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PubMed2006

Thalidomide in rat liver cirrhosis: blockade of tumor necrosis factor-alpha via inhibition of degradation of an inhibitor of nuclear factor-kappaB.

BACKGROUND/AIMS: Thalidomide inhibited tumor necrosis factor-alpha (TNF-alpha) effectively in many trials. The aim of this study was to investigate the effect of thalidomide on the expression of nuclear factor-kappaB (NF-kappaB), inhibitor of NF-kappaB (IkappaB) and TNF-alpha in a rat model of liver cirrhosis. METHODS: Liver cirrhosis was achieved by intraperitoneal injection of carbon tetrachloride thrice weekly, and thalidomide (10 or 100 mg/kg/day) was given daily by intragastric route for 8 weeks. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), prealbumin (PA), hyaluronic acid (HA) and laminin (LN), and hydroxyproline (HYP), NF-kappaBp65, alpha-smooth muscle actin (alpha-SMA) protein and TNF-alpha mRNA were studied in the liver, IkappaBalpha and TNF-alpha protein in the cytoplasm and NF-kappaBp65 protein in the nucleus. RESULTS: Compared with nontreated cirrhotic rats, the histopathology of rats given thalidomide (100 mg/kg) was significantly better. Serum ALT, AST, HA and LN and HYP content in the liver were significantly decreased and PA was elevated (p < 0.01) in this group; the expression of TNF-alpha mRNA and protein, NF-kappaBp65 and alpha-SMA were significantly decreased and IkappaBalpha protein was also elevated (p < 0.01). CONCLUSION: Thalidomide downregulates NF-kappaB-induced TNF-alpha and activates hepatic stellate cells (HSC) via inhibition of IkappaB degradation to prevent liver cirrhosis.

Actins↗
PubMed2006

Maintenance therapy for multiple myeloma with particular emphasis on thalidomide.

Treatment standards are changing as a result of new findings in the therapy of multiple myeloma. So far, prednisone, dexamethasone and interferon-a have mainly been used as maintenance therapy after achieving remission or stable disease. At present, thalidomide is being considered as a new therapeutic option in several studies investigating maintenance therapy. As a result of the dose dependence of adverse effects such as neuropathy, constipation, sedation/vertigo and bradycardia, individual adjustment of the thalidomide dose is recommended. Only isolated cases of thrombosis occurred in the maintenance phase of therapy, and discontinuation of therapy is generally not necessary. While important study results on the efficacy of thalidomide following conventional chemotherapy are still awaited, it is the best documented drug so far for maintenance therapy following autologous stem cell transplantation. An upgrade of the response was seen in 22-73% of patients, as well as a significant prolongation of progression-free survival. For the first time, maintenance therapy with thalidomide showed a significant improvement in overall survival in a phase III study published recently. The tolerability of thalidomide could be further improved by including the option of intermittent administration of the drug.

Angiogenesis Inhibitors↗
PubMed1990

Beneficial effect of thalidomide and ciclosporin combination in heterotopic cardiac transplantation in rats.

The effect of thalidomide on the prevention of early rejection was studied in heterotopic cardiac transplants between ACI (donors) and Lewis (recipients) rats, in combination with subtherapeutic doses of ciclosporin. Although allografts treated solely with thalidomide (5 mg/kg/day intraperitoneally) survived longer than controls (9.4 +/- 2.7 and 6.3 +/- 0.6 days, respectively, p less than 0.001), the survival rates of animals treated with low dose ciclosporin (1.25 mg/kg/day intraperitoneally) plus thalidomide (1.25, 2.5 and 5 mg/kg/day) were significantly better at 21 days (70, 88.9 and 88.9%, respectively), compared to 55.6% in those treated with ciclosporin (1.25 mg/kg/day) alone. Graft survival rates at 90 days were not significantly different in the thalidomide-ciclosporin combination groups (60, 77.8 and 55.6%, respectively) compared to the ciclosporin group alone (55.6%). We conclude that thalidomide is effective in preventing early rejection of rat cardiac allograft when combined with subtherapeutic doses of ciclosporin, thus avoiding the dose-dependent side effects of ciclosporin in the early posttransplant period.

Animals↗
PubMed1997

Sequential combined therapy with thalidomide and narrow-band (TL01) UVB in the treatment of prurigo nodularis.

BACKGROUND: Prurigo nodularis (PN) is a chronic disease of which treatment choices are limited. Among them, thalidomide and phototherapy have been used with satisfactory results. Unfortunately, the possibility of side effects limits their use. OBJECTIVE: To evaluate the efficacy of a sequential combined treatment with thalidomide and ultraviolet B (UVB) therapy in order to minimize side effects and, thus, making possible a long-term treatment. METHODS: A prospective open trial combining thalidomide as initial therapy followed by narrow-band UVB (TL01) irradiation until complete or almost complete remission of the disease was achieved. RESULTS: An excellent response was obtained after an average of 12 weeks of thalidomide therapy and 32 UVB courses. CONCLUSIONS: Sequential combined therapy with thalidomide and narrow-band UVB therapy could improve the management of prurigo nodularis with minimal side effects, although it should probably be reserved to men and women over 50 years of age.

Administration, Oral↗
PubMed2004

Antitumor activity of rituximab plus thalidomide in patients with relapsed/refractory mantle cell lymphoma.

We evaluated a treatment strategy targeting both lymphoma cells (by rituximab) and the microenvironment (by thalidomide) in 16 patients with relapsed/refractory mantle cell lymphoma (MCL). Rituximab was administered at 375 mg/m(2) for 4 weekly doses concomitantly with thalidomide (200 mg daily, with a dose increment to 400 mg on day 15), which was continued as maintenance therapy until progression/relapse. Thirteen patients (81%) experienced an objective response, with 5 complete responders (31%). Median progression-free survival (PFS) was 20.4 months (95% confidence interval [CI], 17.3-23.6 months), and estimated 3-year survival was 75%. In patients achieving a complete response, PFS after rituximab plus thalidomide was longer than PFS after the preceding chemotherapy. Severe adverse events included 2 thromboembolic events and 1 grade IV neutropenia associated with thalidomide. Our results suggest that rituximab plus thalidomide has marked antitumor activity in relapsed/refractory MCL and a low toxicity profile, which warrants further evaluation in MCL.

Aged↗
PubMed2005

Results of a phase 1 clinical trial of thalidomide in combination with fludarabine as initial therapy for patients with treatment-requiring chronic lymphocytic leukemia (CLL).

Tumor necrosis factor alpha (TNF-alpha) and vascular endothelial growth factor (VEGF) play an important role in the biology of chronic lymphocytic leukemia (CLL) cells. Thalidomide is a first-generation immuno-modulating agent that down-regulates TNF-alpha and VEGF. We initiated a phase 1/2 clinical trial to determine the safety and efficacy of combining thalidomide with fludarabine in patients with treatment-naïve CLL. Patients received 6 months of continuous daily thalidomide with standard monthly doses of fludarabine. Three dose levels of thalidomide (100, 200, and 300 mg) were studied. Results from the phase 1 part of this study are reported here. Thirteen patients were enrolled in the phase 1 component of the study. Dose-limiting toxicity was not reached. The most common toxicities noted were fatigue, constipation, and peripheral sensory neuropathy. Overall response rate was 100% with 55% of patients achieving complete remissions. At a median follow-up of 15+ months none of the patients have had a relapse and the median time to disease progression has not yet been reached. Responses were noted at all dose levels. Thalidomide given up to 300 mg/day concurrently with fludarabine in patients with previously untreated CLL shows encouraging clinical efficacy and acceptable toxicity. An ongoing phase 2 part of this study will help validate the clinical efficacy of this regimen.

Antineoplastic Agents↗
PubMed2001

Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy.

The occurrence of deep-vein thrombosis (DVT) in patients with newly diagnosed multiple myeloma, who were randomly assigned to receive identical induction chemotherapy with or without thalidomide, are reported in this study. The 2 study arms were comparable with respect to key myeloma prognostic factors and known risk factors for DVT. One hundred patients received induction chemotherapy including 4 cycles of continuous infusion of combinations of dexamethasone, vincristine, doxorubicin, cyclophosphamide, etoposide, and cisplatin, and each patient completed at least one induction cycle. DVT developed in 14 of 50 patients (28%) randomly assigned to receive thalidomide but in only 2 of 50 patients (4%) not given the agent (P =.002). All episodes of DVT occurred during the first 3 cycles of induction. Administration of thalidomide was resumed safely in 75% of patients receiving anticoagulation therapy. Thus, thalidomide given in combination with multiagent chemotherapy and dexamethasone is associated with a significantly increased risk of DVT, which appears to be safely treated with anticoagulation and does not necessarily warrant discontinuation of thalidomide.

Adult↗
PubMed2006

Valproate, thalidomide and ethyl alcohol alter the migration of HTR-8/SVneo cells.

BACKGROUND: Valproate, thalidomide and alcohol (ethanol) exposure during the first trimester of pregnancy is known to cause several developmental disorders. All these teratogens are known to pass the placental barrier and interfere directly with the normal development of the fetus. However, these teratogens also alter the formation and function of the placenta itself which may in turn affect the proper nourishment and development of the fetus. Optimum development of the placenta requires adequate invasion of trophoblast into the maternal uterine tissues. Changes in the migratory behavior of trophoblast by maternal exposure to these teratogens during placentogenesis may therefore alter the structure and function of the placenta. METHODS: In the present study, the effects of sodium valproate, thalidomide and alcohol on the migration of human first trimester trophoblast cell line (HTR-8/SVneo) were examined in vitro. Cells were cultured in the wells of 48-well culture plates as mono or multilayers. Circular patches of cells were removed from the center of the wells by suction, and the migration of cells into the wound was studied using microscopy. Effects of low and high concentrations of valproate, thalidomide and alcohol were examined on the healing of wounds and on the migration rate of cells by determining the wound areas at 0, 3, 6, 12, 24 and 48 h. Effects of drugs and alcohol on the proliferation and the expression levels of integrin subunits beta1 and alpha5 in cells were examined. RESULTS: The migration rates of trophoblast differed between wounds created in mono and multilayers of cells. Exposure to teratogens altered the migration of trophoblast into mono and multilayer wounds. The effects of valproate, thalidomide and alcohol on the proliferation of cells during the rapid migratory phase were mild. Drug exposure caused significant changes in the expression levels of beta1 and alpha5 integrin subunits. CONCLUSION: Results suggest that exposure to valproate, thalidomide or alcohol during the first trimester of pregnancy may change the ultrastructure of the placenta by altering the migration of trophoblast cells and this effect may be mediated by drug- or alcohol-induced changes in the expression levels of beta1 and alpha5 integrin subunits.

Cell Line↗
PubMed2001

Update on therapy--thalidomide in the treatment of lupus.

Thalidomide has been shown to be an effective treatment for cutaneous forms of lupus erythematous refractory to other therapies. Thalidomide has very serious side effects, including teratogenicity and neuropathy, which limit its clinical use in lupus to such severe refractory cases. Efficacy has been confirmed in several studies, although recurrence after discontinuation of treatment is frequent. More recent experience suggests that lower doses than originally used may be effective, which may result in a reduction in side effects. Much effort has been expended in studying the mechanisms of action of thalidomide, although as yet it is unclear which of the mechanisms identified to date contribute to its efficacy in treating cutaneous forms of lupus erythematosus. Identification of patients suitable for thalidomide therapy requires a rigorous selection process. Potential side effects should be clearly explained, particularly teratogenicity as many patients are young women. Written consent and a negative pregnancy test must be obtained prior to commencement of therapy. Reliable contraceptive measures should be strictly observed by patients taking thalidomide. Close clinical and neurophysiological supervision using nerve conduction studies should be undertaken.

Humans↗
PubMed2005

Long-term thalidomide use in refractory cutaneous lesions of lupus erythematosus: a 65 series of Brazilian patients.

Thalidomide has been reported as efficacious in refractory cutaneous lupus erythematosus (LE). The most fearful side-effects are teratogenicity and neuropathy. We reported clinical efficacy of long-term low-dose use of thalidomide in 65 patients with LE, emphasizing the prevalence of adverse effects, especially of neuropathy and its related factors. Data obtained from medical records included age, sex, disease duration, and the presence of diagnostic criteria for systemic lupus erythematosus (SLE), the extent and activity of cutaneous lesions and previous treatments. Sixty-three patients (98.9%) presented complete or partial improvement with thalidomide therapy. Drowsiness occurred in 50 patients (77%). Twenty-eight patients (43.2%) presented neuropathy symptoms. Nerve conduction studies were done in 21 (75%) of them and were abnormal in 12 (57%). With the interruption of thalidomide, 24 (82.5%) had complete or partial improvement of neuropathy symptoms and 23 (82%) of them had cutaneous relapse. There were no significant differences between those who developed or not neuropathy in treatment duration, age, total dose and systemic versus cutaneous LE. In conclusion, thalidomide can be used in refractory cutaneous LE with great efficacy and relative security. Controlled studies with schemes with lower doses or intermittent usage or alternative drugs are wanted to reduce the burden of cutaneous morbidity of lupus erythematosus.

Adolescent↗
PubMed2002

Temozolomide plus thalidomide in patients with advanced melanoma: results of a dose-finding trial.

PURPOSE: To establish a safe and tolerated regimen of an oral cytotoxic agent, temozolomide, and a cytostatic agent, thalidomide, in patients with unresectable stage III or IV malignant melanoma. PATIENTS AND METHODS: Patients with unresectable stage III or IV melanoma without brain metastases were entered successively onto four treatment cohorts: level 1, temozolomide 50 mg/m(2)/d for 6 weeks followed by a 4-week break; levels 2, 3, and 4, temozolomide 75 mg/m(2)/d for 6 weeks followed, respectively, by breaks of 4, 3, and 2 weeks. Thalidomide was started at 200 mg/d, and escalated to a maximum dose of 400 mg/d. Safety was assessed at weeks 2 and 4 and every 4 weeks thereafter; tumor response was evaluated every 8 to 10 weeks. RESULTS: Twelve patients were enrolled, three on each cohort. Therapy was generally well tolerated on all of the treatment schedules. Thalidomide at a dose of 400 mg/d was well tolerated in patients younger than 70, and 200 mg/d was well tolerated in older patients. The most common adverse events were grade 2 or 3 constipation and neuropathy, which were attributed to thalidomide. Five major responses (one complete, four partial) were documented, all at dose levels 2 to 4. Three of the five responding patients were in the over-70 age group. The median duration of response was 6 months (range, 4 to 17+ months), and the median overall survival was 12.3 months (range, 4 to 19+ months). CONCLUSION: The combination of temozolomide and thalidomide was well tolerated and had antitumor activity in patients with advanced melanoma, including elderly patients over 70 years old.

Aged↗
PubMed2003

Interferon alfa-2b three times daily and thalidomide in the treatment of metastatic renal cell carcinoma.

PURPOSE: The antiangiogenic effect of interferon (IFN) may improve with frequent dosing and by combination with other agents with antiangiogenic activity. To evaluate this potential, we treated patients with metastatic renal cell carcinoma (RCC) with frequently dosed IFN and thalidomide. PATIENTS AND METHODS: Thirty patients were given IFN-alpha-2b 0.9 MU subcutaneously three times daily for 1 month and subsequently 1.2 MU tid unless serious toxicity was encountered. Thalidomide was first given 100 mg/d for 1 week and 300 mg/d thereafter. Sera were collected before and during treatment for serum vascular endothelial growth factor (S-VEGF) analyses performed using enzyme-linked immunosorbent assay. RESULTS: The intention-to-treat response rate was 20% (95% CI, 6% to 34%) and response rate for assessable patients (n = 27) was 22% (95% CI, 6% to 38%). All responses were partial. In addition, 17 patients (63%; 95% CI, 45% to 81%) had stable disease for 3 months or longer. The median time to treatment failure was 7.7 months, and median survival time was 14.9 months. The most common cause of thalidomide discontinuation was neuropathy. S-VEGF levels decreased more in patients who responded to therapy compared with those in patients whose condition had stabilized or who had progressive disease (P =.036). CONCLUSION: The combination of frequently dosed IFN-alpha-2b and low-dose thalidomide is feasible and active in advanced RCC, but the clinical benefit may remain small compared with that of IFN alone. Results from an ongoing phase III trial comparing IFN-alpha with or without thalidomide need to be analyzed before this combination can be recommended for use outside clinical studies.

Angiogenesis Inhibitors↗
PubMed2003

Phase II trial of thalidomide and carmustine for patients with recurrent high-grade gliomas.

PURPOSE: The use of thalidomide as an antiangiogenic agent has met with only limited success in the treatment of malignant gliomas. On the basis of preclinical data demonstrating synergistic antitumor activity when antiangiogenic agents are combined with cytotoxic agents, we explored the clinical activity of the combination of thalidomide and carmustine (BCNU) in patients with recurrent high-grade gliomas. PATIENTS AND METHODS: Patients with a histologic diagnosis of high-grade glioma and radiographic evidence of tumor progression after standard surgery, radiation, and chemotherapy were eligible for the study. Patients received BCNU 200 mg/m2 on day 1 of every 6-week cycle, and 800 mg/d of thalidomide that was escalated to a maximal dose of 1,200 mg/d as tolerated. RESULTS: A total of 40 patients (38 with glioblastomas, two with anaplastic gliomas) were accrued to the study. The combination of thalidomide and BCNU was well tolerated; mild myelosuppression and mild to moderate sedation were the most common side effects. The median progression-free survival (100 days) and the objective radiographic response rate (24%) for patients with glioblastoma compared favorably with data from historical controls. CONCLUSION: This is one of the first clinical trials to evaluate the strategy of combining a putative antiangiogenic agent with a cytotoxic agent in patients with primary brain tumors. Our data demonstrate that thalidomide in combination with BCNU is well tolerated and has antitumor activity in patients with recurrent high-grade gliomas. Although the combination seems to be more active than either agent alone, such conclusions await confirmatory trials.

Adult↗
PubMed2006

Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors.

PURPOSE: Standard, intravenous chemotherapy regimens for neuroendocrine tumors have been associated with limited response rates and significant toxicity. We evaluated the efficacy of an oral regimen of temozolomide and thalidomide in patients with metastatic carcinoid, pheochromocytoma, or pancreatic neuroendocrine tumors. PATIENTS AND METHODS: Twenty-nine patients were treated with a combination of temozolomide, administered at a dose of 150 mg/m2 for 7 days, every other week, and thalidomide at doses of 50 to 400 mg daily. Patients were followed for evidence of toxicity, biochemical response, radiologic response, and survival. RESULTS: Treatment with temozolomide and thalidomide was associated with an objective biochemical (chromogranin A) response rate of 40%, and a radiologic response rate of 25% (45% among pancreatic endocrine tumors, 33% among pheochromocytomas, and 7% among carcinoid tumors). The median duration of response was 13.5 months, 1-year survival was 79%, and 2-year survival was 61%. The median administered dose of temozolomide was 150 mg/m(2), and the median administered dose of thalidomide was 100 mg daily. Grade 3-4 toxicities were uncommon, with the exception of grade 3-4 lymphopenia, which developed in 69% of the patient population. Opportunistic infections occurred in three patients (10%) during the time of lymphopenia, and included single cases of Pneumocystis carinii pneumonia, disseminated varicella zoster virus, and herpes simplex virus. CONCLUSION: Orally administered temozolomide and thalidomide seems to be an active regimen for the treatment of neuroendocrine tumors. In this 29-patient study, this regimen appeared more active in pancreatic endocrine tumors than in carcinoid tumors.

Adrenal Gland Neoplasms↗
PubMed1998

Thalidomide promotes the release of tumor necrosis factor-alpha (TNF-alpha) and lethality by lipopolysaccharide in mice.

We investigated the in vivo effects of thalidomide on the production of tumor necrosis factor-alpha (TNF-alpha). An in vivo systemic release of TNF-alpha occurred after the injection of lipopolysaccharide (LPS) in male ddY mice, and the TNF-alpha serum levels reached 652.2 +/- 75.7 pg/ml 90 min after the injection of LPS (0.3 mg/kg, i. p.). When thalidomide (1, 3, or 6 mg/kg) was administered intraperitoneally 3 h before the injection of LPS (0.3 mg/kg, i. p.), thalidomide markedly enhanced LPS-induced TNF-alpha release in a dose-dependent manner. The TNF-alpha serum levels at 90 min were 640 +/- 58.6, 1985 +/- 132.6, and 2795 +/- 203.5 pg/ml, respectively, compared to 628.6 +/- 64.4 pg/ml in mice treated with LPS-alone. Pretreatment with a single injection of thalidomide (1, 3, or 6 mg/kg, i. p.) dose-dependently increased the subsequent mortality caused by a challenge with LPS (15 mg/kg, i. p.), a dose that caused death in 10% of the control mice. We conclude that thalidomide enhances in vivo TNF-alpha secretion and the lethality of LPS in mice.

Animals↗
PubMed1994

(S)-form of alpha-methyl-N(alpha)-phthalimidoglutarimide, but not its (R)-form, enhanced phorbol ester-induced tumor necrosis factor-alpha production by human leukemia cell HL-60: implication of optical resolution of thalidomidal effects.

The rate of racemization of N(alpha)-phthalimidoglutarimide (thalidomide) was determined as its half life to be 566 min at pH 7.4/37 degrees C. This fast racemization of thalidomide resulted in no apparent difference between (S)- and (R)-forms of the compound on enhancing activity of phorbol ester-induced tumor necrosis factor (TNF)-alpha production by human leukemia HL-60 cells. Optically pure forms of structurally related analog of thalidomide, (S)- and (R)-alpha-methyl-N(alpha)-phthalimidoglutarimides (methylthalidomides), which do not racemize under the physiological condition, were prepared. Only (S)-form of methylthalidomide, but not its (R)-form, elicited TNF-alpha production-enhancing effect, suggesting that the (S)-isomer of thalidomide would be the active form in terms of thalidomidal biological response modifying effects.

Cell Division↗
PubMed2002

Thalidomide use in pediatric patients.

OBJECTIVE: To provide a detailed overview of thalidomide use in pediatric patients. DATA SOURCES: English-language articles were identified through a MEDLINE search (1966-February 2001); key terms included thalidomide, child, graft-versus-host disease, cancer, HIV, Crohn's disease, Behçet's disease, and lupus erythematosus. References cited in those articles were also evaluated. DATA SYNTHESIS: Thalidomide appears to be effective in patients with chronic, not acute, graft-versus-host disease (GVHD) and in healing aphthous ulcers in patients with HIV infection. Limited case reports suggest efficacy of thalidomide in the treatment of cutaneous manifestations of Behçet's disease, Crohn's disease, and lupus in children; however, the recurrence of disease is almost universal on drug discontinuation. CONCLUSIONS: Thalidomide should be used as a last resort when all other therapies fail, preferably in male or prepubescent female patients.

Adolescent↗
PubMed2003

Thalidomide dosing in patients with relapsed or refractory multiple myeloma.

OBJECTIVE: To evaluate the literature regarding the dosing of thalidomide in multiple myeloma. DATA SOURCES: A MEDLINE search (1990-February 2003) using the search terms thalidomide and multiple myeloma was performed to identify clinical trials and abstracts. Identified literature was then cross-referenced for further pertinent data. DATA SYNTHESIS: Patients with relapsed or refractory multiple myeloma have few therapeutic options. Thalidomide is a promising agent, although many dose-related issues are still in question. Starting doses studied ranged from 50 to 200 mg/d, usually given at bedtime. Gradual dose escalation up to 800 mg/d has been studied, with some evidence of improved outcome with doses of 400-600 mg/d, while thalidomide appears to be best tolerated at doses </=400 mg/d. CONCLUSIONS: A reasonable approach for use of thalidomide in multiple myeloma is to initiate therapy at 50-100 mg nightly and escalate every 2 weeks in 50- to 100-mg increments as tolerated. Efforts should be made to titrate the dose to 400-600 mg/d, especially in patients with poor prognostic features. Efficacy should be assessed at approximately 8 weeks and the dose maintained if desired response is achieved.

Antineoplastic Agents↗