Thalidomide: A novel therapy for microsporidiosis
Abstract
BACKGROUND & AIMS: Microsporidiosis is a common cause of chronic diarrhea in human immunodeficiency virus (HIV)-seropositive individuals and often does not respond to treatment. Fecal tumor necrosis factor alpha (TNF-alpha) is elevated in microsporidiosis; therefore, thalidomide, an anti-TNF-alpha agent, was used as therapy. METHODS: Eighteen subjects with chronic diarrhea caused by Enterocytozoon bieneusi that had not responded symptomatically to albendazole and 1 untreated subject with Encephalitozoon intestinalis received 1 month of thalidomide, 100 mg nocte. Clinical response was assessed by stool frequency and body weight, histological response by light microscopy with villus height/crypt depth ratios and electron microscopy, and immunologic response by fecal TNF-alpha level. RESULTS: Seven subjects with chronic diarrhea due to E. bieneusi had a complete clinical response, and 3 had a partial response to thalidomide. There was a significant decrease in stool frequency from 5.3 to 3.1 per day (P = 0.001), and weight increased significantly by 1.2 kg (P < 0.02). Thalidomide significantly increased the villus height/crypt depth ratio (1.95 to 2.07; P = 0.045) and number of abnormal forms of microsporidia (P < 0.01). Fecal TNF-alpha level nonsignificantly decreased from 17.9 to 8.9 U/mL. There was apparent disruption of all stages of the life cycle of E. intestinalis. CONCLUSIONS: Thalidomide may be an effective therapy for diarrhea and weight loss from E. bieneusi. (Gastroenterology 1997 Jun;112(6):1823-9)
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Microsporidiosis
2014, Mandell, Douglas, and Bennett's Principles and Practice of Infectious DiseasesMicrosporidiosis: Epidemiology, clinical data and therapy
2010, Gastroenterologie Clinique et BiologiqueMicrosporidiosis is an emerging and opportunistic infection in AIDS patients, organ transplant recipients, children, travelers, contact lens wearers and the elderly. It is associated with a wide range of clinical syndromes of microsporidiosis in humans. The disease is caused by microsporidia, obligate intracellular microorganisms that were recently reclassified from protozoa to fungi. The 14 species of microsporidia currently known to infect humans, Enterocytozoon bieneusi and Encephalitozoon intestinalis, are the most common causes of human infections and are associated with diarrhea and systemic disease. Species of microsporidia infecting humans have been identified in water sources as well as in wild, domestic and food-producing farm animals, raising concerns of water-borne, food-borne and zoonotic transmission. Various molecules have been tested for treating microsporidiosis in humans with variable success. Albendazole is effective against Encephalitozoon species such us Encephalitozoon intestinalis but not against Enterocytozoon bieneusi. This species has shown excellent clinical therapeutic response to direct action with fumagillin, but this drug is toxic when administered systematically to mammals. Its analog, TNP 470, could be promising alternative. Further work is necessary to identify other drugs, which are both effective and devoid of adverse effects.
La microsporidiose est une infection opportuniste émergente chez les personnes atteintes du sida, les greffés d’organes, les enfants, les voyageurs, les porteurs de lentilles de contact et les personnes âgées. Elle est caractérisée par un spectre clinique varié chez l’homme. Elle est causée par des microsporidies, des microorganismes intracellulaires obligatoires, récemment classées parmi les champignons. Actuellement, 14 espèces sont incriminées en pathologie humaine dont Enterocytozoon bieneusi et Encephalitozoon intestinalis sont les espèces les plus fréquentes. Elles sont associées surtout à des manifestations intestinales ou disséminées. Les espèces de microsporidies infectant l’homme ont été identifiées aussi bien dans des sources d’eau que des aliments ou des animaux de ferme ou domestiques suggérant une transmission hydrique, alimentaire et zoonotique. Différentes molécules ont été testées pour le traitement de la microsporidiose humaine avec un succès variable. L’albendazole est le traitement de choix pour Encephalitozoon dont Encephalitozoon intestinalis mais non contre Enterocytozoon bieneusi. Cette espèce a montré une excellente réponse avec la fumagilline qui est toxique lorsqu’elle est administrée chez les mammifères par voie systémique. Un autre traitement employant le TNP-470, un analogue de la fumagilline, semble assez promoteur. Les efforts doivent continuer afin de développer d’autres molécules efficaces et dénuées d’effets indésirables.
Other protozoal infections
2010, Antibiotic and Chemotherapy: Expert ConsultEnteric Infections in Immunocompromised Hosts
2006, Therapy of Digestive DisordersEnteric infections in immunocompromised hosts
2005, Therapy of Digestive Disorders, Second EditionThalidomide: A review of approved and investigational uses
2003, Clinical TherapeuticsBackground: Thalidomide is best known as a major teratogen that caused birth defects in up to 12,000 children in the 1960s. More recently, this agent has been approved by the US Food and Drug Administration for the treatment of erythema nodosum leprosum (ENL) through a restricted-use program. Its immunomodulatory, anti-inflammatory, and antiangiogenic properties are currently under study in a number of clinical conditions.
Objective: This article reviews the pharmacology of thalidomide; its approved and off-label uses in dermatologic, oncologic, and gastrointestinal conditions; and adverse events associated with its use.
Methods: Relevant articles were identified through searches of MEDLINE (1966–June 2002), International Pharmaceutical Abstracts (1970–June 2002), and EMBASE (1990–June 2002). Search terms included but were not limited to thalidomide, pharmacokinetics, pharmacology, therapeutic use, and teratogenicity, as well as terms for specific disease states and adverse events. Further publications were identified from the reference lists of the reviewed articles. Abstracts of recent symposia were obtained from the American Society of Clinical Oncology Web site.
Results: Thalidomide is thought to exert its therapeutic effect through the modulation of cytokines, particularly tumor necrosis factor-α. In addition to its approved indication for ENL, thalidomide has been studied in various other conditions, including graft-versus-host disease, discoid lupus erythematosus, sarever, the ulcers return on drug discontinuation, leading to concerns about long-term use of thalidomide and the risk of peripheral neuropathy. The preliminary results of thalidomide use in patients with Crohn's disease are encouraging; however, further studies are necessary. Case reports and studies in small numbers of patients have shown effectiveness for thalidomide in other clinical conditions.
Because thalidomide is highly teratogenic, guidelines for its use must be followed carefully. Thalidomide is a toxic medication, and therapeutic and well-tolerated doses have not been established for any condition except ENL. Because long-term use of thalidomide carries a risk of irreversible peripheral neuropathy and because the neuropathy may be asymptomatic, routine testing is necessary. Efforts to develop agents that retain the efficacy of thalidomide without its unwanted effects are ongoing.