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PubMed1993

The influence of thalidomide on the clinical and immunologic manifestation of erythema nodosum leprosum.

Immunologic and clinical manifestations of erythema nodosum leprosum (ENL) and their response to thalidomide therapy were evaluated. Circulating tumor necrosis factor-alpha (TNF alpha) levels were assayed in serum obtained from lepromatous leprosy patients at diagnosis, during multidrug therapy, at the onset of ENL episodes, and during treatment with thalidomide. Patients with systemic ENL demonstrated the highest serum TNF alpha levels, which decreased significantly during thalidomide treatment. Serum TNF alpha in nonreactional patients was associated with mild flu-like symptoms and local inflammatory lesions. Serum interferon-gamma (IFN-gamma) was also elevated in patients with high TNF alpha levels. Thalidomide therapy reduced not only serum TNF alpha levels and the clinical symptoms but also the dermal infiltration of polymorphonuclear leukocytes and T cells. The expression of intercellular adhesion molecule 1 and major histocompatibility complex class II antigens on the epidermal keratinocytes was also down-regulated. These results indicate that the thalidomide-induced alleviation of clinical symptoms of ENL was associated with a reduction of TNF alpha levels.

Adult↗
PubMed1995

Thalidomide inhibits tumor necrosis factor-alpha production by lipopolysaccharide- and lipoarabinomannan-stimulated human microglial cells.

Tumor necrosis factor-alpha (TNF-alpha) is a pathogenic factor in bacterial meningitis. The effect of thalidomide on TNF-alpha production by microglia, the resident macrophages of the brain, was evaluated. In primary human fetal microglial cell cultures stimulated with lipopolysaccharide or lipoarabinomannan, thalidomide inhibited TNF-alpha release in a dose-dependent manner. The inhibitory effect of thalidomide was similar to that of dexamethasone, although expression of TNF-alpha mRNA in microglial cells was reduced only by thalidomide. The results of this in vitro study suggest that thalidomide could have therapeutic potential in gram-negative bacterial and tuberculous meningitis.

Base Sequence↗
PubMed1996

Thalidomide, a hypnotic with immune modulating properties, increases cataplexy in canine narcolepsy.

Thalidomide is a sedative hypnotic that was widely used in the 1950s but was withdrawn due to its teratogenic properties. The compound has recently been reintroduced as an immune modulating agent. Thalidomide significantly aggravates canine cataplexy, a pathological manifestation of rapid eye movement (RFM) sleep atonia seen in narcolepsy. This compound also increases REM sleep and slow wave sleep in these animals. In vitro receptor binding and enzyme assays demonstrate that thalidomide does not bind to or enzymatically modulate the neurotransmitter systems reported to be involved in the regulation of cataplexy. Thalidomide may therefore affect cataplexy through its immune modulation properties. Further studies on the mechanisms of action of thalidomide should increase our understanding of the pathophysiology of this disabling disorder.

Animals↗
PubMed1997

Thalidomide suppresses T- and B-cell responses to myelin antigen in experimental allergic neuritis.

The effects of thalidomide and, for reference, dexamethasone on T- and B-cell functions were assayed in vitro in Lewis rats with experimental allergic neuritis induced by active immunization with bovine peripheral nerve myelin (BPM) and complete Freund's adjuvant. Thalidomide and dexamethasone at the concentration ranges 10(-5)-10(-7) g/ml and 4 x 10(-5)-4 x 10(-9) g/ml, respectively, both inhibited phytohemagglutinin (PHA)- and BPM-induced T-cell proliferation as well as levels of PHA- and BPM-reactive interferon (IFN)-gamma-secreting cells, reflecting the suppression of Th1-like cells. The effect of dexamethasone was most pronounced on PHA-induced T-cell proliferation and IFN-gamma secretion, whereas the effect of thalidomide was most pronounced on BPM-induced T-cell proliferation and IFN-gamma secretion. Thalidomide reduced the B-cell responses to both BPM and Mycobacterium tuberculosis purified protein derivative, but to a lesser extent than dexamethasone. The in vitro design described could be useful to evaluate compounds with putative immunomodulatory activities. The inhibitory effects of thalidomide on autoantigen-induced Th1-cell functions may warrant the use of this substance in T-cell-mediated autoimmune diseases.

Animals↗
PubMed2002

Thalidomide as "salvage" therapy for patients with delayed hypersensitivity response to infliximab: a case series.

Infliximab is efficacious for refractory Crohn's disease, but delayed hypersensitivity reactions preclude retreatment for patients experiencing this complication. We report the results of four patients offered enrollment in an open label trial of thalidomide as "salvage" therapy for their refractory disease. Two patients with active fistulous disease and two with lumenal disease received open-label thalidomide 200 mg every night and were evaluated monthly at the University of Chicago Clinical Research Center for 12 weeks. Before administration, patients signed an informed consent form discussing the potential risks of thalidomide use. Female patients of child-bearing age underwent serum pregnancy testing every 4 weeks. Response was defined as an absolute decrease in Crohn's Disease Activity Index (CDAI) by 100 points or improvement in two of three clinical parameters for fistulous disease. A patient with a single perirectal fistula had complete closure by 4 weeks, the other had noticeable improvement of five perianal fistulae at 4 weeks and complete closure by 12 weeks. One lumenal patient had a CDAI decrease of 250 points in 4 weeks. The fourth patient withdrew secondary to sedation after only a week of therapy. Two patients (one fistula, one lumenal) continued thalidomide past the 3-month study period and remained in remission at 5 and 7 months. Side effects reported were sedation (four of four patients), hypertension (one of four), and peripheral neuropathy (one of four). Thalidomide appears to be a safe and effective alternative for short-term healing in patients who develop infliximab-induced delayed hypersensitivity reaction and may be an alternative strategy for those at risk.

Adult↗
PubMed2004

Phase II study of thalidomide in patients with metastatic melanoma.

The aim of this study was to determine the antitumour activity and toxicity of thalidomide in patients with metastatic melanoma. Between July 1999 and July 2001, 20 patients with metastatic melanoma were enrolled into this study. Patients were required to have progressive disease following standard therapies (unless there was a known contraindication for their usage) and to be free from symptomatic brain metastases. Thalidomide was administered orally at a starting dose of 200 mg/day, with increments of 100 mg every 7 days to a maximum dose of 800 mg/day. Patients experiencing intolerable side effects had their dose reduced to the maximum tolerated dose. Response and tolerance to treatment were assessed at 4 week intervals and therapy was continued until progression of disease or development of intolerable side effects despite appropriate dose reduction. All 20 patients were assessable for response. No objective response (complete or partial remission) was observed. In seven patients (35%), stable disease with a duration of 12-32 weeks (median 16 weeks) was seen. The median time to progression for all patients was 8 weeks (range 5-32 weeks) and the median overall survival was 20 weeks (range 7-130+ weeks). Treatment was generally well tolerated. Nine patients (45%) were able to tolerate the maximal planned dose of thalidomide (800 mg/day). Constipation, fatigue, somnolence and dryness of skin or mouth were the most common side effects. Thalidomide appears to possess cytostatic activity in patients with metastatic melanoma. Further studies of thalidomide in melanoma are warranted.

Adult↗
PubMed2004

Phase II study of thalidomide in patients with metastatic malignant melanoma.

Thalidomide has anti-angiogenic and immunomodulatory activity, exhibiting antitumour effects in patients with multiple myeloma and, more rarely, in several other solid tumours. We evaluated the single-agent antitumour activity and toxicity profile of thalidomide in patients with metastatic malignant melanoma, as well as its plasma pharmacokinetics and pharmacodynamic effects [vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF) levels]. A two-stage Gehan method was used with a stopping rule after 14 consecutive non-responding patients. Thalidomide was given orally at a daily dose of 200 mg/day, which was then escalated every 2 weeks by 200 mg/day as tolerated to a maximum of 800 mg/day. Patients were evaluated every 8 weeks for response using the World Health Organization (WHO)-27 criteria. Fourteen patients were enrolled and no objective responses were observed, with one stable disease and one mixed response. The dose-limiting toxicities were constipation, dizziness and somnolence. Other toxicities were oedema, neuropathy, dry skin, dry mouth, tremor and fatigue. The plasma pharmacokinetics of thalidomide were comparable with those of previous studies in normal volunteers and in patients with advanced prostate cancer. Serum levels of b-FGF and VEGF did not change significantly following drug administration. In conclusion, thalidomide showed poor activity, but acceptable toxicity, in patients with metastatic melanoma. Future studies should explore this agent in combination with other biological agents or cytotoxic agents, such as temozolomide.

Administration, Oral↗
PubMed2006

Refractory bleeding from portal hypertensive gastropathy: a further novel role for thalidomide therapy?

Bleeding from portal hypertensive gastropathy (PHG) can pose a therapeutic challenge. Thalidomide, which selectively inhibits tumour necrosis factor-alpha production by enhancing messenger RNA degradation, has been shown to reduce portal venous pressure in cirrhotic and non-cirrhotic portal hypertension. Thalidomide is also a potent inhibitor of angiogenesis. We describe a case of intractable bleeding from PHG secondary to extrahepatic portal vein obstruction due to malignancy, which was managed successfully by thalidomide, thus obviating the need for major surgery. Although the use of thalidomide for treatment of severe intestinal bleeding has been described previously, this is the first case report, to our knowledge, describing its efficacy in bleeding secondary to PHG. We discuss the possible therapeutic mechanisms for thalidomide in PHG.

Angiogenesis Inhibitors↗
PubMedDate not supplied

Pulmonary toxicity during prostate cancer treatment with docetaxel and thalidomide.

The standard therapies of surgery, radiotherapy, and hormonal manipulations often fail to control metastatic prostate cancer (PC). Docetaxel and thalidomide may have activity in refractory PC. We highlight the potential pulmonary toxicity when docetaxel is combined with thalidomide. We reviewed three examples of docetaxel and thalidomide pulmonary toxicity at the National Cancer Institute (NCI) and summarized the published literature regarding docetaxel and thalidomide pulmonary toxicity. Docetaxel and thalidomide pulmonary toxicity has the following four main presentations: (1). symptomatic effusions; (2). dyspnea on exertion without any objective pathologic evidence; (3). interstitial lung disease; and (4). pulmonary embolus. As chemotherapy becomes more common in the treatment of PC, clinicians must consider possible pulmonary toxicities. If pulmonary symptoms or signs develop, clinicians should consider holding chemotherapy pending a complete evaluation.

Aged↗
PubMed2006

Blood flow changes in hepatocellular carcinoma after the administration of thalidomide assessed by reperfusion kinetics during microbubble infusion: preliminary results.

OBJECTIVES: We sought to investigate whether thalidomide is able to produce tumor vascular changes in patients with untreatable hepatocellular carcinoma (HCC) that can be detected using microbubble contrast agents. MATERIALS AND METHODS: Eleven consecutive patients with untreatable HCC underwent contrast-enhanced ultrasound before and during thalidomide administration. Real-time destruction reperfusion kinetics was obtained from a representative HCC nodule and from the surrounding liver parenchyma during SonoVue infusion (Bracco, Milan, Italy) at a constant rate of 0.10 mL/s by using a syringe pump and modelized according to the mathematical function SI = A(1 - exp(-betat)) where the plateau signal intensity A reflects the percent blood volume, the time constant beta reflects the average speed of blood, and their product A*beta reflects the nutrient blood flow. RESULTS: Size of the representative nodule reduced significantly 3 to 6 months after the start of thalidomide treatment. Before thalidomide administration A, beta, and A*beta of the index lesion were 44 +/- 60 LIU, 0.31 +/- 0.40 seconds and 8.1 +/- 11.8 LIU/s, respectively). A and A*beta reduced significantly after 15 days (26 +/- 50 LIU and 2.9 +/- 4.8 LIU/s, P < 0.01), 3 months (12 +/- 18 LIU, and 4.3 +/- 7.7 LIU/s, P < 0.01), and 6 months (13 +/- 23 LIU and 2.4 +/- 3.7 LIU/s, P < 0.05) of treatment. No statistically significant changes of the exponential time constant beta were observed, nor changes of A, beta and A*beta in the liver parenchyma. CONCLUSIONS: Contrast-enhanced ultrasound can be used effectively to evaluate changes in perfusion parameters of HCC nodules during thalidomide administration.

Aged↗
PubMed2005

Hepatic plasmacytosis as a manifestation of relapse in multiple myeloma treated with thalidomide.

Thalidomide and its analogs have been extensively studied in patients with multiple myeloma. We present the case of a 58-year-old female patient with immunoglobulin GA-kappa multiple myeloma who was receiving thalidomide after failing an autologous transplant. She presented with profound asthenia and several space-occupying hepatic lesions, one of which was shown by a CT-guided percutaneous biopsy to be plasmacytoma. The patient then received bortezomib and had a transient response. Because thalidomide may also increase the expression of cytoadhesion molecules in myeloma cells and in the bone marrow microenvironment, it is possible that some patients with multiple myeloma who relapse on thalidomide may present with extramedullary plasmacytomas, as seen in this case. Therefore, whenever symptoms arise in patients with multiple myeloma who are receiving thalidomide, extramedullary plasmacytomas should be considered.

Antineoplastic Agents↗
PubMed1990

Treatment of severe colitis in Behçet's syndrome with thalidomide (CG-217).

A 35-year-old male patient, known in our department since 1979 on account of a severe and complete Behçet's syndrome, was treated with thalidomide (CG-217) as a final pharmacological measure to avoid colectomy during a severe attack of Behçet colitis. Prior to the administration of thalidomide, the patient had been treated for 7 weeks with full parenteral nutrition and high doses of steroids intravenously without a satisfactory effect on the colitis. Treatment with sulphasalazin was unsuccessful because of a decreasing number of platelets on this drug. After a few days on thalidomide, 300 mg given once daily at bedtime, the patient's stools were normalized and without reaction for blood, his oral ulcers and pleural effusion disappeared, and his steroid doses could be reduced. Gradually he was put on oral nutrition again, and his rectal mucosa became normalized. The dose of thalidomide was reduced to 200 mg, and then to 100 mg daily when the patient was discharged from hospital, less than 3 weeks after institution of the drug treatment. After 5 months as an out-patient his condition is still satisfactory and without symptoms of his former disease. Thalidomide has previously been reported to be of value in treatment of Behçet's syndrome, but to my knowledge never with such a dramatic effect on a severe colitis as reported in this case.

Adult↗
PubMed1994

Immunostimulatory effect of thalidomide in normal C57BL/6 mice is compatible with stimulation of a highly connected central immune system.

Although thalidomide has been used with success in the treatment of increasing numbers of autoimmune diseases, the therapeutic effects have not been satisfactorily explained so far. We describe here some findings that may contribute to a better understanding of the immunomodulatory effects of this drug. Several immunological changes were observed after treating C57BL/6 mice with 3 mg of thalidomide. The numbers of natural IgM PFC against sheep red blood cells were increased in the spleen, and occasionally a dramatic oscillatory increase in the numbers of non-specific splenic IgM and IgG PFC was observed in these mice. However, these oscillatory increases were progressively lower, after two and three treatments with thalidomide at 20-day intervals. Furthermore, the absolute numbers of splenic CD5+ B and CD5- B lymphocytes were increased whereas depletion of CD4+ CD8+ cells in the thymus and of lymphoid cells in the bone marrow was seen after a single treatment with 3 mg of thalidomide. Taken together, these results suggest that thalidomide stimulates both peripheral and central immune systems and consequently enhances the connectivity of the central immune system.

Animals↗
PubMed2002

Thalidomide suppresses the interleukin 1beta-induced NFkappaB signaling pathway in colon cancer cells.

Thalidomide has been shown to have both antiinflammatory and antiangiogenic effects in several diseases. However, its cellular target and mechanism of action are poorly understood. We investigated the action mechanism of thalidomide through the NFkappaB pathway. Thalidomide inhibited interleukin (IL) 1beta-induced NFkappaB transcriptional activation and IL-8 production in Caco-2 colon cancer cells. In addition, thalidomide suppressed NFkappaB nuclear translocation, IkappaB degradation, and NFkappaB-inducing kinase (NIK)-induced NFkappaB transcriptional activation. These results suggest that the molecular target of the effects of thalidomide may be IkappaB phosphorylation by IkappaB kinase (IKK), whose activation follows NIK activation and precedes IkappaB degradation in the NFkappaB pathway.

Colonic Neoplasms↗
PubMed2003

Thalidomide-induced suppression of embryo fibroblast proliferation requires CYP1A1-mediated activation.

An enzyme involved in the metabolic activation of thalidomide has been investigated using embryo fibroblast proliferation as a marker. Thalidomide (30 microM) induced-suppression of embryo fibroblast proliferation was detected in the presence of liver microsomes from rabbit but not from mouse. The addition of a selective inhibitor of CYP1A, alpha-naphthoflavone (4 microM), or furafylline (4 microM), to the incubation mixture abolished the thalidomide-induced suppression. Furthermore, addition of anti-rat CYP1A1 antibody also resulted in inhibition of suppression. The thalidomide-induced suppression was also observed with the microsomal system from human HepG2 cells pretreated with 3-methylcholanthrene (10 microM) but not from those pretreated with the vehicle. Both CYP1A1 and CYP1A2 proteins were detected in the rabbit liver microsomes by immunoblot analyses, but only CYP1A2 protein was detected in the mouse liver microsomes. In addition, CYP1A1 protein was detected in microsomes from HepG2 cells pretreated with 3-methylcholanthrene but not with the vehicle. These results strongly suggest the involvement of CYP1A1 in the thalidomide-induced suppression of embryo fibroblast proliferation.

Animals↗
PubMed2004

Thalidomide for treatment of severe intestinal bleeding.

Apart from its anti-inflammatory activity, which has been used for the treatment of active Crohn's disease, thalidomide is also a potent inhibitor of angiogenesis. We therefore studied the effect of thalidomide in six patients with severe recurrent intestinal bleeding refractory to standard treatment (three patients with Crohn's disease (CD), three patients with obscure intestinal bleeding; mean of 56 blood transfusions within the last 24 months). Bleeding stopped within two weeks after the start of thalidomide in all patients. Haemoglobin normalised without further transfusions for the whole observation period (mean follow up 33 months) while patients needed a mean of 2.2 (CD) and 3.1 (obscure bleeding) blood units/month in the 12 months before treatment. After three months of thalidomide therapy, serum levels of vascular endothelial growth factor were strongly suppressed compared with pretreatment levels. (CD 818 (82) v 129 (86) pg/ml; obscure bleeding 264 (68) v 50 (25) pg/ml). All six patients reported transient fatigue. Peripheral neuropathy was observed in one patient with CD after nine months and was reversible after lowering the dose to 100 mg daily. These results indicate that thalidomide might be useful for patients with otherwise refractory intestinal bleeding.

Adult↗
PubMed2005

Effect of thalidomide in hepatocellular carcinoma: assessment with power doppler US and analysis of circulating angiogenic factors.

PURPOSE: To prospectively evaluate the feasibility of using power Doppler ultrasonography (US) and measurement of circulating angiogenic factors to assess the antiangiogenic effect of thalidomide in hepatocellular carcinoma. MATERIALS AND METHODS: The Ethics Committee of the National Taiwan University Hospital approved the study, and all patients gave prior written informed consent. Evaluation of response to thalidomide treatment was based on findings at computed tomography (CT) and change in serum alpha-fetoprotein level. Tumor vascularity index was evaluated with power Doppler US in patients with advanced hepatocellular carcinoma treated with 200-300 mg/d thalidomide. Serum levels of vascular endothelial growth factor, basic fibroblast growth factor, and placental growth factor were measured with enzyme-linked immunoassay. The chi(2) test or Fisher exact test was used for categorical variables, and the nonparametric Mann-Whitney test was used for numeric variables. A P value of less than .05 was considered to indicate a statistically significant difference. RESULTS: Of 47 patients enrolled in the study who had disease that was bidimensionally assessable on CT scans, 44 were assessable for tumor response. Of the 44 evaluated, five were classified as showing objective response (responders): One each showed a complete and a partial response according to World Health Organization criteria, and three had a decrease in alpha-fetoprotein level by more than 50% and stable disease for 10.4, 5.3, or 3.5 months. The pretreatment vascularity index was significantly higher in responders (median, 7.42; range, 2.99-13.90) than in nonresponders (median, 2.15; range, 0-25.36) (P = .03). Four of five responders had a significant decrease in vascularity index with thalidomide. Serum levels of angiogenic factors did not differ significantly between responders and nonresponders. CONCLUSION: Higher vascularity index may be associated with a better chance of response to thalidomide in patients with advanced hepatocellular carcinoma. Serum levels of circulating angiogenic factors do not appear to be clinically useful as an indicator of response.

Adult↗
PubMedDate not supplied

Thalidomide and prednisolone inhibit growth factor-induced human retinal pigment epithelium cell proliferation in vitro.

Thalidomide and prednisolone were recently introduced as treatment modalities in age-related macular degeneration (AMD). Growth factor-induced activation of retinal pigment epithelial (RPE) cells is a crucial event in this disease. The purpose was to examine the effect of thalidomide and prednisolone on growth factor-preactivated RPE cells. Human RPE cells were stimulated with 10 ng/ml platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), or vascular endothelial growth factor (VEGF) for 24 h. Afterwards, thalidomide (50 microg/ml) or prednisolone (100 ng/ml) were added for 24 h. RPE cell proliferation was determined by [3H]-thymidine incorporation. PDGF and bFGF significantly stimulated human RPE cell proliferation (p < 0.005), the value for VEGF stimulation was not significant (p = 0.3). The effect of the growth factors was diminished after addition of thalidomide and prednisolone (p < 0.005). The current study shows that the inhibitory properties of thalidomide and prednisolone remain even after growth factor activation of the cells.

Angiogenesis Inducing Agents↗