunological characterization of the inflammatory process associated with chagasic cardiomyopathy indicate a positive correlation between tissue parasitism and the severity of cardiac pathological findings. Effective antiparasitic treatment can lead to regression of the inflammatory heart lesions and fibrosis in experimental animals and to stop the progression of the disease in humans. Taken together, these findings support the notion that the presence of the parasite is a necessary and sufficient condition for chagasic cardiomyopathy and confirm the importance of specific etiological treatment in the management of chronic chagasic patients. Received: 30 March 1998 / Accepted: 6 November 1998     

Use of the dopamine receptor agonist Mirapex in the treatment of Parkinson’s disease

We present a review of the literature on dopamine receptor agonists along with our own data on the treatment of Parkinson’s disease (PD) with Mirapex, which was used in 30 patients (mean age 61.8 ± 7.7 years, duration of disease 8.4 ± 1.3 years). Mirapex was used at a dose of 3.5 ± 1.1 mg/day on the background of treatment with levodopa preparations. The efficacy of Mirapex was assessed using quantitative scales. Improvements were demonstrated in general state, motor activity, daily activities, and the quality of life. Attention is drawn to a decrease in the severity of motor fluctuations and dyskinesias and in anxiety and depression, and to improvements in cognitive functions. The significance of the combination of the high efficacy and good tolerance of this agent is emphasized. __________ Translated from Zhurnal Nevrologii i Psikhiatrii imeni S. S. Korsakova, Vol. 106, No. 6, pp. 26–33, June, 2006.     

Vedolizumab for the treatment of Crohn’s disease

Introduction: Crohn’s disease (CD) is an immune-mediated condition characterized by inflammation of the gut tissue, associated with progressive damage of the affected intestinal tract and possible complications. A treat-to-target approach is strongly advocated, consisting of early and aggressive inflammatory control. However, a great proportion of affected subjects lack response or are intolerant to conventional therapy. Even though the first-line biologic therapy targeting tumor necrosis factor-alfa (TNF-α) is associated with improvement of inflammation in some patients, others do not respond at first or lose response over time. These findings brought about the possibility of different mechanisms being involved in perpetuating the chronic inflammatory state. Novel drugs targeting different inflammatory pathways have been studied in CD, specifically addressed to leucocyte trafficking.

Areas covered: We aim to review the relevant data available in the literature and briefly summarize the efficacy and safety profile of vedolizumab in the treatment of CD.

Expert commentary: Vedolizumab has shown, from pivotal and real-life data, significant clinical benefit among CD patients, in addition to a singular safety profile. Future studies will provide helpful data concerning its use in special situations.     

Natalizumab for the treatment of Crohn’s disease

Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disorder characterized by immune-mediated destruction of the salivary and lacrimal glands with unknown etiology. Due to recent research utilizing human subjects as well as laboratory animal models, our understanding of the pathophysiological and immunological mechanisms of pSS has made great strides. As a consequence, targeted, immune-based therapies are gaining increased attention as the ideal way to conquer autoimmune diseases like pSS. Currently, however, there is no effective treatment to target specific immunological events or effector immune cells in the pathogenesis of pSS (discussed in other reviews of the current issue). Here, we summarize our current understanding and knowledge of the roles of monocytes/macrophages in the pathogenesis of pSS. Human studies, especially utilizing salivary gland biopsies, demonstrate the infiltration of macrophages and its correlation with disease severity. Moreover, animal model studies have shown the functional involvement of macrophages in promoting the ocular component of pSS.     

Coaxil (tianeptine) in the treatment of depression in Parkinson’s disease

An open, non-comparative clinical study was performed to assess the efficacy and safety of tianeptine (Coaxil) in Parkinson’s disease (PD). A total of 18 patients with PD were used whose clinical state increased moderately severe and more profound depression (assessed on the Hamilton and Beck scales). After three months of treatment, depression on the Hamilton depression scale was decreased by 34% and on the Beck scale by 31% compared with baseline data (_p < 0.05). Improvements in mental status were noted in 14 of 18 patients (77%); eight patients (44%) showed more than 50% reductions on the Hamilton scale. Analysis of the structure of depressive symptomatology showed that improvement occurred because of decreases in anxiety and the severity of somatoform symptoms and, to a lesser extent, in melancholy and sleep disturbance. There was no significant change in apathy. The decrease in the severity of depression was accompanied by an improvement in the quality of life. The efficacy of Coaxil was greater in patients with less marked depressive and motor symptoms, shorter durations of illness, and less marked cognitive impairments. Coaxil was well tolerated by the patients. The data obtained here provide grounds for recommending the use of Coaxil in the treatment of depression in PD. __________ Translated from Zhurnal Nevrologii i Psikhiatrii imeni S. S. Korsakova, Vol. 106, No. 3, pp. 20–25, March, 2006.     

Capillary damage in skeletal muscle in advanced Chagas’ disease patients

The damage to skeletal muscle capillaries in advanced Chagas disease (stages II and III) was investigated in the vastus lateralis muscle of six patients and compared to that of six normal subjects. Capillaries were visualized by the PAS-amylase reaction and muscle fibres were classified by the ATPase histochemical method. Transmission electron microscopy was used to look for capillary alterations. The capillary-to-fibre ratio and number of capillaries adjacent to type I and type IIa fibres were decreased in the patient group. At the ultrastructural level, all patients showed capillary abnormalities, mainly basement membrane thickening and reduplication, capillary occlusion, proliferative endothelial cell cytoplasm with dense bodies, large vacuoles, altered mitochondria and prominent rough endoplasmic reticulum, as well as pericyte abnormalities. Capillary alterations are similar to those in patients affected by autoimmune diseases, suggesting an autoimmune component in the chronic phase of this disease. The reduction in capillarity may contribute to altered muscle performance in these patients.     

Solanezumab for the treatment of mild-to-moderate Alzheimer’s disease

The Australian Asthma Conference provided a timely forum for rethinking research priorities and strategies at a time when the Australian government is undertaking major national health policy reviews. Until now, asthma has been a national health priority in Australia, and at the conclusion of the conference, delegates issued a strong statement in support of asthma continuing to be a national health priority in Australia.     

Anakinra for the treatment of adult-onset Still’s disease

ABSTRACT

Introduction: Adult onset Still’s disease (AOSD) is an uncommon systemic inflammatory disease on the clinical spectrum of autoinflammatory disorders. Its presentation and clinical course may result in several well-differentiated phenotypes: from a systemic and highly symptomatic pattern to a chronic articular pattern. Overproduction of numerous pro-inflammatory cytokines is observed in AOSD. Anakinra (ANK), a human interleukin (IL)-1R antagonist, has recently been approved in the EU for the treatment of AOSD.

Areas covered: In this review, we discuss the main studies on the efficacy and safety on ANK for the treatment of AOSD. The vast majority of them are retrospective studies and case series.

Expert commentary: Overall, ANK is an effective biologic agent for the treatment of AOSD, especially for the systemic pattern and also for those patients who have life-threatening complications, which frequently occur over the course of the disease. The initial dose usually indicated of ANK in adults is 100 mg/day subcutaneously, although dose reduction can be performed in some cases once the disease is under control. The safety profile of ANK is favorable and similar to that described in other rheumatic diseases. In conclusion, ANK is an effective and safe agent for the treatment of AOSD.     

Adalimumab for the treatment of pediatric Crohn’s disease

Inflammatory bowel diseases are characterized by a chronic relapsing course, high morbidity and impaired quality of life. Their incidence is rising, and about 25% of cases are diagnosed in pediatric age. Anti-TNF-α antibodies, such as infliximab and adalimumab (ADA), are usually administered in patients refractory to conventional therapies. However, increasing evidence suggests that they can be introduced earlier in the course of the disease, especially in patients with aggressive and extensive disease since diagnosis. ADA is a fully human anti-TNF-α antibody recently approved for pediatric Crohn’s disease not only in patients unresponsive to infliximab, but also as a first-line anti-TNF-α therapy. In this review, we aim to summarize the current knowledge on the use of ADA in pediatric Crohn’s disease and to discuss open issues regarding safety as well as future perspectives.     

Certolizumab pegol for the treatment of Crohn’s disease

Certolizumab pegol is a polyethylene glycolated FAb’ fragment of a humanized anti-TNF-α monoclonal antibody. This pegylated molecule binds with circulating TNF-α and forms an inactive complex that is then eliminated from the body. The drug has been shown to be better than placebo in the treatment of Crohn’s disease and maintaining a clinical response in adult patients with moderate-to-severe active disease who have had an inadequate response to conventional therapy, and the treatment of adults with moderately to severely active rheumatoid arthritis. Comparative trials with an active control group are lacking. The most common adverse reactions include abdominal pain, diarrhea, injection site reactions and infection. All necessary live and attenuated vaccines should be given prior to the initiation of certolizumab pegol therapy, patients should be evaluated for TB risk factors and tested for latent TB prior to initiating therapy, and the initiation of therapy should be avoided if the patient has an active infection. Concomitant use with anakinra is not recommended because of the increased risk of serious infections and neutropenia. Therapy should be discontinued if the patient develops a serious infection during therapy.     

Protection of vascular endothelium by aspirin in a murine model of chronic Chagas’ disease

Chronic Chagas’ disease affects 10–30 % of patients infected with Trypanosoma cruzi, and it mainly manifests as cardiomyopathy. Important pathophysiological mechanisms involved in the cardiac lesions include activation of the endothelium and induced microvascular alterations. These processes involve the production of endothelial adhesion molecules and thromboxane A₂, which are involved in inflammatory cell recruitment and platelet aggregation, respectively. Cyclooxygenase inhibitors such as aspirin decrease thromboxane production and alter the course of Chagas’ disease, both in the acute and chronic phases. We studied the effects of the administration of low and high doses of aspirin during the early phase of T. cruzi infection, following microvascular damage in the context of a chronic murine model of Chagas’ disease. The effects of both schedules were assessed at 24 and 90 days postinfection by evaluating parasitemia, mortality, and cardiac histopathological changes as well as the expression of ICAM, VCAM, and E-selectin in cardiac tissue. Thromboxane A₂, soluble ICAM, and E-selectin blood levels were also measured. While aspirin did not affect parasitemia or mortality in the infected mice, it decreased both cardiac inflammatory infiltrates and thromboxane levels. Additionally, at 90 days postinfection, aspirin normalized sICAM and sE-selectin levels. Considering the improved endothelial function induced by aspirin, we propose the possibility of including this drug in clinical therapy to treat chronic Chagas’ disease.     

Patients’ perception of their involvement in shared treatment decision making: Key factors in the treatment of inflammatory bowel disease

Objectives

This study aims to characterize the relationships between the quality of the information given by the physician, the involvement of the patient in shared decision making (SDM), and outcomes in terms of satisfaction and anxiety pertaining to the treatment of inflammatory bowel disease (IBD).

Nutritional therapy for the treatment of pediatric Crohn’s disease

Crohn’s disease and ulcerative colitis are lifelong conditions with particular effects upon nutrition, especially in children and adolescents. Various therapies are available for these conditions but there remains no cure. Over the last decades, exclusive enteral nutrition (EEN) has been demonstrated to have efficacy in the induction of remission, along with numerous other nutritional and inflammatory benefits. This article reviews the benefits and outcomes associated with EEN in Crohn’s disease. The potential mechanisms of this therapy are highlighted, along with factors that are barriers to the wider use of EEN.     

Systemic corticosteroid treatment in Peyronie’s disease

Peyronie’s disease is characterized by penile pain, plaque or indurated area in the tunica albugenia and penile curvature during erection. Peyronie’s disease is a chronic and progressive inflammatory disease. Intralesional corticosteroids have been studied in the treatment of Peyronie’s disease due to its inflammatory pathogenesis but hardness of the penile plaque hinders the effective injection and activity of the compound and leads to local side effects. Corticosteroids are the most effective therapy for many inflammatory disorders and systemic use has not been studied in Peyronie’s disease. Oral corticosteroids may decrease the pain, improve the penile curvature, reduce the plaque size, and inhibit the formation of fibrosis particularly in the acute inflammatory phase.     

Expression of cytokines and chemokines and microvasculature alterations of the tongue from patients with chronic Chagas’ disease

Chagas’ disease is caused by the protozoan Trypanosoma cruzi and continues to be a significant public health problem, since 10 million people are still infected in Latin America. The purpose of this study was to analyze the microvasculature alterations as well the expression of cytokines and chemokines in the tongues from patients with chronic Chagas’ disease (CC; n = 18), comparatively with a non-chagasic group (NC; n = 22). We observed several vascular alterations in the tongue of CC such as a greater vascular diameter, increased vascular wall area, high density of the blood vessels, and increased thickening of the capillary basement membrane. The expression of cytokines interferon gamma and tumor necrosis factor alpha and chemokine macrophage inflammatory protein 1α were significantly down-regulated in the tongue of CC group. These results demonstrated that, in the tongue of chagasic patients, a microvascular abnormality and immunological impairment occurs, probably due to chronic inflammation evoked by T. cruzi antigens.     

Important considerations in the management of Graves’ disease in pregnant women

Graves’ disease is an autoimmune disorder in which autoantibodies to the thyroid-stimulating hormone receptor cause hyperthyroidism through unregulated stimulation of the thyroid-stimulating hormone receptor. Effective management of Graves’ disease in pregnancy must address the competing fetal and maternal priorities of controlling hyperthyroidism in the mother on the one hand, and on the other, minimizing the impact of maternal disease and antithyroid drugs on the well-being of the fetus. Optimal strategies for achieving this intricate balance are currently a source of continued debate among thyroid experts and studies in recent decades are now providing greater clarity into the risk posed to the unborn baby by the combination of biochemical, immunological and pharmacological hazards arising from Graves’ disease and its therapy. This review summarizes the current best practice and highlights important considerations and areas of uncertainty in the management of Graves’ disease in pregnant women.     

Environmental risk factors in the incidence of Johne’s disease

Abstract

This review addresses the survival and persistence of Mycobacterium avium subsp. paratuberculosis (MAP), the causative pathogen of Johne’s disease (JD), once it has left its ruminant host. JD has significant economic impact on dairy, beef and sheep industries and is difficult to control due to the long-term sub-clinical nature of the infection, intermittent or persistent MAP shedding during and after this period, inadequate test effectiveness, and the potential for MAP to exist for extended periods outside the host. The role that environmental factors play in the persistence and spread of MAP and consequent disease is assessed. Published risk factor analysis, organism survival across various environmental media and conditions, presence and spread in ruminant and non-ruminant wildlife, and the general potential for survival and multiplication of MAP ex-host both on and off-farm are discussed and knowledge gaps highlighted. An inclusive approach to disease management that takes into account the persistence and transport of the causative organism in on-farm soils and waters, land use and management, dispersal by domestic and non-domestic host species, as well as general animal husbandry is required on those farms where more traditional approaches to disease management have failed to reduce disease prevalence.