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PubMed2003

Thalidomide and its derivatives: emerging from the wilderness.

Forty years on from its worldwide withdrawal, thalidomide is currently undergoing a remarkable renaissance as a novel and powerful immunomodulatory agent. Over the last decade it has been found to be active in a wide variety of inflammatory and malignant disorders where conventional therapies have failed. Recently, considerable progress has been made in elucidating its complex mechanisms of action, which include both anticytokine and antiangiogenic properties. However, in addition to its well known teratogenic potential, it has a significant side effect profile that leads to cessation of treatment in up to 30% of subjects. In response to this, two new classes of potentially safer and non-teratogenic derivatives have recently been developed. This review summarises the biological effects, therapeutic applications, safety profile, and future potential of thalidomide and its derivatives.

Adjuvants, Immunologic↗
PubMed2004

Disappearance of Crohn's ulcers in the terminal ileum after thalidomide therapy.

A case of intractable Crohn's disease unresponsive to all forms of therapy, including multiple operations and medication, is reported. The patient responded to thalidomide and this has resulted in the disappearance of the disease in the neoterminal ileum. Thalidomide may be a valuable treatment in intractable cases of Crohn's disease. The case is presented in a chronological fashion and endoscopic photographs documenting the disappearance of the disease are presented.

Adult↗
PubMedDate not supplied

Treatment of porphyria cutanea tarda with oral thalidomide.

Eight male patients with overt clinical and biochemical features of porphyria cutanea tarda (PCT) were orally treated with 300 mg/day thalidomide for 1 week and with 200 mg/day for 3 more weeks. Already after the first week of treatment no new vesicles and/or bullae could be observed. Spontaneous blisters completely disappeared, increased skin fragility subsided and skin hyperpigmentation receded about 2 months after completion of therapy, whereas hypertrichosis persisted. There was a rapid decrease in the urinary total porphyrin excretion which reached normal levels in all patients by the end of the fourth week of therapy, whereas the posttreament chromatographic pattern of urinary porphyrins revealed a slight reduction of higher carboxylated porphyrin metabolites and an increase in the amount of the excreted coproporphyrin, as compared to the pretreatment period. Somnolence, intermittent constipation and dry mouth occurred in all patients, 2 patients additionally experienced dizziness. No evidence of peripheral neuropathy could be detected and laboratory investigations revealed no abnormalities, as compared to the pretreatment period. During the 16- to 28-month follow-up of the patients, no clinical or biochemical relapse was observed. In view of the encouraging results of the present investigation, further studies are now warranted in order to definitely answer the question whether oral thalidomide may be regarded as an effective alternative approach to the treatment of PCT.

Administration, Oral↗
PubMedDate not supplied

Predicting the dermal absorption of thalidomide and its derivatives.

Concern has been expressed about the ability of simple algorithms to predict skin permeability and hence skin flux. For a series of thalidomide analogues, a number of software packages have been used to predict octanol water partition coefficients. These, in conjunction with molecular weight, have then been used to calculate skin permeability coefficients. These compare favourably with experimental values. Some of the software packages also predict aqueous solubilities, which can be subsequently used to calculate maximum skin flux. The predicted and measured solubilities have been compared together with the maximum fluxes. The results show that software can be used to predict octanol water partition coefficients and aqueous solubilities (more accurately if the melting point of the compound is known) and hence to obtain very reasonable estimates of skin permeation parameters. These are useful in predicting which analogue has the most appropriate properties for dermal delivery; in the case of the thalidomide analogues, it is the methyl-substituted compound that is best.

Administration, Cutaneous↗
PubMed2007

Scleromyxedema: successful treatment with thalidomide in two patients.

BACKGROUND: Scleromyxedema is an unusual skin disease characterized by mucinous infiltration of the skin. There is no satisfactory treatment for this disorder. CASE REPORT: We report 2 cases of scleromyxedema, both associated with an IgG-lambda paraprotein. Treatment with thalidomide was started and great improvement of the lesion was noted as shown by a quality of life questionnaire similar to those used in rheumatoid arthritis. TNF-alpha value was elevated in both cases during this treatment. DISCUSSION: We hypothesize that the efficiency of thalidomide could be mediated by its costimulatory effect on T cytotoxic lymphocytes.

Adult↗
PubMed1981

Iron content of skin before and after thalidomide treatment of lepra reaction. A preliminary report.

THe concentration of copper, zinc and iron in the skin of patients suffering from lepra reaction was measured by diagnostic X-ray spectrometry (DXS) at the sites of the lesions before and after treatment with thalidomide. The results were compared with the levels of these elements in the skin of healthy individuals. No significant changes in the copper level of leprous skin were found. The zinc levels showed significant elevations in some lesions with no apparent trend. The iron level in the affected areas had highly elevated values in all cases of lepra reaction. However, in contrast to the fast clinical improvement which followed the treatment with thalidomide, the iron levels did not decrease for prolonged periods.

Adult↗
PubMed1981

In vivo measurements of iron, copper and zinc in the skin of prurigo nodularis patients treated with thalidomide.

The concentration of iron, cooper and zinc in the skin of patients with prurigo nodularis was measured by diagnostic X-ray spectrometry before and after treatment with thalidomide. Before treatment, larger skin lesions were associated with significantly higher zinc levels and higher iron levels than the smaller ones. Upon treatment the zinc and iron content in these lesions decreased towards normal range. Copper values were found to be within the normal range in lesions before and after thalidomide treatment.

Adult↗
PubMed2004

Immunomodulatory derivative of thalidomide (IMiD CC-4047) induces a shift in lineage commitment by suppressing erythropoiesis and promoting myelopoiesis.

Immunomodulatory derivative (IMiD) CC-4047, a new analog of thalidomide, directly inhibits growth of B-cell malignancies in vivo and in vitro and exhibits stronger antiangiogenic activity than thalidomide. However, there is little information on whether CC-4047 affects normal hematopoiesis. Here we investigated the effect of CC-4047 on lineage commitment and differentiation of hematopoietic stem cells. We found that CC-4047 effectively inhibits erythroid cell colony formation from CD34+ cells and increases the frequency of myeloid colonies. We also demonstrate that development of both erythropoietin-independent and erythropoietin-dependent red cell progenitors was strongly inhibited by CC-4047, while terminal red cell differentiation was unaffected. DNA microarray analysis revealed that red cell transcription factors, including GATA-1, GATA-2, erythroid Kruppel-like factor (EKLF), and growth factor independence-1B (Gfi-1b), were down-regulated in CC-4047-treated CD34+ cells, while myeloid transcription factors such as CCAAT/enhancer binding protein-alpha (C/EBPalpha), C/EBPdelta, and C/EBPepsilon were induced. Analysis of cytokine secretion indicated that CC-4047 induced secretion of cytokines that enhance myelopoiesis and inhibit erythropoiesis. In conclusion, these data indicate that CC-4047 might directly influence lineage commitment of hematopoietic cells by increasing the propensity of stem and/or progenitor cells to undergo myeloid cell development and concomitantly inhibiting red cell development. Therefore, CC-4047 provides a valuable tool to study the mechanisms underlying lineage commitment.

Cell Differentiation↗
PubMed2006

Thalidomide, dexamethasone, and pegylated liposomal doxorubicin (ThaDD) for patients older than 65 years with newly diagnosed multiple myeloma.

We present the results of a phase 2 study using thalidomide, dexamethasone, and pegylated liposomal doxorubicin (ThaDD) in the treatment of 50 patients older than 65 years with newly diagnosed multiple myeloma. Thalidomide 100 mg was administered orally at bedtime continuously, dexamethasone 40 mg was administered orally on days 1 to 4 and 9 to 12, and pegylated liposomal doxorubicin 40 mg/m2 was administered intravenously on day 1 over the 28-day cycle. Response was assessed according to the EBMT criteria. Seventeen (34%) patients achieved CR, 7 (14%) nCR, 5 (10%) VGPR, 15 (30%) PR, and 5 (10%) MR, resulting in an ORR of 98%. Only 1 patient (2%) presented progressive disease. Time to progression (TTP), event-free survival (EFS), and overall survival (OS) projected at 3 years were 60%, 57%, and 74%, respectively, and these parameters were significantly higher in those patients achieving a response of at least VGPR versus those who did not. Grade 3 and 4 nonhematologic adverse events were constipation (10%), fatigue (6%), tremors (4%), mucositis (4%), and palmar-plantar erythrodysesthesia (2%). Grade 3 and 4 neutropenia occurred in 12% of patients. Grade 3 and 4 infections and thromboembolic accidents were observed in 22% and 14% of patients, respectively. In the treatment of elderly patients with newly diagnosed multiple myeloma, ThaDD is a very effective regimen with manageable toxicity.

Aged↗
PubMed2006

Selective leukemic-cell killing by a novel functional class of thalidomide analogs.

Using a novel cell-based assay to profile transcriptional pathway targeting, we have identified a new functional class of thalidomide analogs with distinct and selective antileukemic activity. These agents activate nuclear factor of activated T cells (NFAT) transcriptional pathways while simultaneously repressing nuclear factor-kappaB (NF-kappaB) via a rapid intracellular amplification of reactive oxygen species (ROS). The elevated ROS is associated with increased intracellular free calcium, rapid dissipation of the mitochondrial membrane potential, disrupted mitochondrial structure, and caspase-independent cell death. This cytotoxicity is highly selective for transformed lymphoid cells, is reversed by free radical scavengers, synergizes with the antileukemic activity of other redox-directed compounds, and preferentially targets cells in the S phase of the cell cycle. Live-cell imaging reveals a rapid drug-induced burst of ROS originating in the endoplasmic reticulum and associated mitochondria just prior to spreading throughout the cell. As members of a novel functional class of "redoxreactive" thalidomides, these compounds provide a new tool through which selective cellular properties of redox status and intracellular bioactivation can be leveraged by rational combinatorial therapeutic strategies and appropriate drug design to exploit cell-specific vulnerabilities for maximum drug efficacy.

Calcium Signaling↗
PubMed2001

Thalidomide produces transfusion independence in long-standing refractory anemias of patients with myelodysplastic syndromes.

Thalidomide was administered to 83 patients with myelodysplastic syndrome (MDS), starting at 100 mg by mouth daily and increasing to 400 mg as tolerated. Thirty-two patients stopped therapy before 12 weeks (minimum period for response evaluation), and 51 completed 12 weeks of therapy. International Working Group response criteria for MDS were used to evaluate responses. Intent-to-treat (ITT) analysis classified all off-study patients as nonresponders. Off-study patients belonged to a higher risk category (P =.002) and had a higher percentage of blasts in their pretherapy bone marrow than patients who completed 12 weeks of therapy (P =.003). No cytogenetic or complete responses were seen, but 16 patients showed hematologic improvement, with 10 previously transfusion-dependent patients becoming transfusion independent. Responders had lower pretherapy blasts (P =.016), a lower duration of pretherapy platelet transfusions (P =.013), and higher pretherapy platelets (P =.003). Among responders, 9 had refractory anemia (RA); 5 had RA with ringed sideroblasts; and 2 had RA with excess blasts. By ITT analysis, 19% of patients (16 of 83) responded, and when only evaluable patients were analyzed, 31% (16 of 51) responded. It was concluded that thalidomide, as a single agent, is effective in improving cytopenias of some MDS patients, especially those who present without excess blasts. (Blood. 2001;98:958-965)

Aged↗
PubMed2003

Generating hypotheses by discovering implicit associations in the literature: a case report of a search for new potential therapeutic uses for thalidomide.

The availability of scientific bibliographies through online databases provides a rich source of information for scientists to support their research. However, the risk of this pervasive availability is that an individual researcher may fail to find relevant information that is outside the direct scope of interest. Following Swanson's ABC model of disjoint but complementary structures in the biomedical literature, we have developed a discovery support tool to systematically analyze the scientific literature in order to generate novel and plausible hypotheses. In this case report, we employ the system to find potentially new target diseases for the drug thalidomide. We find solid bibliographic evidence suggesting that thalidomide might be useful for treating acute pancreatitis, chronic hepatitis C, Helicobacter pylori-induced gastritis, and myasthenia gravis. However, experimental and clinical evaluation is needed to validate these hypotheses and to assess the trade-off between therapeutic benefits and toxicities.

Databases, Bibliographic↗
PubMed2004

Thalidomide sensory neurotoxicity: a clinical and neurophysiologic study.

The clinical and neurophysiologic data from 65 patients taking thalidomide were reviewed. Thalidomide sensory neurotoxicity was found to be cumulative dose dependent but occurs only when the total dose is relatively high (>20 g). The risk of developing sensory neuropathy is around 10% below this threshold but increases with higher doses.

Adult↗
PubMed2002

Use of melphalan, thalidomide, and dexamethasone in treatment of refractory and relapsed multiple myeloma.

Twenty-one patients with relapsed and refractory Durie-Salmon stage III multiple myeloma who had either failed at least three previous regimens or presented with poor performance status, neutropenia, or thrombocytopenia were treated with up to four cycles of combination melphalan (50 mg intravenously), thalidomide (titrated to target of 400 mg orally daily), and dexamethasone (40 mg/day orally on d 1 to 4) every 4-6 wk. Maintenance treatment consisting of daily thalidomide and monthly dexamethasone was continued until disease progression. Although generally tolerated, combination melphalan/thalidomide/dexamethasone produced grade 4 neutropenia and thrombocytopenia in 52% and 38% of patients, respectively. Grade 3 nonhematologic toxicities included fatigue (14% of patients), neuropathy/paresthesia (5%), and nausea (5%). Four patients died while on therapy: two from neutropenic complications and two from progressive disease. Melphalan/ thalidomide/dexamethasone was highly active in this poor prognosis population: Serum monoclonal protein reductions > or = 25% occurred in 14 (70%) of 20 evaluable patients, including 1 patient with a complete response and 2 (13%) patients with reductions of 96%. Median progression-free-survival was 270 d (range: 73 to > 787 d) and median overall survival was 382 d. Median progression-free survival (> 420 d) has not been reached among patients responding to melphalan/thalidomide/dexamethasone. These results show that melphalan/thalidomide/dexamethasone therapy is active and generally tolerated in heavily pretreated multiple myeloma patients whose prognosis is otherwise poor.

Antineoplastic Combined Chemotherapy Protocols↗