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PubMed2004

Phase II study of temozolomide and thalidomide with radiation therapy for newly diagnosed glioblastoma multiforme.

PURPOSE: The chemotherapeutic agent temozolomide (TMZ) and the antiangiogenic agent thalidomide have both demonstrated antitumor activity in patients with recurrent malignant glioma. The objectives of this study were to determine if the combined strategy of these oral agents with radiation therapy (RT) is associated with an improved median survival of patients with newly diagnosed glioblastoma multiforme and to evaluate toxicity. METHODS AND MATERIALS: Sixty-seven patients were enrolled in this trial. Radiotherapy parameters were a total dose of 60 Gy delivered in 2 Gy fractions over 6 weeks. Temozolomide was administered starting the first day of RT at 150 mg/m(2) daily for 5 days every 4 weeks for the first cycle and escalated to a maximum dose of 200 mg/m(2). Thalidomide was started on Day 7 of RT at 200 mg and escalated by 100-200 mg every 1-2 weeks depending on patient tolerance, to a maximum of 1,200 mg daily. RESULTS: Sixty-one patients have progressed, with a median time to progression of 22 weeks. Fifty-six patients have died, and the median survival was 73 weeks. CONCLUSIONS: This strategy of combination TMZ, thalid and RT was relatively well tolerated with favorable survival outcome for patients with GM when compared to patients not treated with adjuvant chemotherapy and similar to those who have received nitrosourea adjuvant chemotherapy. It is unclear the added advantage thalid has in combination with TMZ for this patient population.

Adult↗
PubMed2005

LASSBio-468: a new achiral thalidomide analogue which modulates TNF-alpha and NO production and inhibits endotoxic shock and arthritis in an animal model.

As part of a program researching the synthesis and immunopharmacological evaluation of novel synthetic compounds, we have described the immune modulatory profile of the new achiral thalidomide analogue LASSBio-468 in the present work. This compound was planned as an N-substituted phthalimide derivate, structurally designed as a hybrid of thalidomide and aryl sulfonamides, which were previously described as tumor necrosis factor-alpha (TNF-alpha) and PDE4 inhibitors. LASSBio-468 was recently demonstrated to inhibit the TNF-alpha production induced by lipopolysaccharide (LPS), in vivo. Here, we investigated whether this compound would affect chronic inflammation processes associated with the production of this pro-inflammatory cytokine. Treatment with LASSBio-468 before a lethal dose injection of LPS in animals greatly inhibited endotoxic shock. This effect seems to be mediated by a specific down regulation of TNF-alpha and nitric oxide production, regulated mainly at the RNA level. In another model, histopathological analysis indicated that this compound also inhibited adjuvant-induced arthritis in rats. Taken together, our data demonstrated a potent anti-inflammatory effect of LASSBio-468, suggesting its use as a potential drug against chronic inflammatory diseases.

Animals↗
PubMed2005

Thalidomide treatment reduces apoptosis levels in bone marrow cells from patients with myelodysplastic syndromes.

We treated with thalidomide seven patients with primary MDS and observed reduction of the transfusion requirement in three cases and reduction of bone marrow blasts in one case. The apoptotic rate of bone marrow cells diminished significantly from a mean of 43.8% to a mean of 17.5%, whereas the proliferative activity did not change. Plasma TNF-alpha, bFGF, IL-1beta levels decreased variably, whereas VEGF levels tended to increase. Matrix metalloproteinases 2 and 9 expression decreased in bone marrow cells of responders. A reduction of CD4 cells and an increase of NK cells was observed in the peripheral blood. Thus, thalidomide may produce a fairly good hematological improvement in erythroid series in MDS, with complex biological mechanisms.

Aged↗
PubMed2005

Hairy cell leukemia (HCL) with extensive myelofibrosis responds to thalidomide.

We present a 75-year-old man who was admitted to our hospital because of splenomegaly, transfusion-dependent anemia and thrombocytopenia. The diagnosis of idiopathic myelofibrosis was suggested by the bone marrow trephine biopsy, which was hypocellular with myelofibrosis. Thalidomide was started at a daily dose of 100 mg/d and increased to 400 mg/d. Within 12 weeks, thrombocytes increased to 100.000/microl, hemoglobin normalized, lasting for about 11 months. Then, thalidomide had to be discontinued because of mild polyneuropathy. A second bone marrow biopsy showed fibrosis as well as a diffuse infiltration of the bone marrow (80%) by lymphocytes with expression of CD11c, CD19, CD20, CD103. Tartrate resistant acid phosphatase test (TRAP) was also positive. Hairy cell leukemia was diagnosed and he was administered 2-chlorodeoxyadenosine (2-CDA) achieving a complete remission.

Aged↗
PubMed2005

Bortezomib (Velcade) for progressive myeloma after autologous stem cell transplantation and thalidomide.

Twenty-one patients with multiple myeloma, all relapsed after frontline autologous stem cell transplantation and all relapsed again after or resistant to thalidomide (employed as second line treatment) received bortezomib (1.3 mg/m(2) body surface twice weekly for 2 weeks followed by an interval of 10-12 days) without adjunct of steroids as third line therapy. Three patients died of progressive disease during the first 2 cycles with bortezomib. Eighteen patients received at least 2 cycles and were evaluated for response. According to EBMT criteria, two complete (negative immunofixation) and seven partial (reduction of M-component > 50-75%) remissions were achieved (ITT response rate 42.8%). Duration of response lasted from 2 to 14+ months. Grades 3-4 toxicities (thrombocytopenia, leucopenia, peripheral neuropathy and vasculitis) were observed in seven patients, but no patient interrupted the treatment due to side effects. We conclude that bortezomib alone may induce high quality responses as third line salvage therapy with acceptable toxicity in a significant proportion of homogeneously pre-treated myeloma patients with progressive disease after autologous transplantation and thalidomide.

Adult↗
PubMed2006

Prenatal exposure to thalidomide, altered vasculogenesis, and CNS malformations.

Malformations of cortical development (MCD) result from abnormal neuronal positioning during corticogenesis. MCD are believed to be the morphological and perhaps physiological bases of several neurological diseases, spanning from mental retardation to autism and epilepsy. In view of the fact that during development, an appropriate blood supply is necessary to drive organogenesis in other organs, we hypothesized that vasculogenesis plays an important role in brain development and that E15 exposure in rats to the angiogenesis inhibitor thalidomide would cause postnatal MCD. Our results demonstrate that thalidomide inhibits angiogenesis in vitro at concentrations that result in significant morphological alterations in cortical and hippocampal regions of rats prenatally exposed to this vasculotoxin. Abnormal neuronal development was associated with vascular malformations and a leaky blood-brain barrier. Protein extravasation and uptake of fluorescent albumin by neurons, but not glia, was commonly associated with abnormal cortical development. Neuronal hyperexcitability was also a hallmark of these abnormal cortical regions. Our results suggest that prenatal vasculogenesis is required to support normal neuronal migration and maturation. Altering this process leads to failure of normal cerebrovascular development and may have a profound implication for CNS maturation.

Action Potentials↗
PubMed2000

Expression of adhesion receptors on rat limb bud cells and results of treatment with a thalidomide derivative.

The expression of several adhesion surface receptors was studied on cells of early limb bud development of 58 Wistar rats treated orally with two daily doses of the thalidomide derivative EM12 (2 x 50 mg/kg body weight) from day 7 to 10 of pregnancy. EM12 is a more potent teratogen than thalidomide. Limb bud cells of 56 untreated animals served as controls. The studies revealed that the integrins CD11a, CD11b, CD18, CD49d, and CD61, as well as the additional adhesion receptors CD54, CD62L, and the transferrin receptor CD71 were expressed on day 11 of gestation to various degrees on these embryonic cells. In contrast to results of previous studies with a non-human primate (Callithrix jacchus) there was no down-regulation of any of these receptors on the surface of limb bud cells of the rat embryos after treatment with EM12. This result is in accordance with the lack of teratogenicity in this rodent species.

Animals↗
PubMed2004

Thalidomide.

Despite its history as a human teratogen, thalidomide is emerging as a treatment for cancer and inflammatory diseases. Although the evolution of its clinical application could not have been predicted from the tragedy associated with its misuse in the past, its history serves as a lesson in drug development that underscores the need to understand the molecular pharmacology of a compound's activity, including associated toxicities. Here, we summarise the applications for thalidomide with an emphasis on clinical trials published over the past 10 years, and consider our knowledge of the molecular pharmacology of the drug in the context of clinical trial data, attempting to provide a mechanism-guided understanding of its activity.

Clinical Trials as Topic↗
PubMed1982

Thalidomide: use and possible mode of action in reactional lepromatous leprosy and in various other conditions.

The literature concerning the use and possible mode of action of thalidomide in reactional lepromatous leprosy and in various other conditions is reviewed. Although it has no action against the leprosy bacillus, its value in the treatment of the adverse reactions in this type of leprosy is well established, many leprologists considering it to be superior to any other drug for this purpose. Its efficacy in actinic prurigo is also impressive, and there are reports suggesting benefit in discoid lupus erythematosus. By contrast, its reported action in a number of other conditions, including severe aphthous stomatitis, Behçet's syndrome, pyoderma gangrenosum, nodular prurigo, and postherpetic neuralgia, needs confirmation in a larger number of cases, backed in some instances by clinical trial. The mechanism of action of this drug may be related to (1) anti-inflammatory effects, particularly an inhibition of neutrophil chemotaxis, (2) immunosuppressive effects, or (3) effects on neural tissue. Furthermore, structure-activity studies may allow separation of these and other possible effects. This review is in no way intended to lend support to the indiscriminate use of a potentially hazardous drug in various diseases of unknown cause, but rather to draw attention to a number of conditions in which the drug has been found effective. The further judicious use of thalidomide or a nonteratogenic analogue, with careful observation of results, may contribute to knowledge of the underlying pathology in some of these conditions, and possibly also to the mechanism of action of the drug itself.

Anti-Inflammatory Agents↗
PubMed1985

Significant response of oral aphthosis to thalidomide treatment.

The results are reported of the treatment of forty patients who had aphthous manifestations with the administration of thalidomide in daily doses ranging between 100 and 300 mg, over a period of 1 to 3 months. The study comprised nineteen patients with severe aphthosis, 17 with mild aphthosis, three with bipolar manifestations, and one with Sutton and Sutton's periadenitis mucosa necrotica recurrens. The results obtained were judged as remissions (35%) and marked improvements (40%). It is felt that thalidomide constitutes the most effective therapeutic approach so far available for oral aphthae, not only because it rapidly controls their manifestation but also because it controls recurrences.

Adolescent↗
PubMed1989

Treatment of aphthae with thalidomide.

We report our experience in the treatment of major and minor aphthae with thalidomide. With doses of 100 to 300 mg daily for 3 months, a cure was obtained in 34% of cases, and marked improvement was evident in the rest. The follow-up period varied from 1 to 8 years. Two patients experienced dysesthesias, which disappeared when the medication was stopped. Thalidomide cannot be prescribed to women of childbearing potential because of its teratogenic potential.

Adolescent↗
PubMed1998

Disfiguring cutaneous manifestation of sarcoidosis treated with thalidomide: a case report.

A patient with sarcoidosis was treated with thalidomide for disfiguring and painful steroid unresponsive sarcoidal granulomas of the skin. The duration of the therapy was 14 months, during which time, the skin lesions resolved almost completely. The initial dosage was 200 mg a day, which was increased to 400 mg a day after 4 months. Episodic paresthesia of the finger tips and one lower extremity was the only side effect noted, which resolved promptly after discontinuation of the drug. The dramatic response of sarcoidal granulomas of the skin to thalidomide observed in this patient demonstrates the usefulness of this drug as a possible long-term monotherapeutic or steroid-sparing agent in the treatment of sarcoidosis.

Dermatologic Agents↗
PubMed2003

The potential efficacy of thalidomide in the treatment of recalcitrant alopecia areata.

Thalidomide has been used in the treatment of many dermatological disorders. This drug is a potent suppressor of IL-12 production which plays a critical role in the development of cellular immune responses mediated by helper T-cells. It induces a drop in helper T-cell counts and a corresponding, though relatively small, rise in suppressor T-cells. It seems that cellular, not humoral, immune mechanisms are involved in the pathogenesis of alopecia areata. Also, decreased suppressor T-cell numbers in the active disease have been reported. Therefore, it could be postulated that thalidomide, especially in combination with other agents, could be of help in the treatment of resistant cases of alopecia areata.

Alopecia Areata↗
PubMed1998

Was tumour necrosis factor-alpha responsible for the fetal malformations associated with thalidomide in the early 1960s?

Prescription of thalidomide as a sedative to pregnant women in the early 1960s resulted in a dramatic number of fetal malformations that affected over ten thousand babies. Although tumour necrosis factor-alpha (TNF-alpha) is basically a cytotoxic molecule produced by macrophages when activated by invasive stimuli (such as bacterial endotoxin or tumour growth), it could have an important role in pregnancy, especially in early embryonic development. On these lines, both in human subjects and experimental animals, the cytokine is expressed and synthesized in endometrium, placenta and fetus. Evidence is presented here suggesting that the embryonic action of thalidomide was mediated by TNF-alpha, since the drug is a powerful inhibitor of the synthesis of this cytokine.

Abnormalities, Drug-Induced↗
PubMed2001

Thalidomide.

Thalidomide has been successful in the treatment of several dermatologic conditions unresponsive to other agents. Further experience may lead to a better understanding of its mechanism of action in these various diseases. Thalidomide should be considered an extremely valuable therapeutic option in selected patients when the benefits clearly outweigh the risks of teratogenicity and peripheral neuropathy.

Dermatologic Agents↗
PubMed2002

Thalidomide in Behçet's disease.

Behçet's disease is a chronic relapsing multisystem disease of unknown aetiology. It has a relapsing cyclical course, and is characterized by the triad of aphthous stomatitis, genital ulcerations and uveitis. There is familial and geographical clustering of cases, especially around the Mediterranean, the Middle East and East Asia. The condition is uncommon, but lesions sometimes are recalcitrant and can be debilitating to the affected individual. The treatment of Behçet's currently involves the use of steroids, immunomodulaters and immunosuppressives. Thalidomide has been used in cases of Behçet's disease with some success. This review will discuss Behçet's disease and the current information we have about using thalidomide for its treatment.

Abnormalities, Drug-Induced↗
PubMed2002

Thalidomide, an antiangiogenic agent with clinical activity in cancer.

Despite the teratogenic past of thalidomide, there is recent evidence indicating the drug's efficacy in the management of various diseases from immune disorders to cancers. The history, pharmacodynamic and pharmacokinetic properties of thalidomide in the clinic are discussed in this review article.

Angiogenesis Inhibitors↗
PubMed2003

Rasmussen syndrome and long-term response to thalidomide.

We report a 13-year-old female who experienced symptoms and signs of Rasmussen encephalitis for the first time at the age of 5 years. Various therapeutic procedures, including conventional and new antiepileptic drugs, steroids, immunoglobulin, plasma exchanges, and partial hemispherectomy, were applied, but their results were unsatisfactory. During one of the exacerbations, when the patient's life was endangered, thalidomide was administered. Frequency and intensity of epileptic seizures were reduced significantly, and the quality of her life improved. Except for moderate neutropenia, the other adverse effects were not recognized. In our opinion, thalidomide is not a first-choice drug for Rasmussen encephalitis but is a good alternative only for cases refractory to other well-known and accepted therapeutic procedures.

Adolescent↗