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PubMed2001

[Evaluation of blood morphology in patients with refractory multiple myeloma treated with thalidomide].

Thalidomide, a derivative of alpha-N-phthalimidoglutarimide acid, was withdrawn from the market in the 1960s because of severe birth defects. Recent reports have suggested antiangiogenic and antitumor activity of this drug. We have treated 52 patients with refractory multiple myeloma at age from 32 to 79 years (mean 63) with thalidomide at a dose of 200-400 mg daily. Out of the group of 52 patients, 27 patients (52%) responded to the therapy, in 25 patients (48%) a response was not achieved (decline in monoclonal protein was smaller than 25%). There was a systematic improvement in haemoglobin concentration, erythrocyte count and thrombocyte count during thalidomide therapy. Leukocyte count showed an inclination to decrease, however observed changes were not statistically significant. The improvement in morphotic parameters of blood was observed both in responder and nonresponder patients.

Adult↗
PubMed2003

Expression of angiogenic factors including VEGFs and the effects of hypoxia and thalidomide on human myeloma cells.

Angiogenic factors are major causes of tumor progression in hematological malignancies, particularly multiple myeloma, as well as solid tumors. The introduction of thalidomide as an anti-angiogenic agent in myeloma treatment has demonstrated the importance of angiogenic factors in the progression of myeloma. However, the direct effects of angiogenic factors, particularly VEGFs, hypoxia, and thalidomide, on myeloma cells are not been documented. In this study, we demonstrate increased expression and production levels of VEGF in myeloma compared to non-myelomatous hematological lines, resistance to hypoxia and enhancement of VEGF-A production by hypoxia in myeloma, and direct growth inhibition of myeloma cells due to apoptosis and G1 arrest caused by TNFalpha upregulation induced by thalidomide. These findings may encourage the clinical use of anti-angiogenic agents for their cytostatic effects and the prevention of progression.

Angiogenesis Inducing Agents↗
PubMed2002

[Therapeutic effectiveness of thalidomide to multiple myeloma and its mechanism].

OBJECTIVE: To observe the effective mechanism and side effects of thalidomide to multiple myeloma (MM). METHODS: Ten cases of MM were studied, of which 3 were previously untreated and 7 refractory or relapsed. Bone marrow microvascular density (MVD) was detected by factor-VIII related antigen and CD(34) immunohistological staining and serum concentration of vascular endothelial growth factor (VEGF) before and after treatment was determined by ELISA. The initial dosage of thalidomide was 100 approximately 200 mg/d with a weekly escalation of 50 mg/d to 450 approximately 650 mg/d. The therapeutic effectiveness is classified into partial remission, improvement and uneffective according to the decrease of serum M protein and bone marrow myeloma cells. Anemia, renal function and blood electrolytes were also observed. RESULTS: Before treatment, MVD was 73.32 +/- 28.80 and 32.30 +/- 12.50 in MM and control group, respectively, (P < 0.01). MVD in MM group decreased to 56.12 +/- 19.34 after treatment, and was of significant difference (P < 0.05) as compared to the pretreatment value. However, there was still a significant difference as compared to control (56.12 +/- 19.34 vs 32.30 +/- 12.50, P < 0.01). The concentration of VEGF significantly decreased after treatment [from (178.23 +/- 26.56) ng/L to (78.48 +/- 19.98) ng/L, P < 0.01)]. The total effective rate was 70%. There were no serious side effects. CONCLUSION: MVD and VEGF concentration were decreased obviously by thalidomide treatment. The dosage of 450 approximately 650 mg/d might be effective in refractory or initial MM.

Aged↗
PubMed2003

[The thalidomide story: a new chapter].

Thalidomide, a medication the use of which was banned about forty years ago due to its teratogenic effect, has returned into use due to its anti-angiogenic and immunomodulatory virtues. It is used now as a novel treatment in several malignant diseases as well as in the treatment of various inflammatory conditions. Recently it has been found that thalidomide may antagonize corneal blood vessels growth which is a late results of exposure to mustard gas. The story of thalidomide, which is very unusual, may serve as the snake symbol in medicine, to remind us about the possible double face of every medication, of which every physician should be aware.

Humans↗
PubMed2003

[Using thalidomide against pathological neovascularization].

Thalidomide was first used during the 50's-60's, especially for morning sickness in pregnant women. It was found to be a powerful teratogen only years later and was banned from use. At the same time it was found to have anti-inflammatory and anti-angiogenic properties and was approved as treatment for leprosy. As such, thalidomide might be used against pathological neovascularization, as seen in mustard gas exposure. From past experience we know that the eyes are the most vulnerable organ to mustard gas exposure. In some of the casualties there is a late sequella including pathological corneal neovascularization. So far there is no specific effective treatment against this neovascularization. The purpose of this review is to examine current research about the potential use of thalidomide as an anti-angiogenic agent, including potential role in treating mustard gas eye injury.

Angiogenesis Inhibitors↗
PubMed2003

Thalidomide as elective treatment in persistent erythema multiforme; report of two cases.

Recurrent erythema multiforme is a rare disorder, clinically characterized by symmetrically distributed, erythematous, and bullous skin and mucous lesions, mainly precipitated by a preceding herpes simplex infection. In rare cases, EM presents continuous or persistent relapses, and has been related to an Epstein-Barr virus infection. We report 2 cases of severe, persistent erythema multiforme, treated with thalidomide, with complete disease suppression in both cases. Thalidomide induces immunomodulator, anti-inflammatory, and anti-angiogenic effects, and may be considered as the elective treatment of this rare variety of erythema multiforme. However, in order to avoid neuropathic side effects, patients under thalidomide therapy should be monitored every 6 months with nerve conduction studies while taking the drug.

Adult↗
PubMed2003

Thalidomide-based treatment for HIV-associated multiple myeloma: a case report.

The spectrum of hematologic and immunologic abnormalities induced by HIV infection is broad. Although the incidence of HIV-associated B-cell neoplasms has increased, relatively few cases of multiple myeloma have been reported, and even fewer cases have detailed treatment outcome. The case of an HIV-infected man in whom multiple myeloma was diagnosed following progressive anemia and fatigue is described. The patient began treatment consisting of thalidomide, dexamethasone, and clarithromycin, which led to a rapid and dramatic antitumor response. He experienced modest regimen-related toxicities while retaining a normal CD4+ T-lymphocyte count and a nondetectable HIV viral load. The immunologic and antitumor effects of thalidomide in the context of multiple myeloma and HIV infection are also briefly reviewed. Given thalidomide's relatively favorable side-effect profile and purported immunologic benefit, further studies of this drug in the treatment of HIV-associated multiple myeloma should be pursued.

Anti-Bacterial Agents↗
PubMed2003

Thalidomide for severe refractory ankylosing spondylitis: a 6-month open-label trial.

OBJECTIVE: To examine the efficacy of thalidomide in the treatment of active ankylosing spondylitis (AS) refractory to conventional therapies. METHODS: In a 6-month open-label trial, we studied 13 men with different subtypes of active AS: 3 juvenile AS, 9 adult AS, and one AS with psoriasis. All patients were resistant to conventional nonbiologic therapies including nonsteroidal antiinflammatory drugs, sulfasalazine, and methotrexate. After 3 months' observation on a preexisting regimen, oral thalidomide was added, starting at 100 mg/day for 1 week, then 200 mg/day for another 23 weeks. Outcome measures included the Bath AS Disease Activity Index (BASDAI), Functional Index (BASFI), Global Index (BAS-G), IgA, C-reactive protein (CRP), and eosinophil sedimentation rate (ESR). Response to treatment was defined following the Ankylosing Spondylitis Assessment criteria. RESULTS: Three patients withdrew due to rash. Two patients were lost to followup due to lack of efficacy. Eight patients completed the trial. Four patients attained > 50% improvement (2 juvenile AS, 1 peripheral AS, and 1 psoriatic arthritis). Four patients attained > 20% improvement (2 axial and 2 peripheral AS). Total response rate accordingly was 80% (8/10). Mean BASDAI improved significantly from baseline to Week 24 (4.97 vs 3.1; p = 0.0156). Mean BASFI improved from baseline to Week 24 (5.24 vs 3.06; p = 0.0078), and BAS-G from 6.02 to 3.21 (p = 0.0078). Significant laboratory improvements were found in ESR (from 69.5 to 34.2 mm/h; p = 0.0156), but not CRP (from 6.08 to 3.01 mg/dl; p = 0.078) or IgA (from 496 to 505 mg/dl; p = 0.375). Dry mouth, constipation, and dizziness were common, but no severe adverse events were found. CONCLUSION: Thalidomide is a promising treatment for patients with active AS who are resistant to conventional therapies other than biologics.

Adult↗
PubMed2001

Thalidomide: from teratogen to anti-angiogenic.

Thalidomide, infamous for its teratogenic potential is now emerging as a therapeutic option for many disorders owing to its immunomodulant and anti-angiogenic effect. The demonstration of its ability to inhibit experimental angiogenesis in corneal micro-pocket assay in experimental animals led to the speculation that it might prove to be effective in certain angiogenesis dependent tumors. However, contrary to expectations, it failed to prevent tumor growth in certain animal models. The clinical study evaluating the effects of thalidomide in large number of patients suffering from refractory myeloma have shown encouraging results. Further trials are in progress to evaluate its effects in various other malignancies. In this review, various experimental and clinical studies demonstrating anti-angiogenic and anti-tumor effect of thalidomide are discussed with emphasis on its mechanism of action.

Angiogenesis Inhibitors↗
PubMed2005

[Study of thalidomide on the growth and angiogenesis of ovary cancer SKOV3 transplanted subcutaneously in nude mice].

OBJECTIVE: To study the effect of thalidomide (Thd) used alone and in combination with cytoxan (CTX) on the growth and angiogenesis of human ovarian cancer transplanted subcutaneously in nude mice. METHODS: Human ovarian cancer model transplanted subcutaneously in nude mice was established, and divided into 3 groups: control group, Thd group, and Thd + CTX group. Tumor volume and weight, vascular endothelial growth factor (VEGF) mRNA, VEGF protein, microvascular density (MVD) were detected. The level of VEGF mRNA in tumor tissue was determined by relative quantative reverse transcription polymerase chain reaction. VEGF protein level in serum was determined by enzyme-linked immunosorbent assay (ELISA). MVD was calculated by immunohistochemistry. RESULTS: (1) Tumor volumes in Thd group and Thd + CTX group were smaller than those in control group (P < 0.05). (2) Expression of VEGF mRNA level in Thd group (55 +/- 9) and Thd + CTX group (26 +/- 7) was significantly lower than that in control group (79 +/- 7, P < 0.01). Serum VEGF level in Thd group, [(29 +/- 10) pg/ml] and Thd + CTX group [(12 +/- 6) pg/ml] was significantly lower than that in control group, [(71 +/- 16) pg/ml, P < 0.01]. (3) MVD in Thd group (12.6 +/- 3.3) and Thd + CTX group (10.6 +/- 1.9) was significantly smaller than that in control group (19.3 +/- 2.8, P < 0.01). CONCLUSIONS: Thalidomide can inhibit the growth and angiogenesis of human ovarian cancer transplanted subcutaneously in nude mice. Treatment with thalidomide is a potentially useful antitumor therapy for ovarian cancer.

Animals↗
PubMed2005

A randomized, double-blind, double-dummy, controlled dose comparison of thalidomide for treatment of erythema nodosum leprosum.

In a randomized, double-blind, double-dummy controlled study, 22 men with erythema nodosum leprosum (ENL) received six capsules containing either 100 mg (group A, n = 12) or 300 mg (group B, n = 10) of thalidomide daily for one week. A six-week, four capsules per day taper followed, in which group A received 50 mg/day of thalidomide in weeks 2 and 3, then dummy capsules in weeks 4 through 7, while group B had gradual decrements every two weeks. Both regimens caused comparable improvement in 19 patients at day 7 (group A [12 of 12] versus group B [7 of 10]; P = 0.08), but slower tapering in group B showed less re-emergence of ENL through week 7 (P = 0.02, versus group A). Most patients developed new lesions soon after stopping treatment. Slower tapering from a higher initial thalidomide dose may improve clinical ENL responses, but high recurrence rates after discontinuation indicates further assessment is needed to identify better tapering regimens.

Adolescent↗
PubMed2005

Influence of angiostatin and thalidomide on lymphangiogenesis.

Malignant cancers commonly invade locally followed by spread through venous or lymphatic channels or both to distant sites. Hemangiogenesis and its relation to tumor growth and metastasis have been extensively studied. However, the role played by lymphangiogenesis in growth and metastasis of cancer has been largely neglected until just recently. Inhibition of lymphangiogenesis, as compared to inhibition of hemangiogenesis, may provide new insights into the mechanisms of cancer metastasis. The current study was designed to examine the in vitro effect of two commonly used inhibitors of hemangiogenesis, angiostatin and thalidomide, on the growth and proliferation of lymphatic endothelial cells isolated from pig thoracic ducts. We first isolated and characterized the lymphatic endothelial (LE) cells using specific markers for VEGFR3 and LYVE-1. The experimental results showed that treatment of the LE cells with these two drugs resulted in a decrease in the rate of cell proliferation in a dose-dependent manner as assessed by MTT assays. Cell migration rate was assessed by the speed of cell migration from the scrape-wound margin, and the results showed that migration of LE cells was also significantly inhibited in a dose-dependent fashion compared to controls. Treatment with angiostatin and thalidomide both resulted in an increase in apoptosis of LE cells as assessed by Hoechst staining and flow cytometry. We conclude that both angiostatin and thalidomide are able to inhibit LE cell growth in a dose-dependent manner and that the inhibition may be through induction of apoptosis.

Angiogenesis Inhibitors↗
PubMed2006

[The effect of cyclophosphamide, thalidomide and dexamethasone combination therapy in relapsed/refractory multiple myeloma].

OBJECTIVE: To investigate the effect of the combination of thalidomide, cyclophosphamide and dexamethasone for the treatment of relapsed/refractory multiple myeloma. METHODS: 20 relapsed/refractory multiple myeloma patients received thalidomide (200 mg/d), cyclophosphamide (300 mg.m(-2).d(-1), d1-4, every 4 weeks) and pulsed dexamethasone (20-40 mg/d, d1-4, every 4 weeks). RESULTS: After 3 cycles of therapy, 9 cases obtained partial remission (PR), 4 had minimal responses (MR), 5 were of no change and 2 had progressive disease. After 6 cycles of therapy, 13 patients achieved PR and 5 had MR. CONCLUSION: The combination of thalidomide, cyclophosphamide and dexamethasone is a promising treatment regime for relapsed/refractory multiple myeloma.

Aged↗
PubMed2006

[Deep vein thrombosis and pulmonary embolism in a patient with multiple myeloma treated with thalidomide and dexamethasone].

A 51-year-old man visited our hospital because of fever in 2003. With the discovery of the presence of a chest wall tumor, pleural effusion and M-protein, and increased plasma cells in the bone marrow, a diagnosis of multiple myeloma was established. Since the effect of combination chemotherapy followed by tandem auto-PBSCT lasted only one year, thalidomide and dexamethasone administration was started in November 2004. However, three months later, his lower limbs became swollen. Elevation of fibrin degradation product (FDP) and computed tomography findings suggested deep vein thrombosis and pulmonary embolism. With heparin and warfarin, these thromboses disappeared. Furthermore, chemotherapy strategies in addition to thalidomide were safely performed with anti-coagulation therapy. As thalidomide has become an accepted component in therapeutic strategies for multiple myeloma, careful attention must be paid to the prevention of thrombosis.

Angiogenesis Inhibitors↗
PubMed1989

Treatment of refractory rheumatoid arthritis--the thalidomide experience.

In an open study, 17 patients (16 women, 1 man) with refractory or severe rheumatoid arthritis were treated with thalidomide. Two withdrew from the study in the first weeks. Thirteen patients received 531 +/- 63 mg/day of thalidomide for 18.8 +/- 8.8 weeks; in 2 the dose was 300 mg/day during 62 and 65 weeks. Seven patients attained complete remission, 5 partial remission, and the last 3 no improvement at all. Remissions lasted 6 years in 1 patient, 2 years in 3, 1 year in one, and varied between 8 months and 8 weeks in 7. After relapse, 5 patients received a 2nd course of treatment and attained remission again. This lasted 24, 10, and 9 months in 3; two are taking 100 mg/day of thalidomide as a maintenance dose and remain asymptomatic after 36 and 30 months. The side effects were drowsiness, constipation, hard swelling of the lower limbs, erythema of the face and limbs with local pruritus or burning sensation, hair loss, cough, nasal obstruction, fever, and skin and mucosal dryness. In 8 patients there was mild eosinophilia (less than 10%) and in 2 leukopenia. A 33-year-old woman showed amenorrhea up to 2 months after stopping treatment. After a 2nd course of treatment, 2 patients developed peripheral sensory neuropathy, which resolved spontaneously in 6 months. We believe these findings justify controlled trials with this agent.

Adult↗
PubMed1985

Temporomandibular malformations in the bonnet monkey (Macaca radiata) fetus following maternal ingestion of thalidomide.

Structural abnormalities of the temporomandibular region were seen and described in the fetal bonnet monkey (Macaca radiata) after maternal ingestion of thalidomide. A single oral dose of 10 mg/kg of thalidomide was given on day 24, 25, 26, 27, 28 or 29 or 30 mg/kg on day 25 or 28 of gestation to 25 pregnant monkeys (day of mating = 0). The skeletons, processed and stained with alizarin red S, were examined for gross changes in configuration of craniofacial bones. Temporomandibular defects, in varying severity, were seen in four 70-day-old and seven 100-day-old fetuses associated with a single treatment between day 24 and day 28. The highest risk appeared to occur following treatment on day 25 (4/5) and the lowest on day 28 (2/8). Characteristic expression of the defects included 1) temporo-zygomatic hyperplasia involving the articular tubercle and postglenoid process and 2) mandibular hypoplasia, primarily of the condyles and the angular and coronoid processes. Micrognathia, apertognathia, and partial extraarticular ankylosis were seen. Although the sensitivity periods of the temporomandibular and ear regions seem to overlap and the embryonic origins are similar, the defects of each region appeared to be independent. Although the ear demonstrated a definite temporal relationship characterized by a decrease in severity in the expression of the ear malformations with respect to increased gestational age at the time of thalidomide insult, the temporomandibular region failed to exhibit a specific pattern. Although the temporo-zygomatic hyperplasia was dissimilar to any reported human condition, the mandibular changes were similar.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Thalidomide in lepra reaction (ENL) in lepromatous leprosy patients.

Six male bacteriologically highly positive patients of lepromatous leprosy with ENL reaction not adequately controlled by conventional antireaction drugs were put on thalidomide 400 mg per day in four divided doses. Reaction was controlled between 13th to 18th day of therapy. There was no change in the bacteriological status. Liver functions, renal functions and hemogram were normal before therapy and remained unaltered at the end of treatment. Apart from fatigue, drowsiness and occassional constipation, thalidomide had no adverse effect. Control of ENL reaction by thalidomide in these patients is probably due to its immunosuppressive effect, more likely by its stablising action on lysosomes.

Erythema Nodosum↗
PubMed1983

Chronic cutaneous lupus erythematosus. Thalidomide treatment of 11 patients.

Eleven patients with severe, chloroquine-resistant chronic cutaneous lupus erythematosus were treated with oral thalidomide. Seven patients responded with a complete remission, and two patients' conditions improved significantly. One patient did not respond well to therapy and another patient had to be withdrawn from the treatment trial because of side effects. Six patients, who relapsed after discontinuing thalidomide treatment, were re-treated with maintenance drug dosages and achieved good results with no further relapses or exacerbations. In all subjects the side effects from the thalidomide were minor and reversible.

Adult↗