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PubMedDate not supplied

Inhibition of human prolyl hydroxylase as common biochemical denominator of the non-sedative effects of thalidomide in man.

The two main non-sedative effects of thalidomide (2-phtalimido-glutarimide) in man are the embryopathy, which finally forced termination of its use as a sedative, and the excellent efficacy in leprosy reactions, alone for whose prevention and treatment the drug is still available. Both effects can be explained on the molecular level by assuming that a non-sedative metabolite of thalidomide mediates inhibition of human prolyl hydroxylase, as suggested by steric considerations and correlation to known data. This metabolite may well be a suitable model compound for drugs designed for selective fibrosuppression and selective immunosuppression.

Collagen↗
PubMed2005

Combination therapy with thalidomide, incadronate, and dexamethasone for relapsed or refractory multiple myeloma.

The feasibility and efficacy of a combination of thalidomide, incadronate, and dexamethasone (TID) were studied in 12 patients with relapsed or refractory multiple myeloma. The protocol, consisting of 300 mg/day of thalidomide administered orally, intravenous incadronate (10 mg/day) administered weekly, and 12 mg/day dexamethasone for 4 days, was repeated every 3 weeks. Evaluations of efficacy and toxicity were carried out every 3 weeks and were continued for 3 cycles. Three patients were excluded during the study because of apnea, severe somnolence, and pancytopenia. Of 9 evaluated patients, the partial responses achieved in 3 patients and the minor responses achieved in 4 patients corresponded to a response rate of 78% according to the criteria of the European Group for Blood and Marrow Transplantation. In addition, painful osteolytic symptoms improved rapidly after 1 cycle of TID therapy in the 10 patients evaluated. These data suggest that TID is a feasible and promising therapeutic approach for refractory and relapsed multiple myeloma.

Aged↗
PubMed1999

Thalidomide responsiveness in an infant with Behçet's syndrome.

BACKGROUND: Behçet's syndrome is a chronic relapsing vasculitis characterized by aphthous stomatitis, genital ulcerations, and uveitis. The disease is a multisystem illness, which may involve the skin, joints, gastrointestinal tract, blood vessels, central nervous system, and other organs. CASE STUDY: We report a case of an infant with features of Behçet's syndrome who did not respond to conventional immunosuppression with high-dose corticosteroids and cytotoxic agents. Thalidomide, a potent immune response-modifying drug, was used with marked improvement and resolution of symptoms. CONCLUSION: This finding supports a trial of thalidomide treatment in patients with Behçet's syndrome who are unresponsive to other forms of immunosuppressive therapy or develop undesirable side effects.

Behcet Syndrome↗
PubMed2005

Thalidomide: present and future in multiple myeloma.

Multiple myeloma continues to be an incurable disease. The understanding of the disease's pathophysiology has significantly improved over the past few years, partly due to the discovery of the role of immunomodulatory agents and the study of their mechanism of action. Thalidomide, the first of the immunomodulatory family to be used in the management of multiple myeloma, proved not only to be effective in the treatment of multiple myeloma, but also instigated a wide range of in vitro and in vivo studies to define the pathophysiology of the plasma cell dyscrasia. The attention thalidomide has received in the past and recent history has not been without a price. The drug has a side-effect profile that, if managed appropriately, provides the most unique active molecule in the management of the disease, where it maintains the same response rate in newly diagnosed patients as in advanced relapsed/refractory multiple myeloma patients.

Angiogenesis Inhibitors↗
PubMed2006

Treatment of chronic hepatitis C in non-responsive patients with pegylated interferon associated with ribavirin and thalidomide: report of six cases of total remission.

Hepatitis C virus (HCV) infection is an important public health issue worldwide. It is estimated that over 170 million people are infected with the virus. The present study reports six cases in which patients did not respond to combination therapy with pegylated interferon and ribavirin. However, after the addition of thalidomide to the therapy, the patients presented negative RNA PCR. The use of thalidomide combined with pegylated interferon and ribavirin for the treatment of hepatitis C is described here for the first time in the related literature.

Adult↗
PubMed2003

Modifications to therapy for multiple myeloma: pegylated liposomal Doxorubicin in combination with vincristine, reduced-dose dexamethasone, and thalidomide.

The combination of vincristine, doxorubicin, and dexamethasone is an effective treatment for multiple myeloma that produces a more rapid response than other regimens, probably a function of the high-dose, intense steroid schedule. However, vincristine/doxorubicin/dexamethasone administration requires a 96-hour continuous infusion delivered via a central venous catheter, which necessitates hospitalization in a large number of patients and may increase the risk for infection. Moreover, the high dosages of corticosteroids required with this regimen can cause substantial toxicity. Therefore, a number of modifications to the regimen have been evaluated in an effort to improve its tolerability and efficacy. These include replacing doxorubicin with pegylated liposomal doxorubicin and using a reduced frequency of dexamethasone, and, later, the addition of thalidomide. The results of an ongoing study demonstrated that this latest regimen (including thalidomide) is associated with an improved response rate and a higher quality of response compared with previous regimens in patients with relapsed/refractory multiple myeloma. This modified regimen is well tolerated when prophylactic and supportive measures are incorporated. Although additional follow-up is required to determine the effect on survival, this modified regimen has significant potential in the management of advanced myeloma.

Angiogenesis Inhibitors↗
PubMed2006

[A case report of unresectable gallbladder cancer that responded remarkably to the combination of thalidomide, celecoxib, and gemcitabine].

Gallbladder cancer is an asymptomatic disease in the early stage and no therapeutic measure is available except surgical intervention. The prognosis for patients with advanced,i.e., unresectable or metastatic disease is dismal, with median survival usually being less than 6 months if not treated with chemotherapy. To date, chemotherapy for gallbladder cancer has been limited by the absence of agents with effective cytotoxic activity. Thalidomide has been shown to have antiangiogenic and immunomodulatory effects, including the inhibition of vascular endothelial growth factor, basic fibroblast growth factor and tumor necrosis factor alpha. Celecoxib is a potent selective COX-2 inhibitor. The reported biological consequences of COX-2 up-regulation include inhibition of apoptosis, increased metastatic potential and promotion of angiogenesis. These events may contribute to cell transformation and tumor progression. Antiangiogenesis represents a significant new strategy for cancer treatment. Therefore,it is important to accept a wide range of different inhibitors such as thalidomide and selective COX-2 inhibitors with conventional cytotoxic agents. Here we show a case of unresectable gallbladder cancer with remarkable improvement in CA19-9 and prolongation of life.

Aged↗
PubMed2006

Immunomodulatory analogues of thalidomide in the treatment of multiple myeloma.

The design of innovative, more effective, less toxic therapy for multiple myeloma (MM) is emerging in parallel to a better understanding of the underlying pathophysiology of this common hematologic malignancy. Thalidomide has changed the treatment paradigm for patients with myeloma. Its efficacy, however, has been compromised to some degree by its side effects. Immunomodulatory drugs (IMiDs) are structural and functional analogues of thalidomide that were specifically designed to produce new agents with enhanced immunomodulating and anticancer properties but with less toxicity. In this article, we review the clinical trial development of second-generation IMiDs lenalidomide and CC-4047. Both agents demonstrate potent activity with manageable toxicities and provide another treatment opportunity for patients with MM.

Humans↗
PubMed2002

A case of refractory Henoch-Schönlein purpura treated with thalidomide.

Henoch-Schönlein purpura is an acute, self-limited vasculitis syndrome which shows characteristic skin, joint, renal and gastrointestinal manifestations. It is common in childhood and may also occur in adults with fatal complications such as nephritis and gastrointestinal bleeding. We experienced a case of a 20-year-old woman who presented with palpable purpura and severe arthritis. The histopathologic examination of the skin revealed leukocytoclastic vasculitis with perivascular deposition of IgA and she was diagnosed with Henoch-Schönlein purpura. Despite treatment with prednisolone for one month, she had more aggravated purpura and fatal gastrointestinal bleeding. The symptoms were improved shortly by cyclophosphamide pulse therapy with plasmapheresis but symptoms were aggravated and symmetric mononeuropathy of the ulnar nerve developed. She was treated with 400 mg/day of thalidomide and symptoms were improved. We herein report a case of Henoch-Schönlein purpura successfully treated with thalidomide which was refractory to prednisolone, immunosuppressive drugs and plasmapheresis.

Adult↗
PubMed2002

Protective antitumor immunity induced by a costimulatory thalidomide analog in conjunction with whole tumor cell vaccination is mediated by increased Th1-type immunity.

Thalidomide and its novel T cell costimulatory analogs (immunomodulatory drugs) are currently being assessed in the treatment of patients with advanced cancer. However, neither tumor-specific T cell costimulation nor effective antitumor activity has been demonstrated in vivo. In this study, we assessed the ability of an immunomodulatory drug (CC-4047/ACTIMID) to prime a tumor-specific immune response following tumor cell vaccination. We found that the presence of CC-4047 during the priming phase strongly enhanced antitumor immunity in the vaccinated group, and this correlated with protection from subsequent live tumor challenge. Protection was associated with tumor-specific production of IFN-gamma and was still observed following a second challenge with live tumor cells 60 days later. Furthermore, CD8(+) and CD4(+) splenocyte fractions from treated groups secreted increased IFN-gamma and IL-2 in response to tumor cells in vitro. Coculture of naive splenocytes with anti-CD3 mAb in the presence of CC-4047 directly costimulated T cells and increased Th1-type cytokines. Our results are the first to demonstrate that a costimulatory thalidomide analog can prime protective, long-lasting, tumor-specific, Th1-type responses in vivo and further support their ongoing clinical development as novel anti-cancer agents.

Adjuvants, Immunologic↗
PubMed2000

Recalcitrant pyoderma gangrenosum treated with thalidomide.

Pyoderma gangrenosum is a painful, noninfectious, ulcerating skin disorder often associated with systemic disease. Thalidomide has been used to treat many inflammatory dermatologic conditions and has been reintroduced in the United States to treat immune-modulated diseases such as pyoderma gangrenosum. The patient described, a 47-year-old man, had histologically confirmed pyoderma gangrenosum that did not respond to treatment with several courses of methylprednisolone. The ulcer healed with 10 weeks of oral thalidomide administration.

Anti-Inflammatory Agents↗
PubMed2004

Remission of nephrotic syndrome after thalidomide therapy in a patient with Castleman's disease.

Castleman's is an uncommon lymphoproliferative disorder secondary to lymphoid follicle hyperplasia and marked capillary proliferation with endothelial hyperplasia. This illness can be associated with glomerulonephritis (GN). Here, we report a case with steroid-dependent nephrotic syndrome secondary to proliferative mesangial glomerulonephritis in a patient with Castleman's disease, that was diagnosed several years before. Considering the involvement of IL-6 in Castleman's disease we treated the patient with thalidomide obtaining the remission of the nephrotic syndrome. Our experience suggests a possible role of thalidomide in the treatment of glomerular pathology when a role of IL-6 is hypothesized.

Aged↗
PubMed1999

A looking glass perspective: thalidomide and cyclopamine.

Numerous naturally-occurring and synthetic compounds that were discovered initially because of their toxic properties, were later shown to possess biological activities beneficial to humans that enabled them to serve as templates for the development of useful medicinal agents. A prominent example is thalidomide, a synthetic drug that gained notoriety originally due to its catastrophic teratogenicity in humans. The discovery of thalidomide's efficacy in treating several diseases has resulted in the recrudescence of the drug to society's usage. A current example of this phenomenon is the plant teratogen cyclopamine (11-deoxojervine), whose deleterious terata-inducing effects were restricted to grazing animals, but whose recently discovered inhibition of Sonic hedgehog signal transduction has provided both the potential to increase our understanding of organogenesis and to serve as a lead compound in drug development.

Abnormalities, Drug-Induced↗
PubMed2000

Dynamic contrast-enhanced T2-weighted MR imaging of recurrent malignant gliomas treated with thalidomide and carboplatin.

BACKGROUND AND PURPOSE: Dynamic, contrast-enhanced MR imaging has allowed quantitative assessment of cerebral blood volume (CBV) in brain tumors. The purpose of our study was to compare postcontrast T1-weighted imaging with dynamic, contrast-enhanced T2*-weighted echo-planar imaging in the evaluation of the response of recurrent malignant gliomas to thalidomide and carboplatin. METHODS: Serial MR imaging was performed in 18 consecutive patients with recurrent malignant gliomas receiving both thalidomide and carboplatin for 12-month periods. Six patients undergoing carboplatin therapy alone were chosen as control subjects. Conventional postcontrast T1-weighted images were compared with relative CBV (rCBV) maps calculated on a pixel-by-pixel basis from dynamic echo-planar imaging data. Tumor progression was evaluated clinically using established criteria for malignant gliomas. Studies were performed at 2- to 3-month intervals, and imaging and clinical findings were compared. RESULTS: Tumor response to treatment, based on clinical findings, did not correlate well with conventional imaging findings. The rCBV values decreased significantly in all patients between the start of therapy and the first follow-up in the study group, but not in the control group. The difference in rCBV values between the clinically stable and the progressive group at 12-month follow-up was statistically significant, with the progressive group having higher values. CONCLUSION: Dynamic, contrast-enhanced MR imaging is a valuable adjunct to conventional imaging in assessing tumor activity during antiangiogenic therapy, and correlates better than conventional studies with clinical status and response to therapy.

Adult↗
PubMed2000

[How I treat... refractory multiple myeloma with thalidomide].

Despite the use of high-dose chemotherapy with autologous hematopoietic stem cell transplantation, multiple myeloma remains largely uncurable. Indeed complete remission rate is about 50% and median survival reaches 5 years without plateau. Recently thalidomide has been identified as a promising agent. We report the clinical story of 2 patients with refractory myeloma that we treated successfully with thalidomide.

Aged↗
PubMed2000

New approaches in the treatment of metastatic melanoma: thalidomide and temozolomide.

Although melanoma is a relatively chemoresistant malignancy, systemic chemotherapy remains the primary treatment for metastatic melanoma. The observation of vasculogenic mimicry in aggressive melanoma has prompted investigation into using an antiangiogenic agent to enhance the antitumor activity of chemotherapy in metastatic melanoma. Thalidomide (Thalomid) exhibits antiangiogenic activity and other biological modulatory effects that may provide additive or synergistic antitumor effects when given concurrently with chemotherapy. A phase I/II study of thalidomide and temozolomide in the treatment of metastatic melanoma is in progress. Preliminary results of this combination therapy have shown significant antitumor activity, including some striking responses in brain metastases.

Adult↗
PubMed2000

Thalidomide for recurrent renal-cell cancer in a 40-year-old man.

A pilot study was performed at The University of Texas M. D. Anderson Cancer Center to determine the feasibility of using thalidomide in a population of renal-cell carcinoma patients who had progressive disease despite chemotherapy and immunotherapy. Metastatic renal-cell carcinoma patients with adequate oral function were entered onto a study after signing an internal review board-approved informed consent. There were no exclusion criteria for prior therapy. Nineteen previously treated patients and one untreated patient with progressive renal-cell carcinoma received oral thalidomide as a single agent. The starting dose was 200 mg and the dose was increased by 100 to 200 mg every week until it reached 1,200 mg/d. Response was assessed on the basis of a radiographic reduction of the metastatic sites involved. A case report describing one of the patients involved in the pilot trial is included.

Adenocarcinoma, Clear Cell↗