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PubMed2000

Thalidomide suppresses Up-regulation of human immunodeficiency virus coreceptors CXCR4 and CCR5 on CD4+ T cells in humans.

Concurrent infection in patients with human immunodeficiency virus (HIV) infection increases the expression of HIV coreceptors CXCR4 and CCR5. Thalidomide has beneficial effects in a number of HIV-associated diseases. The effect of thalidomide on CXCR4 and CCR5 expression on CD4+ T cells was determined. Thalidomide produced a dose-dependent inhibition of lipopolysaccharide (LPS)-induced up-regulation of CXCR4 and CCR5 in vitro. Antibody to tumor necrosis factor-alpha (TNF-alpha) also attenuated the LPS-induced HIV coreceptor up-regulation, which was not further reduced by thalidomide. Thalidomide (400 mg) was orally administered to 6 men, and their blood was stimulated ex vivo with LPS, staphylococcal or mycobacterial antigens, or antibody to CD3 or CD28 cells. All stimuli induced up-regulation of HIV coreceptors, which was reduced after ingestion of thalidomide. Thalidomide may be beneficial in the treatment of intercurrent infections during HIV infection by reducing the up-regulation of CXCR4 and CCR5 expression on CD4+ T cells induced by bacterial and mycobacterial antigens, by a mechanism that involves inhibition of TNF-alpha.

Adult↗
PubMed1999

Thalidomide as therapy for human immunodeficiency virus-related oral ulcers: a double-blind placebo-controlled clinical trial.

A double-blind, randomized, placebo-controlled clinical trial was performed in Mexico City to evaluate the efficacy of thalidomide in treating oral recurrent aphthae in human immunodeficiency virus (HIV)-infected subjects. Sixteen HIV-infected patients with clinical and histological diagnosis of oral recurrent aphthous ulcerations received randomly an 8-week course of either thalidomide or placebo, with an initial oral dosage of 400 mg/d for 1 week, followed by 200 mg/d for 7 weeks. Ten subjects received thalidomide and six received placebo. At 8 weeks, nine subjects (90%) in the thalidomide group had complete healing of their ulcers, compared with two (33.3%) of the six patients in the placebo group (P = .03). There was a significant reduction in largest ulcer diameter in the thalidomide group. Rash was observed in 80% of the thalidomide patients. Although thalidomide demonstrated an unquestionable benefit in treatment of oral ulcers in HIV patients, caution must be taken given the frequent occurrence of side effects.

AIDS-Related Opportunistic Infections↗
PubMed1996

The effect of thalidomide on experimental tumors and metastases.

Thalidomide has recently been shown to antagonize basic fibroblast growth factor-induced angiogenesis in the rat corneal micropocket assay. We have investigated the effect of thalidomide on growth, radiosensitivity and metastasis in murine SCCVII and Lewis Lung tumors. We found that daily thalidomide administration (0.77 mmol/kg/day, i.p.) does not alter primary tumor growth of SCCVII or Lewis Lung tumors. However, thalidomide administration does reduce radiosensitivity of the Lewis Lung tumor, and increases its sensitivity to combined treatment with radiation and the bioreductive cytotoxin tirapazamine. These findings suggest that thalidomide is elevating tumor hypoxia in the Lewis Lung tumor, presumably via an anti-angiogenic mechanism. We also found that thalidomide administration reduces the incidence of lung metastases from primary Lewis Lung tumors. Thalidomide may therefore have utility in the management of solid tumors, especially when combined with drugs that are selectively toxic to cells at reduced oxygen tension (e.g. bioreductive cytotoxins).

Animals↗
PubMed2001

Efficacy of long-term treatment with thalidomide in children and young adults with Crohn disease: preliminary results.

BACKGROUND: Several proinflammatory cytokines are involved in the pathogenesis of inflammatory bowel diseases. A significant role has been given to tumor necrosis factor alpha (TNF-alpha) as a guide proinflammatory cytokine. Thalidomide selectively reduces TNF-alpha production by inflammatory cells. The aim of the study was to assess the efficacy of thalidomide to induce and maintain remission in refractory Crohn disease. METHODS: The decision to administer thalidomide was made on the basis of patient intolerance or resistance to conventional medical treatment or as the last medical resort before surgical intervention. Only 5 of 96 patients with inflammatory bowel disease satisfied these criteria. All five patients had Crohn disease (male: mean age, 17 years). Thalidomide was administered at night at a dose of 1.5-2 mg/kg/day. The Pediatric Crohn Disease Activity Index, modified Harvey-Bradshaw scores, and steroids reduction were used to assess clinical response. RESULTS: Disease activity decreased consistently in four patients with a reduction of mean Pediatric Crohn Disease Activity Index from 36,9 to 2,5 and the mean Harvey-Bradshaw from 8.5 to 0.75 after 3 months of treatment. Steroid treatment (mean dose, 35 mg/day before treatment) was tapered and then discontinued, in four patients, within 1-3 months. Four patients are in remission after 19-24 months of treatment. The fifth patient discontinued thalidomide after 1 week because of distal paresthesia. CONCLUSION: Thalidomide seems to be an effective and safe treatment in patients with refractory Crohn disease. This is the first report of long-term use of thalidomide in refractory Crohn disease in pediatric patients.

Adolescent↗
PubMed1996

The effect of thalidomide on the pathogenesis of human immunodeficiency virus type 1 and M. tuberculosis infection.

Tumor necrosis factor alpha (TNF-alpha), a cytokine produced during the host defense against infection, is associated with fevers, weakness, and progressive weight loss. Thalidomide inhibits the synthesis of TNF-alpha both in vitro and in vivo and may have clinical usefulness. We therefore initiated a pilot study of thalidomide treatment in patients with human immunodeficiency virus type 1 (HIV-1)-associated wasting with or without concomitant infection with tuberculosis. Thirty-nine patients were randomly allocated to treatment with either thalidomide or placebo in a double-blind manner for 21 days. Thirty-two patients completed the study. In patients with concomitant HIV-1 and tuberculosis infections, thalidomide therapy was associated with a reduction in both plasma TNF-alpha levels and HIV-1 levels. No significant reduction in either TNF-alpha or HIV- 1 levels was observed in patients with HIV-1 infection only. During the study period, patients receiving thalidomide treatment (n=16) showed a significant weight gain (mean +/- SEM: 6.5 +/- 1.2%; p<0.02) relative to placebo-treated patients (n=16). Patients with simultaneous HIV-1 and tuberculosis infections experienced a higher mean weight gain during thalidomide treatment than the group of patients with HIV-1 infection only. The results of this pilot study suggest that thalidomide may have a clinical role in enhancing weight gain and possibly reducing TNF-alpha and HIV-1 levels in patients with HIV-1 and concomitant mycobacterial infections.

Adult↗
PubMed1981

Inhibition of de novo IgM antibody synthesis by thalidomide as a relevant mechanism of action in leprosy.

Thalidomide is well documented to be an effective treatment for erythema nodosum leprosum (ENL) occurring in lepromatous leprosy. To be beneficial, thalidomide must interfere with one or more of the several essential steps in the pathogenesis of this syndrome, which is presumed to be a clinical manifestation of an Arthur-type hypersensitivity. Since complexes of antigen and antibody would initiate these events, thalidomide could exert its most direct influence on reactants in this essential step. To determine whether thalidomide affected de novo antibody synthesis, the effect of the drug on the antibody response to sheep erythrocytes in mice was determined. Thalidomide significantly inhibited IgM antibody formation when fed to mice for 5 or 7 days before immunization with sheep erythrocytes. There was also a selective decrease in serum IgM concentrations among leprosy patients being treated with thalidomide for ENL. A clinically relevant site of action of thalidomide in ENL appears to be on the synthesis of IgM antibody. The target site of the drug among the macrophage, antibody-forming, and helper or suppressor lymphocytes remains to be elucidated.

Animals↗
PubMed2004

Common and rare side-effects of low-dose thalidomide in multiple myeloma: focus on the dose-minimizing peripheral neuropathy.

OBJECTIVES: Thalidomide has demonstrated a remarkable efficacy in the treatment of multiple myeloma but its use may cause several toxicities. We have investigated the common and rare side-effects, especially analysing peripheral neuropathy, in order to optimise the thalidomide dose for minimizing this harmful side-effect. METHODS: Fifty-nine patients were treated with thalidomide alone or combined with oral melphalan. The median age was 69 yr. The initial dose of thalidomide was 100 mg/day increasing weekly by 100 mg increments until a maximum dose of 400 mg was attained. Melphalan was administered at a dose of 0.20 mg/kg/d for 4 d every 28 d. RESULTS AND CONCLUSIONS: Nearly one-fourth of patients discontinued thalidomide because of toxicity. Constipation (71%), somnolence (36%) and fatigue (20%) were the most common side-effects and they were not dose dependent. Peripheral neuropathy occurred in 39% of patients and a thalidomide median daily dose of more than 150 mg was significantly associated with higher frequency and actuarial risk of peripheral neuropathy without improving the response rate. Deep venous thrombosis was observed in 7% of patients and other side-effects were rare. In patients with advanced multiple myeloma we found that a thalidomide daily dose of 150 mg minimizes peripheral neuropathy without jeopardizing response and survival.

Aged↗
PubMed1986

Thalidomide enhances superoxide anion release from human polymorphonuclear and mononuclear leukocytes.

The effect of thalidomide on the function of human polymorphonuclear leukocytes (PMNs) and blood monocytes was tested in vitro. The chemotactic and spontaneous migration was not affected by thalidomide between 0.001 and 0.1 mg/ml. PMN oxygen consumption was not changed after pre-incubation with thalidomide. However, superoxide anion release upon stimulation of the cells with phorbol-myristate-acetate or the chemotactic tripeptide N-f-Methionyl-Leucyl-Phenylalanine was enhanced in a dose-dependent manner after pre-incubation with thalidomide. Both PMNs and monocytes were influenced. Leukocytes from two patients with chronic granulomatous disease (defective in oxidative burst response) remained unable to produce superoxide anion after pre-incubation with thalidomide. Thus, we suggest that thalidomide primes the phagocytes to respond with an enhanced superoxide anion release upon stimulation. These findings do not explain the anti-inflammatory effect of thalidomide but could have relevance in conditions with quantitative defects in phagocyte oxidative responsiveness.

Chemotaxis↗
PubMed2006

A novel anticancer effect of thalidomide: inhibition of intercellular adhesion molecule-1-mediated cell invasion and metastasis through suppression of nuclear factor-kappaB.

PURPOSE: Thalidomide has been reported to have antiangiogenic and antimetastatic effects. Intercellular adhesion molecule-1 (ICAM-1) was shown to be involved in monocyte adherence to epithelial cells and cancer cell invasion. In this study, we further investigated the role of ICAM-1 in tumorigenesis, including tumor formation and metastasis. ICAM-1 as a molecular target for cancer and the anticancer effect of thalidomide were investigated. EXPERIMENTAL DESIGN: Expression of ICAM-1 protein in human lung cancer specimens was assessed by immunohistochemistry. ICAM-1 overexpressing A549 cells (A549/ICAM-1) were established to investigate the direct effect of ICAM-1 on in vitro cell invasion and in vivo tumor metastasis. Transient transfection and luciferase assay, electrophoretic mobility shift assay, and chromatin immunoprecipitation were done to assess the activity and binding of nuclear factor-kappaB to the ICAM-1 promoter. A xenograft model in nude mice was conducted to evaluate the anticancer effect of thalidomide. RESULTS: High expression of ICAM-1 in human lung cancer specimens was correlated with a greater risk of advanced cancers (stages III and IV). A549/ICAM-1 cells were shown to induce in vitro cell invasion and in vivo tumor metastasis. Anti-ICAM-1 antibody and thalidomide had inhibitory effect on these events. Thalidomide also suppressed tumor necrosis factor-alpha-induced ICAM-1 expression through inhibition of nuclear factor-kappaB binding to the ICAM-1 promoter. The in vivo xenograft model showed the effectiveness of thalidomide on tumor formation. CONCLUSION: These studies provide a framework for targeting ICAM-1 as a biologically based therapy for cancer, and thalidomide might be effective in human lung cancer.

Adenocarcinoma↗
PubMed2005

The future role of thalidomide in multiple myeloma.

Treatment for multiple myeloma typically is chemotherapy, high-dose therapy with stem cell transplantation or radiation. Thalidomide shows promise, but to improve knowledge and understanding of this drug, more clinical data is required. Workshops designed to propose new studies providing much needed data on the use of thalidomide as first-line therapy, as maintenance therapy and as treatment for refractory or relapsed disease are reported here. Thalidomide has been shown to be effective in previously untreated patients as monotherapy (36% remission), although greater remission is seen in combination therapy, for example, thalidomide with dexamethasone (72% remission). Thalidomide is an interesting maintenance therapy. It has the advantages of being effective in the bone marrow and having a long-lasting effect but suffers because of its significant side-effect profile; however, it is tolerated by most patients. The adverse effects are thought to be dose-limiting, and most are seen in all patients at the beginning of treatment. Further clinical evidence is needed to determine the effectiveness of thalidomide as maintenance therapy in patients with multiple myeloma, having been shown to be active against refractory multiple myeloma, even in patients who relapse after high-dose chemotherapy. The workshop acknowledged the problems associated with designing a phase III study, and it is clear that many areas need to be addressed in the use of thalidomide for the treatment of multiple myeloma.

Angiogenesis Inhibitors↗
PubMed2005

Effect of thalidomide on cardiac remodeling in chronic heart failure: results of a double-blind, placebo-controlled study.

BACKGROUND: Inflammation and matrix degradation may play a pathogenic role in chronic heart failure (CHF), and therefore, we examined whether thalidomide, a drug with potential immunomodulating and matrix-stabilizing properties, could improve left ventricular (LV) function in patients with CHF secondary to idiopathic dilated cardiomyopathy (IDCM) or coronary artery disease (CAD). METHODS AND RESULTS: Fifty-six patients with CHF and an LV ejection fraction (LVEF) <40% who were already on optimal conventional cardiovascular treatment were randomized to thalidomide (25 mg QD increasing to 200 mg QD) or placebo and followed up for 12 weeks. Our main findings were as follows: (1) During thalidomide treatment but not during placebo, there was a marked increase in LVEF (&7 EF units) along with a significant decrease in LV end-diastolic volume and heart rate. (2) This improvement in LVEF was accompanied by a decrease in matrix metalloproteinase-2 without any changes in its endogenous tissue inhibitor, suggesting a matrix-stabilizing net effect. (3) Thalidomide also induced a decrease in total neutrophil count and an increase in plasma levels of tumor necrosis factor-alpha, suggesting both proinflammatory and antiinflammatory effects. (4) The effect of thalidomide on LVEF was more marked in IDCM than in CAD, possibly partly reflecting that the former group was able to tolerate a higher thalidomide dosage. CONCLUSIONS: Although our results must be confirmed in larger studies that also examine the effects on morbidity and mortality, our findings suggest a role for thalidomide in the management of CHF in addition to traditional cardiovascular medications.

Aged↗
PubMed2000

Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas.

PURPOSE: Little progress has been made in the treatment of adult high-grade gliomas over the last two decades, thus necessitating a search for novel therapeutic strategies. Malignant gliomas are vascular or angiogenic tumors, which leads to the supposition that angiogenesis inhibition may represent a potentially promising strategy in the treatment of these tumors. We present the results of a phase II trial of thalidomide, a putative inhibitor of angiogenesis, in the treatment of adults with previously irradiated, recurrent high-grade gliomas. PATIENTS AND METHODS: Patients with a histologic diagnosis of anaplastic mixed glioma, anaplastic astrocytoma, or glioblastoma multiforme who had radiographic demonstration of tumor progression after standard external-beam radiotherapy with or without chemotherapy were eligible. Patients were initially treated with thalidomide 800 mg/d with increases in dose by 200 mg/d every 2 weeks until a final daily dose of 1,200 mg was achieved. Patients were evaluated every 8 weeks for response by both clinical and radiographic criteria. RESULTS: A total of 39 patients were accrued, with 36 patients being assessable for both toxicity and response. Thalidomide was well tolerated, with constipation and sedation being the major toxicities. One patient developed a grade 2 peripheral neuropathy after treatment with thalidomide for nearly a year. There were two objective radiographic partial responses (6%), two minor responses (6%), and 12 patients with stable disease (33%). Eight patients were alive more than 1 year after starting thalidomide, although almost all with tumor progression. Changes in serum levels of basic fibroblastic growth factor (bFGF) were correlated with time to tumor progression and overall survival. CONCLUSION: Thalidomide is a generally well-tolerated drug that may have antitumor activity in a minority of patients with recurrent high-grade gliomas. Future studies will better define the usefulness of thalidomide in newly diagnosed patients with malignant gliomas and in combination with radiotherapy and chemotherapy. Additionally, studies will be needed to confirm the potential utility of changes in serum bFGF as a marker of antiangiogenic activity and/or glioma growth.

Adult↗
PubMed2005

Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group.

PURPOSE: To determine if thalidomide plus dexamethasone yields superior response rates compared with dexamethasone alone as induction therapy for newly diagnosed multiple myeloma. PATIENTS AND METHODS: Patients were randomly assigned to receive thalidomide plus dexamethasone or dexamethasone alone. Patients in arm A received thalidomide 200 mg orally for 4 weeks; dexamethasone was administered at a dose of 40 mg orally on days 1 to 4, 9 to 12, and 17 to 20. Cycles were repeated every 4 weeks. Patients in arm B received dexamethasone alone at the same schedule as in arm A. RESULTS: Two hundred seven patients were enrolled: 103 were randomly assigned to thalidomide plus dexamethasone and 104 were randomly assigned to dexamethasone alone; eight patients were ineligible. The response rate with thalidomide plus dexamethasone was significantly higher than with dexamethasone alone (63% v 41%, respectively; P = .0017). The response rate allowing for use of serum monoclonal protein levels when a measurable urine monoclonal protein was unavailable at follow-up was 72% v 50%, respectively. The incidence rates of grade 3 or higher deep vein thrombosis (DVT), rash, bradycardia, neuropathy, and any grade 4 to 5 toxicity in the first 4 months were significantly higher with thalidomide plus dexamethasone compared with dexamethasone alone (45% v 21%, respectively; P < .001). DVT was more frequent in arm A than in arm B (17% v 3%); grade 3 or higher peripheral neuropathy was also more frequent (7% v 4%, respectively). CONCLUSION: Thalidomide plus dexamethasone demonstrates significantly superior response rates in newly diagnosed myeloma compared with dexamethasone alone. However, this must be balanced against the greater toxicity seen with the combination.

Adult↗
PubMed2003

Dermatologic and nondermatologic uses of thalidomide.

OBJECTIVE: To review published data on thalidomide, with emphasis on current knowledge about mechanism of action, new and/or potential dermatologic and nondermatologic therapeutic applications, well-known and emerging adverse effects, and current indications for its safe use. DATA SOURCES: Review articles, in vitro research studies, references from retrieved articles, case reports, and clinical trials were identified from a computerized literature search using MEDLINE and OVID (1966-January 2003) and on the Cochrane Clinical Trials Register (January 2003). Information available from meetings' abstract books, Internet, or pharmaceutical companies was also considered. STUDY SELECTION AND DATA EXTRACTION: All articles identified as relevant, including those from non-English literature, were considered in an attempt to provide to the reader both the theoretical basis and practical guidelines for thalidomide pharmacotherapy. DATA SYNTHESIS: Thalidomide has hypnosedative, antiangiogenic, antiinflammatory, and immunomodulatory properties. Moreover, it has been shown to selectively inhibit the production of tumor necrosis factor-alpha and reduce the expression of various integrin receptors on the membrane of leukocytes and other cell types in a dose-dependent fashion. Controlled trials demonstrated the efficacy of thalidomide in a number of diseases, including erythema nodosum leprosum, lupus erythematosus, aphthosis, graft-versus-host disease, prurigo nodularis, and actinic prurigo. Single case reports or studies in small series have also suggested a possible role for thalidomide in numerous other dermatologic and nondermatologic disorders. Possibly severe and sometimes irreversible risks related to the clinical use of thalidomide include teratogenicity and neurotoxicity. CONCLUSIONS: Although teratogenicity and neurotoxicity are significant adverse effects requiring cautious use, thalidomide is an effective therapeutic modality in a variety of difficult-to-treat disorders and, providing careful selection of patients, should offer an acceptable risk-to-benefit ratio.

Angiogenesis Inhibitors↗
PubMed2002

Thalidomide for chronic sarcoidosis.

STUDY OBJECTIVES: Thalidomide therapy has been shown to modify granulomatous diseases, such as tuberculosis and leprosy. Lupus pernio is a skin manifestation of sarcoidosis that does not remit spontaneously, and was used as a marker of efficacy of thalidomide for sarcoidosis. DESIGN: An open-label, dose-escalation trial of thalidomide. SETTING: Patients were seen at one of four specialized sarcoidosis clinics in the United States. PATIENTS: Fifteen patients with lupus pernio and other manifestations of sarcoidosis unresponsive to prior therapy were enrolled. INTERVENTIONS: Skin lesions were assessed with visual examination by the treating physician, and photographic evaluation by a blinded panel of physicians reviewing photographs of the lesions before and after therapy. MEASUREMENTS AND RESULTS: Fourteen patients completed 4 months of therapy. All patients experienced some improvement in their skin lesions subjectively, and 10 of 12 evaluable patients showed improvement using photograph scoring. Five patients were better after 1 month (treated with 50 mg/d of thalidomide), seven more patients improved after 2 months (treated with 100 mg/d of thalidomide in the second month), and two patients required an additional month of 200 mg of thalidomide to achieve a response. Patients reported increased somnolence (n = 9), numbness (n = 7), dizziness (n = 2), constipation (n = 6), rash (n = 1), and increasing shortness of breath (n = 1). One patient discontinued therapy because of new-onset dyspnea, due to probably unrelated new-onset congestive heart failure. CONCLUSION: Thalidomide was an effective form of treatment for chronic cutaneous sarcoidosis. The drug was well tolerated and may be a useful alternative to systemic corticosteroids.

Adult↗
PubMed2002

Negligible clinical effects of thalidomide in patients with myelofibrosis with myeloid metaplasia.

We conducted a nonrandomized prospective phase II study of thalidomide in anemic patients with myelofibrosis with myeloid metaplasia (MMM), with or without preceding polycythemia vera or essential thrombocythemia, with a primary aim to improve anemia. Thalidomide was given in escalating doses with a target dose of 800 mg daily, but the median dose of thalidomide that was actually tolerated was 400 mg daily. Fifteen patients were entered into the study and 14 were evaluable for response. Five of 14 (36%) patients discontinued thalidomide before 3 mo because of side effects, and none of these five patients had a response at the time when thalidomide was stopped. When evaluated after 3 mo of therapy, none of the remaining nine patients exhibited a discernible clinical response. Three patients showed progressive disease defined as > 50% increase in the need for red cell transfusions. Treatment was poorly tolerated, with all patients reporting side effects of thalidomide, the most prominent being fatigue documented in 80% of patients. Two patients died while on study, one from acute myelogenous leukemia and one from pneumonia. We conclude that thalidomide given in doses employed in the treatment of multiple myeloma gives no clinically relevant hematological effects in advanced MMM and is hampered by a very high incidence of side effects.

Adult↗
PubMed1997

Thalidomide protects mice against LPS-induced shock.

Thalidomide has been shown to selectively inhibit TNF-alpha production in vitro by lipopolysaccharide (LPS)-stimulated monocytes. TNF-alpha has been shown to play a pivotal role in the pathophysiology of endotoxic shock. Using a mouse model of LPS-induced shock, we investigated the effects of thalidomide on the production of TNF-alpha and other cytokines and on animal survival. After injection of 100-350 micrograms LPS into mice, cytokines including TNF-alpha, IL-6, IL-10, IL-1 beta, GM-CSF and IFN-gamma were measured in the serum. Administration of 200 mg/kg thalidomide to mice before LPS challenge modified the profile of LPS-induced cytokine secretion. Serum TNF-alpha levels were reduced by 93%, in a dose-dependent manner, and TNF-alpha mRNA expression in the spleens of mice was reduced by 70%. Serum IL-6 levels were also inhibited by 50%. Thalidomide induced a two-fold increase in serum IL-10 levels. Thalidomide treatment did not interfere with the production of GM-CSF, IL-1 beta, or IFN-gamma. The LD50 of LPS in this model was increased by thalidomide pre-treatment from 150 micrograms to 300 micrograms in 72 h. Thus, at otherwise lethal doses of LPS, thalidomide treatment was found to protect animals from death.

Animals↗
PubMed2004

Experimental murine mycobacteriosis: evaluation of the functional activity of alveolar macrophages in thalidomide- treated mice.

Thalidomide is a selective inhibitor of tumor necrosis factor-alpha (TNF-alpha), a cytokine involved in mycobacterial death mechanisms. We investigated the role of this drug in the functional activity of alveolar macrophages in the presence of infection induced by intranasal inoculation of Mycobacterium avium in thalidomide-treated and untreated adult Swiss mice. Sixty animals were inoculated with 5 x 10(6) M. avium by the respiratory route. Thirty animals received daily thalidomide (30 mg/kg mouse) and 30 received water by gavage up to sacrifice. Ten non-inoculated mice were used as a control group. Lots of animals from each group were evaluated until 6 weeks after inoculation. Infection resulted in an increased total number of inflammatory cells as well as increased activity of pulmonary macrophages. Histologically, intranasal inoculation of bacilli resulted in small mononuclear infiltrates located at the periphery of the organ. Culture of lung fragments revealed the presence of bacilli only at the beginning and at the end of the experimental period. Thalidomide administration did not affect the microbiological or histological features of the infection. Thalidomide-treated and untreated animals showed the same amount of M. avium colonies 3 weeks after infection. Although it did not affect bacillary clearance, thalidomide administration resulted in a decreased percent of spread cells and release of hydrogen peroxide, suggesting that factors other than TNF-alpha play a role in the killing of mycobacteria by alveolar macrophages. Thalidomide administration also reduced the number of spread cells among resident macrophages, suggesting a direct effect of the drug on this phenomenon.

Animals↗