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PubMed1967

The fate of the hydrolysis products of thalidomide in the pregnant rabbit.

1. The fate in the pregnant New Zealand White rabbit of oral doses of four (14)C-labelled hydrolysis products of thalidomide, namely alpha-(o-carboxybenzamido)-glutarimide, 2-phthalimidoglutaramic acid, 2-phthalimidoglutaric acid and 2-(o-carboxybenzamido)glutaramic acid, administered on the 192nd hour of pregnancy has been studied. 2. About 60-95% of the administered (14)C of each compound appears in the urine in 58hr. and the remainder is found in the faeces and in the gut and its contents. 3. Radioactivity is present in the plasma, liver, kidney, brain, muscle, fat and embryo. 4. The (14)C-labelled substances in the plasma and embryo consist of the unchanged compounds and their further hydrolysis products. 5. Since the above four thalidomide hydrolysis products are found in the rabbit conceptus together with their further hydrolysis products after their oral administration to the pregnant rabbit, it appears that the teratogenic activity of thalidomide is due to the compound itself rather than to one or more of its hydrolysis products.

Adipose Tissue↗
PubMed2002

A pilot study of thalidomide for patients with symptomatic mesenteric panniculitis.

BACKGROUND: Mesenteric panniculitis is a rare condition with no standard therapy. AIM: To assess the safety and efficacy of thalidomide for the treatment of patients with symptomatic mesenteric panniculitis using a newly established clinical disease activity index (Mesenteric Panniculitis Subjective Assessment Score). METHODS: In an open-label pilot study, five patients with symptomatic mesenteric panniculitis received oral thalidomide, 200 mg nightly, for 12 weeks. The primary end-point was a reduction in the Mesenteric Panniculitis Subjective Assessment Score by > or = 20% at 12 weeks or complete remission (absence of symptoms). RESULTS: Four (80%) of the five patients responded. The median Mesenteric Panniculitis Subjective Assessment Score at baseline was 39 and at week 12 was 25 (average decrease of 44%). One patient achieved complete remission by week 4, which was sustained. At 12 weeks, three (75%) patients experienced a global response, five (100%) patients had a > or = 20% (range, 29-98%) decrease in erythrocyte sedimentation rate and three (75%) patients had a > or = 20% (range, 61-93%) decrease in C-reactive protein. Abdomino-pelvic computed tomography scans were unchanged in all five patients. There were no serious adverse events. CONCLUSIONS: Thalidomide is safe, well tolerated and efficacious in the treatment of some patients with symptomatic mesenteric panniculitis. Further study is indicated.

Aged↗
PubMed2001

Safety and efficacy of thalidomide in patients with myelofibrosis with myeloid metaplasia.

We administered the anti-angiogenic drug thalidomide to 21 patients (12 men) with myelofibrosis with myeloid metaplasia (MMM), who were not responsive to standard treatment. Patients received thalidomide at an escalating dose from 100 to 400 mg/d. Administration of the drug was discontinued before the planned 6 months of treatment in 19 patients (90.5%), mainly because of somnolence and/or fatigue, neurological symptoms or neutropenia. Of the 13 evaluable patients (who received more than 30 d of therapy), anaemia improved in three out of seven (43%) who were treated because of anaemia; thrombocytopenia improved in two out of three (66.6%) who were treated because of thrombocytopenia; splenomegaly was reduced in four (30.8%). Undesired increases in white blood cell and platelet counts were observed in three (23.1%) and five (38.5%) patients respectively. A severity score, indexed on haematological and clinical parameters, improved in two patients (15.4%), but worsened in five (38.5%). In conclusion, standard-dose thalidomide in MMM patients is burdened with a high rate of side-effects, which prevent prolonged treatment. Because the drug is effective in improving anaemia and thrombocytopenia and in reducing splenomegaly, low-dose therapy warrants evaluation. The unexpected observation of leucocytosis and thrombocytosis suggests biological studies and better criteria for selection of patients for treatment.

Adult↗
PubMed2003

Thromboembolic events in patients with myelodysplastic syndrome receiving thalidomide in combination with darbepoietin-alpha.

A phase II trial was conducted to explore the efficacy and tolerability of combining thalidomide (100 mg/d p.o.) with an erythropoietic growth factor (darbepoietin-alpha 2.25 micro g/kg/d s.c.) in patients with low-to-intermediate-risk myelodysplastic syndromes (MDS). However, the trial had to be discontinued early because of an unexpectedly high incidence of thromboembolic events. Of the first seven patients enrolled, two developed deep-vein thrombosis and one died of massive pulmonary embolism. We concluded that thalidomide might significantly increase the thromboembolic risk of erythropoietic proteins in MDS patients. Careful clinical surveillance and thrombosis prophylaxis (heparin or oral anticoagulation) should be considered for MDS patients undergoing combined treatment with thalidomide and erythropoietic growth factors.

Aged↗
PubMed2003

Hyperfractionated cyclophosphamide in combination with pulsed dexamethasone and thalidomide (HyperCDT) in primary refractory or relapsed multiple myeloma.

Sixty patients with advanced multiple myeloma received 2-6 monthly treatment courses combining hyperfractionated cyclophosphamide (300 mg/m2 i.v. over 3 h q 12 h x 6, d 1-3) with pulsed dexamethasone (20 mg/m2/d p.o., d 1-4, 9-12, 17-20) and once daily thalidomide at individually escalating doses (100-400 mg/d) depending on tolerability (HyperCDT). Responding patients were maintained on daily thalidomide and monthly dexamethasone pulses. Complete, partial and minor response rates were 4%, 68% and 12% respectively; overall response rate was 84% (efficacy analysis). Median event-free and overall survival was 11 and 19 months respectively. During at least one treatment cycle, 67% of patients experienced grade 4 neutropenia resulting in 17% grade 3 and 9% grade 4 infections. Side-effects, presumably related to thalidomide, included neuropathy (40% grade 2, 16% grade 3), constipation (17%), oedema (5%), bradycardia (5%), skin reactions (3%), cerebrovascular events (5%) and deep vein thromboses (8%). Thromboses were not related to known thrombophilic risk factors. Four patients with prior myeloma therapy > 50 months developed myelodysplastic syndrome or secondary acute myeloid leukaemia 2-4 months after study entry. HyperCDT is a highly active and reasonably well-tolerated salvage regimen in advanced or refractory multiple myeloma.

Acute Disease↗
PubMed2001

A case of severe actinic prurigo successfully treated with thalidomide.

Actinic prurigo is an uncommon and usually persistent idiopathic photodermatosis with typical human leukocyte antigen (HLA) associations (HLA-DR4, particularly subtypes DRB1*0407 and DRB1*0401). Although its mechanism of action is not clearly understood, thalidomide has been shown to be particularly efficacious in treating actinic prurigo, among other conditions. A 31-year-old Australian woman who had suffered actinic prurigo for most of her life was treated with two courses of thalidomide (50-100 mg nocte) over consecutive summers. Remission was observed after cessation of the second course of thalidomide and had continued 4 years later. Abnormalities in the cutaneous response to ultraviolet radiation at the time of diagnosis, detected by monochromator phototesting, reverted to normal following treatment.

Adult↗
PubMed1999

Antitumor activity of thalidomide in refractory multiple myeloma.

BACKGROUND: Patients with myeloma who relapse after high-dose chemotherapy have few therapeutic options. Since increased bone marrow vascularity imparts a poor prognosis in myeloma, we evaluated the efficacy of thalidomide, which has antiangiogenic properties, in patients with refractory disease. METHODS: Eighty-four previously treated patients with refractory myeloma (76 with a relapse after high-dose chemotherapy) received oral thalidomide as a single agent for a median of 80 days (range, 2 to 465). The starting dose was 200 mg daily, and the dose was increased by 200 mg every two weeks until it reached 800 mg per day. Response was assessed on the basis of a reduction of the myeloma protein in serum or Bence Jones protein in urine that lasted for at least six weeks. RESULTS: The serum or urine levels of paraprotein were reduced by at least 90 percent in eight patients (two had a complete remission), at least 75 percent in six patients, at least 50 percent in seven patients, and at least 25 percent in six patients, for a total rate of response of 32 percent. Reductions in the paraprotein levels were apparent within two months in 78 percent of the patients with a response and were associated with decreased numbers of plasma cells in bone marrow and increased hemoglobin levels. The microvascular density of bone marrow did not change significantly in patients with a response. At least one third of the patients had mild or moderate constipation, weakness or fatigue, or somnolence. More severe adverse effects were infrequent (occurring in less than 10 percent of patients), and hematologic effects were rare. As of the most recent follow-up, 36 patients had died (30 with no response and 6 with a response). After 12 months of follow-up, Kaplan-Meier estimates of the mean (+/-SE) rates of event-free survival and overall survival for all patients were 22+/-5 percent and 58+/-5 percent, respectively. CONCLUSIONS: Thalidomide is active against advanced myeloma. It can induce marked and durable responses in some patients with multiple myeloma, including those who relapse after high-dose chemotherapy.

Angiogenesis Inhibitors↗
PubMed2001

Low-dose thalidomide is an effective second-line treatment in cutaneous lupus erythematosus.

BACKGROUND: The use of thalidomide in inflammatory cutaneous disorders has increased over recent years. Its use in cutaneous lupus erythematosus is now well documented, although most groups favour high-dose regimes (200 mg twice daily), where side effects are common and may limit drug use. METHODS: A total of 27 patients with cutaneous lupus erythematosus were treated using a low-dose thalidomide regime (starting dose of 50 mg twice daily). RESULTS: Results have been favourable, with a good response or total disease remission seen in 66% of patients. The prevalence of side effects was low. Nausea, sedation or tremor were seen in 8 patients but these were tolerable in all but four patients. No patient had symptoms of peripheral neuropathy. Owing to its teratogenicity, adequate counselling must be given to female patients of child-bearing age. CONCLUSION: On the basis of these findings, low-dose thalidomide is advocated as a second-line treatment in cutaneous lupus erythematosus.

Adult↗
PubMed2002

Thalidomide in the management of multiple myeloma.

The discovery that multiple myeloma is associated with new vessel formation and is correlated with survival and proliferation led initially to the use of thalidomide for patients with relapsed or refractory disease. The outcome with conventional chemotherapy in this setting has historically been very poor. New insights into the biology of the disease suggests that thalidomide may work via a number of other mechanisms and the advent of the thalidomide analogues with their differential effects on survival and proliferation pathways has opened up a new era in the understanding and treatment of the disease. The encouraging results from phase I/II trials of these agents has meant that for the first time in 50 years there is the opportunity to improve outcome. Further work is in progress to define how best to use these drugs and their role in treatment at different stages of the disease.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Intermediate dose thalidomide (200 mg daily) has comparable efficacy and less toxicity than higher doses in relapsed multiple myeloma.

Thalidomide at doses >200 mg has 100% grade 1-2 and 25% grade 3-4 toxicities requiring discontinuation. We report a retrospective study of relapsed myeloma patients treated with thalidomide 200 mg with no dose escalation. Thirty patients were identified; 43% of patients responded with paraprotein decline >75% -- 2 (6%), 50-75% -- 7 (23%), 25-50% -- 4 (14%) and 2 (6%) were stable. All five patients with 13q deletion responded. Only 54% reported grade 1-2 toxicities (none reporting > grade 2) with 5 (17%) discontinuing treatment due to toxicity. Thalidomide 200 mg daily with no dose escalation appears as effective and better tolerated than escalated doses for relapsed myeloma patients.

Adult↗
PubMed2003

Thalidomide in relapsed or refractory multiple myeloma: how much and for how long?

The optimum dose and duration of treatment with thalidomide for relapsed or refractory multiple myeloma are not known. Long term responses were seen in 5 patients given low doses of thalidomide (100-200 mg) with or without pulsed dexamethasone, for between 48 and 108 weeks. The responses were sustained for between 23 and 67 weeks after stopping treatment. We recommend that the lowest effective dose (LED) and optimum duration of therapy with thalidomide should be determined within the framework of a well conducted clinical trial in order to answer these important questions.

Aged↗
PubMed2005

Arterial thrombosis in four patients treated with thalidomide.

Thalidomide has been associated with venous thrombotic events, as reported in the post-marketing surveillance reports by Celgene Corporation; as well as case reports in the literature. Seven arterial thrombotic events have been reported in patients receiving thalidomide with 3 cases occurring in patients with other predisposing conditions. We report 4 additional cases of arterial thromboses in 1 lymphoma and 3 myeloma patients treated with thalidomide. The mechanism for these events is unclear; however, it is significant that 2 patients were receiving concomitant anticoagulation with aspirin and warfarin.

Aged↗
PubMed2005

Low-dose thalidomide-induced agranulocytosis in a multiple myeloma patient treated at diagnosis.

Thalidomide represents a recent and innovative therapeutic approach in multiple myeloma. Main toxicity usually consists in somnolence, constipation, peripheral neuropathy and deep vein thrombosis, but, unlike alkylating agents, thalidomide is reported to rarely induce severe hematologic toxicity. The majority of patients developing neutropenia are heavily pretreated with three or more lines of chemotherapy. Here, we report, for the first time, clinical and laboratory data of a 66-year-old female patient with multiple myeloma at diagnosis who, after 4 weeks of thalidomide treatment, developed a grade 4 WHO neutropenia with septicemia. A brief review of the literature and suggestions for possible predictive factors of this toxicity are made.

Aged↗
PubMed2006

Phase II study of topotecan and thalidomide in patients with high-risk myelodysplastic syndromes.

This phase II trial investigated the safety and preliminary efficacy of a topotecan/thalidomide combination therapy in patients with myelodysplastic syndrome who had refractory anemia with excess blasts (RAEB), RAEB with transformation, or chronic myelomonocytic anemia. Patients received three 21-day cycles of topotecan 1.25 mg/m(2) on days 1-5, which was repeated for two additional cycles in patients whose bone marrow blast percentages did not decrease. Oral thalidomide was then started at 100 mg/day (with the dose escalated up to 300 mg/day if well tolerated) for up to 1 year. Patients were monitored throughout the trial for hematologic and clinical adverse events, and efficacy was assessed using International Working Group (IWG) criteria. Forty-five patients, mostly elderly (median age 68 years; range 52-79 years), were enrolled. Therapy was generally well tolerated compared to high-dose chemotherapy. Three patients died from disease progression/infections during topotecan therapy, and four patients discontinued topotecan because of high-grade neutropenia (two patients), syncope (one patient), or hip surgery (one patient). Of 24 patients who received thalidomide, three discontinued because of treatment-related toxicity. Thirty-eight patients were evaluable for response: nine (24%) had hematologic improvement and 13 (34%) had stable disease. Responses occurred in patients with all disease subtypes. Six patients achieved transfusion independence, and one patient had a trilineage response. Approximately one-third of the patients had decreases in bone marrow blasts of 50%. Therefore, a topotecan and thalidomide combination therapy is promising, although further studies are needed to determine the optimum doses and schedule.

Aged↗
PubMed2004

Chemoresistant myeloma: phase II clinical study with low-dose thalidomide plus high-dose dexamethasone.

Thalidomide produces a response rate from 32 to 66% of pre-treated myeloma patients with doses ranging from 100 to 800 mg/daily. Common, dose-related side effects are sedation, constipation, polyneuropathy. Increased incidence of thromboembolic events were observed in myeloma patients receiving thalidomide as front-line therapy or in association with chemotherapy. Less common adverse reactions are central nervous system (CNS) dysfunction and cutaneous reactions. We describe the update of our experience with low dose thalidomide plus monthly high dose dexamethasone and zolendronate. Most patients were able to tolerate this regimen with few side effects. Erythrocyte sedimentation rate (ESR) lowering was early observed in patients who subsequently responded.

Aged↗
PubMed1993

Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation.

We have examined the mechanism of thalidomide inhibition of lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-alpha) production and found that the drug enhances the degradation of TNF-alpha mRNA. Thus, the half-life of the molecule was reduced from approximately 30 to approximately 17 min in the presence of 50 micrograms/ml of thalidomide. Inhibition of TNF-alpha production was selective, as other LPS-induced monocyte cytokines were unaffected. Pentoxifylline and dexamethasone, two other inhibitors of TNF-alpha production, are known to exert their effects by means of different mechanisms, suggesting that the three agents inhibit TNF-alpha synthesis at distinct points of the cytokine biosynthetic pathway. These observations provide an explanation for the synergistic effects of these drugs. The selective inhibition of TNF-alpha production makes thalidomide an ideal candidate for the treatment of inflammatory conditions where TNF-alpha-induced toxicities are observed and where immunity must remain intact.

Animals↗
PubMed1997

Adverse reactions to thalidomide in patients infected with human immunodeficiency virus.

Thalidomide is emerging as a useful agent in the management of several complications of disease due to human immunodeficiency virus (HIV). We conducted three prospective studies of 56 HIV-infected patients who were treated with thalidomide for 14-21 days; 24 (43%) of these patients discontinued therapy owing to adverse reactions. Cutaneous and/or febrile reactions were the most frequent toxicities, arising in 20 (36%) of the patients. These reactions occurred after a mean interval (+/-SD) of 10 +/- 3 days and were associated with significantly lower CD4 T lymphocyte counts in reactors than in nonreactors (median count, 52.5/mm3 vs. 242 cells/mm3, respectively; P = .009). Four of four rechallenged patients experienced accelerated hypersensitivity; hypotension occurred in one case. Although sedation was an almost universal side effect among the patients, it was moderate or severe in only seven (13%); constipation was moderate or severe in five (9%) of the patients. Severe neuropathic symptoms and mood changes were each noted in two (4%) of the 56 patients. We conclude that the increasing use of thalidomide to treat HIV-infected patients must be accompanied by recognition of the drug's increased potential for toxicity in this population.

Adult↗
PubMed2002

The adverse effects of thalidomide in relapsed and refractory patients of multiple myeloma.

Thalidomide has shown efficacy in relapsed or refractory patients of multiple myeloma (MM). We present the adverse effect profile of thalidomide in 23 relapsed or refractory MM patients treated with this drug over a period of 15 months. Constipation (100% incidence) and sedation (87%) were the most common adverse effects. Neuropathy had low incidence and was late in onset (>12 months). Tolerance developed to sedation, constipation and skin lesions. All the adverse drug reactions were tolerable and did not warrant decrease or termination of therapy, except for peripheral neuropathy. Contrary to Western reports, peripheral neuropathy in Indian patients developed at a cumulative dose of 200 g or more after 10 months or more of therapy. Therapy was discontinued in one patient due to marked elevation of liver enzyme that was later attributed to acute hepatitis C infection. Only one patient dropped out of the trial for unknown reasons. Overall, thalidomide was found to be a relatively safe drug that can be used over a prolonged period of time.

Adult↗