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PubMed2006

Immunological consequences of thalidomide treatment in Sjögren's syndrome.

OBJECTIVE: To study the immunological consequences of systemic thalidomide treatment in patients with Sjögren's syndrome. METHODS: Cytokine (tumour necrosis factor alpha (TNFalpha), interleukin (IL) 6) and soluble receptor (sIL2R) levels were measured in patient and control plasma (n = 7), before and after thalidomide treatment. Peripheral blood mononuclear cells were examined by FACS analysis for potential changes in specific cell populations (T cells, B cells, monocytes), and for the expression of activation markers (CD25, HLA-DR), costimulatory molecules (CD40, CD40L), TNF receptors, chemokine receptors, and adhesion molecules (L-selectin (L-sel)). RESULTS: Owing to adverse effects of thalidomide, the treatment interval was limited. None the less, statistically significant changes in markers of cell activation were recorded in the four treated patients. Before treatment, HLA-DR, TNFRI, CXCRI, and CXCRII were raised in the patients compared with healthy controls (p<0.05) and their expression was down regulated after treatment. B cell numbers and expression of the adhesion molecule L-sel also declined with thalidomide. CONCLUSION: Significant changes in measures of cell activation were detected during thalidomide treatment within this limited study, which upon further investigation may offer insight into the underlying immunoregulatory pathways of thalidomide.

Cytokines↗
PubMed2005

A multicenter phase II trial of thalidomide and celecoxib for patients with relapsed and refractory multiple myeloma.

Preclinical data indicates that cyclooxygenase-2 (COX-2) inhibition impairs plasma cell growth and potentially synergizes with thalidomide. We performed a trial in previously treated patients with myeloma using thalidomide up to a maximum dose of 800 mg/d with celecoxib (400 mg bid). Outcomes were compared with a prior trial of thalidomide. Sixty-six patients with median age of 67 (range, 43-85) received a median dose of thalidomide and celecoxib of 400 and 800 mg/d, respectively, with median durations of treatment of 27 and 13 weeks, respectively. The most common toxicities associated with premature discontinuation of celecoxib (n = 30 of 53, 57%) were fluid retention and deterioration of renal function. Overall response rate (RR) was 42% and with 20 months median follow-up; the actuarial median progression-free survival and overall survival were 6.8 and 21.4 months, respectively. Unlike our prior study, age >65 years was not predictive of inferior RR due to improvement in RR in older patients with the combination (37% versus 15%, P = 0.08). The RR was superior in patients who received a total dose of celecoxib exceeding 40 g in the first 8 weeks of therapy (62% versus 30%, P = 0.021). Progression-free survival and overall survival were also improved. Other predictors for inferior progression-free survival were age >65 years (P = 0.016) and elevated beta(2)-microglobulin (P = 0.017). This study provides evidence that the addition of high-dose celecoxib adds to the antimyeloma activity of thalidomide but this comes with unacceptable toxicity. Future studies should use newer COX-2 inhibitors with thalidomide, or their respective derivatives.

Adult↗
PubMedDate not supplied

Thalidomide inhibits leukocyte-endothelium interaction in endotoxin-induced uveitis.

To investigate the effects of thalidomide on leukocyte-endothelium interaction in iris vessels of rats with an endotoxin-induced uveitis (EIU), intravital fluorescence microscopy was used to quantify leukocyte adhesion to the vascular endothelium of iris venules in Lewis rats at 2, 4, 8 and 24 h after induction of EIU. Animals (n = 84) received a single intraperitoneal dose of either thalidomide (80 mg/kg body weight) or prednisolone (10 mg/kg body weight). Both drugs significantly reduced firm adhesion of leukocytes at 4, 8 and 24 h. Thalidomide caused earlier suppression of leukocyte rolling than prednisolone (4 vs. 8 h). TNF-alpha plasma levels peaked at 2 h and were not significantly reduced in any group compared with controls. Cell count and protein concentration in aqueous humor were significantly reduced by prednisolone and thalidomide at 24 h (p < 0.05). Thalidomide exerts its anti-inflammatory effects by an inhibition of leukocyte-endothelium interaction. Compared with prednisolone, thalidomide shows earlier inhibition of leukocyte rolling, indicating modulation of adhesion molecule expression and/or function.

Animals↗
PubMed2006

Effects of thalidomide treatment in heart failure patients.

BACKGROUND: Several studies have reported a direct association between elevated plasma levels of inflammatory cytokines and worse functional class (New York Heart Association [NYHA]) and cardiac function, measured as left ventricular ejection fraction (LVEF). Thalidomide has recently shown to improve LVEF in chronic heart failure patients, accompanied by a marked decrease in plasma levels of tumor necrosis factor alpha (TNF-alpha). METHODS: In a randomized prospective open label study of men and women with heart failure (HF) due to ischemic and non-ischemic cardiomyopathy who had systolic dysfunction (LVEF <40%) and NHYA classification, functional classes II and III were assigned to control (without thalidomide, 60 patients) or thalidomide group (20 patients). The initial dose of thalidomide was 100 mg once a day, and it was increased to 100 mg twice a day after a period of 10 days, if the prior dosage was well-tolerated. Demographic characteristics, etiology of HF, prior myocardial infarction, co-morbidities associated were registered and laboratory routine test, TNF-alpha serum levels, and echocardiogram were obtained at the beginning and after 6 months of follow-up. RESULTS: Clinical status (NYHA) at the end of the follow-up period, improved moderately in both groups. TNF-alpha levels were initially of 5.88 +/- 0.9 and 6.49 +/- 1.82 vs. 6.32 +/- 1.6 and 7.94 +/- 3.8 pg/ml during follow-up, for thalidomide and control groups, respectively. There were non-significant differences in echocardiography variables. CONCLUSION: In conclusion, although there is a large amount of information supporting a direct relationship between TNF-alpha and worsening of symptoms and prognosis in patients with HF and recently, the beneficial effect on thalidomide treatment has been suggested, these preliminary observations should be confirmed in a larger prospective study, specially trying to clarify the action mechanisms.

Aged↗
PubMed1996

Thalidomide and its metabolites have no effect on human lymphocyte proliferation.

Thalidomide is a drug that is being used in several diseases with an immunological component, but the effects on the different immune functions have only been studied partially. Therefore, we studied the effect of thalidomide on PPD-or Con-A-induced proliferation of human mononuclear cells. We found no direct effect of thalidomide at up to 50 micrograms/ml on the cultures. Cells taken from subjects 6 h after ingestion of 200 mg of thalidomide proliferated equally well to PPD and Con-A than cells taken prior to drug administration. Plasma taken from subjects that ingested 200 mg of thalidomide 6 h before did not affect the proliferative response of their own cells when added to the cultures. Plasma from rabbits that were injected with doses 5 or 15 times higher than the dose given to humans did not diminish the proliferative response of human mononuclear cells to PPD. We conclude that neither thalidomide nor its metabolites affect the proliferative response of human mononuclear cells.

Adolescent↗
PubMed1996

Thalidomide and recurrent aphthous stomatitis: a follow-up study.

BACKGROUND: Thalidomide is used for the symptomatic treatment of recurrent aphthous stomatitis (RAS). Some authors reported remissions, but this was not evaluated. OBJECTIVE: To evaluate the number of patients who could stop or reduce thalidomide treatment. METHODS: Twenty-five patients with RAS treated with thalidomide and followed during at least 1 year were retrospectively studied. RESULTS: Six patients could stop the treatment and further presented minor aphthae, 10 needed minimal daily doses of thalidomide and 7 did not respond to 100 mg daily. One patient was not evaluated because of an early side effect and one was lost to follow-up. CONCLUSION: This study showed that a minority of patients responded and could stop thalidomide therapy whereas another group of patients could be maintained in remission with low doses of thalidomide which may represent a means to reduce the potentially severe side effects.

Adult↗
PubMed2001

Thalidomide dose proportionality assessment following single doses to healthy subjects.

Thalidomide is approved in the United States for treating erythema nodosum leprosum, a complication of leprosy. The present study determined the single-dose oral pharmacokinetics and dose proportionality from 50 to 400 mg of Celgene's commercial Thalomid thalidomide formulation in an open-label, single-dose, three-way crossover study. Fifteen healthy subjects were given 50, 200, and 400 mg of thalidomide on three occasions, and blood samples were collected over 48 hours. Pharmacokinetic parameters were determined using noncompartmental methods, and dose proportionality was assessed by linear regression of dose-normalized Cmax and AUC0-infinity. No serious or unexpected adverse events occurred. The most common adverse events were dizziness, somnolence, headache, and nausea. One patient was discontinued because of pharyngitis. There was a significant deviation from proportionality for Cmax with increases being less than proportional than changes in dose. AUC0-infinity increased proportionally with dose, suggesting that the overall amount of thalidomide absorbed, as well as its clearance, is independent of dose over the range used. V/F was found to increase with dose. This was most likely due to the terminal rate constant, which is used to calculate V/F, actually representing the absorption process rather than elimination (i.e., flip-flop phenomenon). The terminal rate constant (absorption rate constant) for the highest dose was 50% less than for the other two lower doses. The less than proportional increases in Cmax were most likely due to thalidomide's low aqueous solubility. Thalidomide shows reasonable dose proportionality with respect to AUC from 50 to 400 mg.

Adult↗
PubMed2000

Adjunctive thalidomide therapy of childhood tuberculous meningitis: possible anti-inflammatory role.

The objective of this study was to determine the safety and tolerability of the immunomodulatory agent thalidomide as adjunct therapy in children with tuberculous meningitis. Children with stage 2 tuberculous meningitis received oral thalidomide for 28 days in a dose-escalating study, in addition to standard four-drug antituberculosis therapy, corticosteroids, and specific treatment of complications such as raised intracranial pressure. Clinical and laboratory evaluations were carried out. Fifteen patients (median age, 34 months) were enrolled. Thalidomide was administered via nasogastric tube in a dosage of 6 mg/kg/day, 12 mg/kg/day, or 24 mg/kg/day. The only adverse events possibly related to the study drug were transient skin rashes in two patients. Levels of tumor necrosis factor-alpha in the cerebrospinal fluid decreased markedly during thalidomide therapy. Clinical outcome and neurologic imaging showed greater improvement than that experienced with historical controls. Thalidomide appeared safe and well tolerated in children with stage 2 tuberculous meningitis and could have important anti-inflammatory effects. These promising results have led us to embark on a randomized, double-blind, placebo-controlled trial of the efficacy of thalidomide in tuberculous meningitis.

Adjuvants, Immunologic↗
PubMed2003

Multicenter phase 2 trial of thalidomide in relapsed/refractory multiple myeloma: adverse prognostic impact of advanced age.

Relapsed or refractory multiple myeloma has a poor outlook. Some patients respond to thalidomide; however, criteria for predicting response have not been conclusively identified. We initiated a prospective multicenter phase 2 trial in patients with relapsed/refractory myeloma using thalidomide up to the maximum dose, 800 mg/d. Interferon-alpha-2B (1.5-3.0 x 10(6) U, subcutaneously, 3 times per week) was added at week 12 if disease was responsive or stable. Patients intolerant of interferon continued thalidomide alone. Thalidomide with or without interferon was continued until disease progression. Objectives were to determine toxicity, response rate (RR), progression-free survival (PFS), and overall survival (OS) and to elucidate relevant prognostic factors. We enrolled 75 patients, with median age 64 years (range, 36-83 years). Median individual maximum-tolerated dose of thalidomide was 600 mg/d; 41% reached 800 mg/d. Overall RR was 28%, and 55% stable disease (SD). The only predictor for response was age 65 years or younger (38% versus 17%; P =.043). At 18 months median follow-up, the actuarial median PFS and OS were 5.5 and 14.6 months, respectively. Multivariate analysis for OS demonstrated age exceeding 65 years (median, 9.2 months versus longer than 26 months; P =.011), raised serum lactate dehydrogenase (P =.002), and raised serum creatinine (P =.007) predicted inferior outcomes. Nineteen patients received interferon. Ten discontinued owing to toxicity. Four of 12 patients who received interferon for longer than 4 weeks were converted from SD to partial response. Our findings confirm substantial activity of thalidomide in relapsed/refractory myeloma. Interferon may improve response in selected patients, but is often not tolerated. The inferior outcome demonstrated in those with the identified prognostic factors is important in planning management for such patients.

Adult↗
PubMed2001

Treatment of Waldenstrom's macroglobulinemia with thalidomide.

PURPOSE: We performed a prospective phase II study to assess the activity of thalidomide in patients with Waldenstrom's macroglobulinemia (WM). PATIENTS AND METHODS: Twenty patients with WM were treated with thalidomide at a starting dose of 200 mg daily with dose escalation in 200-mg increments every 14 days as tolerated to a maximum of 600 mg. All patients were symptomatic, their median age was 74 years, and 10 patients were previously untreated. RESULTS: On an intent-to-treat basis, five (25%) of 20 patients achieved a partial response after treatment. Responses occurred in three of 10 previously untreated and in two of 10 pretreated patients. None of the patients treated during refractory relapse or with disease duration exceeding 2 years responded to thalidomide. Time to response was short, ranging between 0.8 months to 2.8 months. Adverse effects were common but reversible and consisted primarily of constipation, somnolence, fatigue, and mood changes. The daily dose of thalidomide was escalated to 600 mg in only five patients (25%), and in seven patients (35%), this agent was discontinued within 2 months because of intolerance. CONCLUSION: Our data indicate that thalidomide has activity in WM but only low doses were tolerated in this elderly patient population. Confirmatory studies as well as studies that will combine thalidomide with chemotherapy or with rituximab may be relevant.

Administration, Oral↗
PubMed2002

Phase II trial of thalidomide for patients with advanced renal cell carcinoma.

PURPOSE: To assess efficacy and toxicity of thalidomide in patients with advanced renal cell carcinoma (RCC). PATIENTS AND METHODS: Twenty-six patients with RCC were treated with thalidomide at a starting dose of 200 mg daily. Thalidomide was increased by 200 mg every 2 weeks until a maximum dose of 800 mg or prohibitive toxicity was reached. Fifteen patients had prior nephrectomy, 11 patients had no prior systemic therapy, and 15 had received one prior systemic regimen. RESULTS: A maximum dose of 800 mg, 600 mg, 400 mg, and 200 mg was reached in five, 10, eight, and three patients, respectively. Grade 2 and 3 dyspnea occurred in four and three patients, respectively. Grade 2 and 3 neurologic toxicity was observed in five and two patients, respectively. Of the 25 assessable patients, the best response was stable disease in 16 (95% confidence interval [CI], 43% to 82%) patients. The 6-month progression-free survival rate was 32% (95% CI, 14% to 50%). Three patients achieved prolonged stable disease of 16, 16+, and 18+ months, including two patients who were refractory to previous cytokine therapy. Fifty-seven percent were alive at 1 year (95% CI, 37% to 76%). CONCLUSION: This trial does not support the routine use of thalidomide to induce partial response for metastatic RCC. Because disease stabilization occurs as a part of the natural history of metastatic RCC, the potential effect of thalidomide on progression-free and overall survival for patients with advanced RCC is being addressed in a randomized phase III trial. New immunomodulatory analogs of thalidomide that have shown potentially greater antitumor effects in preclinical models warrant study in metastatic RCC.

Adult↗
PubMed2004

Thalidomid: current role in the treatment of non-plasma cell malignancies.

Thalidomide, initially introduced as a sedative, was withdrawn from the market in the early 1960s after it was found to be a teratogen. However, it later found use as an investigational agent in the treatment of erythema nodosum leprosum, oral ulcers, graft versus host disease, and wasting associated with the human immunodeficiency syndrome. Its antiangiogenic properties were recognized in the early 1990s during a period where the importance of angiogenesis became increasingly apparent as a critical step in the in the proliferation and spread of malignant neoplasms. This led to the evaluation of thalidomide as an antiangiogenic agent in the treatment of several cancers. Thalidomide has already become part of standard therapy for the treatment of patients with relapsed and refractory multiple myeloma. It has also been found to have varying degree of benefit in various other malignancies. Although more clinical trials are needed, Kaposi' s sarcoma and myelofibrosis represent other malignancies in which thalidomide has already demonstrated promising activity. The mechanism of action of thalidomide in cancer is still unclear, but do appear to be mediated by several other mechanisms in addition to its anti-angiogenic properties. This article reviews the current status of thalidomide for the treatment of non-plasma-cell malignancies.

Angiogenesis Inhibitors↗
PubMed2002

Thalidomide-induced neuropathy.

BACKGROUND: Thalidomide is effective for the treatment of some refractory dermatologic and oncologic diseases. Toxic neuropathy limits its use, as embryopathy can be avoided by contraceptive measures. OBJECTIVE: To describe the clinical, electrophysiologic, and pathologic features of thalidomide-induced peripheral neuropathy. METHODS: Clinical and electrophysiologic examinations were performed in seven patients with thalidomide-induced peripheral neuropathy. Thalidomide was used for graft-vs-host disease, pyoderma gangrenosum, and discoid lupus with dosages ranging from 100 to 1,200 mg/day for 5 to 16 months (cumulative dosages of 24 to 384 g). RESULTS: All seven patients had clinical and electrophysiologic evidence of a sensory more than motor, axonal, length-dependent polyneuropathy that presented as painful paresthesias or numbness. Sural nerve biopsies, done in three patients, showed evidence of Wallerian degeneration and loss of myelinated fibers. The symptoms, signs, and electrophysiologic data correlated with total cumulative dose of thalidomide. CONCLUSIONS: Thalidomide induces a dose-dependent sensorimotor length-dependent axonal neuropathy; it should be judiciously used with close neurologic monitoring.

Adult↗
PubMed2001

Thalidomide in the treatment of multiple myeloma.

Thalidomide--banned from clinical use in the 1960s because of severe teratogenicity--is now back in clinical practice as an effective agent in the treatment of relapsed and refractory multiple myeloma. Several clinical trials have determined that thalidomide is active in 25-35% of patients with relapsed myeloma. The role of thalidomide in early-stage myeloma is being actively investigated. Thalidomide has antiangiogenic and immunomodulatory properties and is an effective inhibitor of TNF-alpha. However, the mechanism of its action in myeloma remains unclear. Major toxicities of thalidomide include constipation, sedation, skin rash, fatigue and peripheral neuropathy. This paper summarizes the current status of thalidomide in multiple myeloma.

Angiogenesis Inhibitors↗
PubMedDate not supplied

[Thalidomide in Brazil: monitoring with shared responsibility?].

This paper discusses issues related to the regulation and rational use of thalidomide in Brazil, by means of a historical approach comprising three different stages. The first part is a historical review of the controversial drug since it was first synthesized, then marketed and subsequently banned during the 1950s and 60s, until the present, when an apparently irreversible process of rehabilitating the drug is under way. Brazilian experience with the use of thalidomide is described, emphasizing legal, political, and institutional work led by two social movements, the Brazilian Association of People with Thalidomide Syndrome (ABPST) and the Movement for Reintegration of People with Hansen's Disease (Morhan). The article describes the results and analyzes an active search of new cases in what is a second generation of thalidomide syndrome in Brazil. Finally, based on clinical and scientific evidence of thalidomide's therapeutic efficacy, the growth of social movements struggling both for and against authorization of the drug, and a restrictive regulation proposed by the Ministry of Health, the article discusses the implementation of policies for the regulation and rational use of thalidomide in Brazil.

Adolescent↗
PubMedDate not supplied

Long-term thalidomide use in refractory cutaneous lesions of systemic lupus erythematosus.

OBJECTIVE: To evaluate the efficacy of long-term thalidomide treatment in cutaneous lesions of systemic lupus erythematosus (SLE), not responsive to conventional therapy. PATIENTS AND METHODS: Were selected 18 SLE patients (ACR criteria) with active cutaneous lesions not responsive to chloroquine, photoprotectors and low doses prednisone and who presented good response to thalidomide but relapsed after withdrawal of the drug. All female patients had no risk of pregnancy. Thalidomide was reintroduced and maintained at low dose (25-100 mg/day) for a minimum of 6 months. RESULTS: Eighteen patients (16 females) with mean age of 34.2 yo (16-57 y.o.) received thalidomide for 6-21 months (mean 8.5 m). The mean dose of prednisone at beginning of study was 38.3 mg/d and at the end was 9.7 mg/d (p < 0.05). Complete remission of cutaneous lesions was observed in thirteen patients (72%) and partial remission in five (28%). Side effects observed were: drowsiness in eight patients, intestinal constipation in 5, transient oliguria in 1, paresthesia of hand with normal electromyography in another one. All side effects disappeared with reduction of thalidomide dose and no patient needed to stop treatment owing to side effect. CONCLUSION: Thalidomide is a good alternative therapy to SLE patients with refractory cutaneous lesions and without any risk of pregnancy.

Adolescent↗
PubMed2006

Thalidomide-induced severe hepatotoxicity.

Thalidomide is a relatively safe and efficacious form of therapy in the treatment of advanced, refractory multiple myeloma. Hepatotoxicity is listed as an extremely rare adverse effect associated with its use. We describe a 76-year-old woman with multiple myeloma who was treated with dexamethasone and thalidomide. By week 6 of therapy, she had developed acute increases in her aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels to more than 50 times the upper limit of normal. Her liver function test results had been within the normal ranges before and immediately after the start of therapy, and the patient had no known history of underlying liver disease. A liver biopsy specimen demonstrated evidence of acute injury with chronic changes of underlying steatosis and bridging fibrosis due to previously undiagnosed nonalcoholic steatohepatitis. Immediately after discontinuing thalidomide, her liver function test results began trending downward. Seven days later, her AST and ALT levels had improved to 86 and 165 U/L, respectively. This case and a limited number of other reports demonstrate severe hepatotoxicity as a rare but potentially serious adverse effect of thalidomide therapy. With the expanding use of thalidomide as a therapeutic agent, clinicians must recognize severe hepatotoxicity as a potential complication. Whether patients with preexisting liver disease are at increased risk when receiving thalidomide remains to be seen.

Aged↗
PubMed2006

Effects of combined therapy with thalidomide and glucantime on leishmaniasis induced by Leishmania major in BALB/c mice.

For treating Leishmania major infection in BALB/c mice, we used thalidomide in conjunction with glucantime. Groups of mice were challenged with 510(3) metacyclic promastigotes of L. major subcutaneously. A week after the challenge, drug treatment was started and continued for 12 days. Thalidomide was orally administrated 30 mg/kg/day and glucantime was administrated intraperitoneally (200 mg/kg/day). It was shown that the combined therapy is more effective than single therapies with each one of the drugs since the foot pad swelling in the group of mice received thalidomide and glucantime was significantly decreased (0.9 +/- 0.2 mm) compared to mice treated with either glucantime, thalidomide, or carrier alone (1.2 +/- 0.25, 1.4 +/- 0.3, and 1.7 +/- 0.27 mm, respectively). Cytokine study showed that the effect of thalidomide was not dependent on IL-12; however, it up-regulated IFN-gamma and down-regulated IL-10 production. Conclusively, thalidomide seems promising as a conjunctive therapy with antimony in murine model of visceral leishmaniasis.

Animals↗