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PubMed2005

Successful management of cryoglobulinemia-induced leukocytoclastic vasculitis with thalidomide in a patient with multiple myeloma.

Leukocytoclastic vasculitis (LV) is a systemic inflammatory disorder involving mostly the small vessels. It is characterised by segmental angiocentric neutrophilic inflammation, endothelial cell damage and fibrinoid necrosis. LV is related to a variety of clinical disorders including cryoglobulinemia and, very rarely, multiple myeloma (MM), among many others. The development of LV in patients with MM has been linked to cryoglobulinemia, infections, drugs and paraneoplasia. It has been speculated that myeloma patients with a poorer prognosis and progressive disease are more prone to develop LV. Thalidomide is a rediscovered old drug with anti-angiogenic, immunomodulatory and anti-inflammatory properties. It is highly effective in the treatment of MM and other clinical disorders such as leprosy, various cancers, graft-versus-host disease and autoimmune diseases. We report here a female patient with Durie-Salmon stage IIA MM who initially presented with cryoglobulinemia and LV. LV in this patient was primarily considered to be the result of progressive cryoglobulinemia, which was closely associated with MM. She was successfully managed with thalidomide and dexamethasone.

Cryoglobulinemia↗
PubMed2005

Do new therapeutic approaches (autotransplants, thalidomide, dexamethasone) improve the survival of patients with multiple myeloma followed in a rheumatology department?

Survival of patients with multiple myeloma (MM) showed no improvement between the 1960s and 1990s. During the last decade, new therapeutic approaches seemed likely to offer hope of prolonging survival. The aim of this study was to examine if this survival increased with the usage of new treatments. The method involves a retrospective study of 123 patients with MM, diagnosed between 1975 and 1999, all receiving treatment. They were divided into two groups: group 1 included 55 patients given the so-called "old treatments" [melphalan-prednisone, cyclophosphamide-prednisone, polychemotherapy (vincristine, melphalan, cyclophosphamide, prednisone (VMCP), VMCP-VBAP)], and group 2 included 68 patients receiving at least one of the so-called "new treatments" (dexamethasone, thalidomide, high-dose chemotherapy followed by autotransplants, bisphosphonates, interferon). The two groups were similar in terms of age, sex ratio and renal impairment, and the percentage of light-chain MM was identical in both groups. Patients who had been given a "new" treatment (group 2) had longer median survival than the patients in group 1 (54 vs 42 months). Independent analysis of each treatment modality showed increased median survival in MM patients treated using autotransplantation compared with untreated patients (125 vs 45 months). Survival was also longer in MM patients treated with thalidomide than in untreated patients (72 vs 42 months). On the other hand, neither bisphosphonates, interferon-alpha nor dexamethasone result in improved survival. Our findings emphasize the increased survival of the MM patients treated with new therapeutic approaches.

Adult↗
PubMed2006

Interferon-alpha plus capecitabine and thalidomide in patients with metastatic renal cell carcinoma: a pilot study.

PURPOSE: To assess the activity and toxicity of interferon-alpha (IFN-alpha), capecitabine, and thalidomide in patients with metastatic renal cell carcinoma (MRCC). PATIENTS AND METHODS: Twenty-seven patients were enrolled in a pilot study to receive oral capecitabine 1,900 mg/m2/day in 2 daily doses, 2 weeks on, l week off; daily subcutaneous IFN-alpha 1 mIU without interruption; and daily oral thalidomide 200 mg/day for the first seven days, then escalated to 400 mg/day without interruption. Dosages were reduced for toxicity as necessary. RESULTS: Two patients discontinued treatment during the first week of the study, leaving 25 patients evaluable. There were 5 (20%) partial responses (PRs), 1 (4%) minor response (MR), 6 (24%) cases of stable disease (SD) > or = 6 months, and 13 (52%) cases of progressive disease (PD). The interval from first response to disease progression varied from 0-23 months: 17 patients progressed in 0-6 months; 4 progressed in 7-12 months; and 4 progressed in 12-24 months. Median survival was > 22 months, 14 months, and 1 month, respectively, for patients with PR, SD, and PD. Grade 3/4 toxicities consisted of hand-foot syndrome, neuropathy, fatigue, anemia, and deep venous thrombosis were common. CONCLUSION: This study demonstrates antitumor activity of combination IFN-alpha/capecitabine/thalidomide in MRCC. The 20% PR rate was notable, as the patient population had advanced disease and inferior performance status. Treatment was generally well tolerated, and further research is warranted to explore the efficacy of this combination for treating MRCC.

Adult↗
PubMed2006

Phase II trial of interferon and thalidomide in metastatic renal cell carcinoma.

OBJECTIVES: To evaluate the toxicity and efficacy of interferon and thalidomide combination in a phase II clinical trial. PATIENTS AND METHODS: Eligibility included metastatic renal cancer with a maximum of two prior regimens, performance status of 0-2 and adequate renal, hepatic and bone marrow function. RESULTS: Twenty patients were enrolled on this phase II trial. Median age was 60.5 years (Range: 39-75 years). 17 patients had visceral metastases (lung/liver/both) and 3 patients had lymph node only metastases. A total of 26 cycles of 4 weeks each were administered; median of 1 cycle and range from 0-9 cycles. The therapy was poorly tolerated with grade 3 adverse events noted in 12 (60%) of the 20 patients. No objective responses were noted. Of the 14 response evaluable patients, one had an unconfirmed response (38% decrease in size) and one had prolonged disease stabilization for 10 months. The median time to progression was 1.0 month and median survival was 2.8 months. Pre and post therapy PET scans were performed nine weeks apart on one patient. The mean standardized uptake values (SUV) declined from 1.45 (SUV min-max 0.89-1.76) to 1.12 (SUV min-max 0.55-1.47), denoting anti vascular effect. The patient did not have an objective response but had a disease stabilization sustained for 10 months. CONCLUSION: The combination of interferon and thalidomide has minimal efficacy and considerable toxicity which makes this combination unworthy of future investigation in metastatic renal cancer.

Administration, Oral↗
PubMed1996

Down-regulation of adhesion receptors on cells of primate embryos as a probable mechanism of the teratogenic action of thalidomide.

In spite of ongoing speculation, there has been no evidence that adhesion receptors are expressed on the cells of mammalian embryos. In this report, we provide the first proof that a variety of such receptor (beta 1-, beta 2-, and beta 3-integrins and selectin) are indeed expressed on cells of essentially all primordia of marmoset embryos at early organogenesis (developmental stages 11 to 13, or even earlier). Treatment with low doses (20 or as little as 1 mg/kg body weight) of a highly teratogenic derivative (EM12) of thalidomide, the most notorious human teratogen, triggers a dramatic and statistically highly significant down-regulation of several surface adhesion receptors (e.g. CD11a/CD18, CD49d/CD29, CD61, etc.) on early limb bud cells and on cells of some other primordia during early organogenesis of embryos of a primate (marmoset, Callithrix jacchus). Some of these receptors almost disappear, or they are expressed at a lower epitope density in the exposed embryos. These down-regulations of surface adhesion receptors may be expected to alter cell-cell- and cell-extracellular matrix interactions, and they are suggested to be a long-sought primary mechanism of the teratogenic action of thalidomide-type substances.

Animals↗
PubMed1987

Recurrent aphthous stomatitis of the Behçet's type: successful treatment with thalidomide.

A 48-year-old man with a 27-year history of debilitating recurrent aphthous stomatitis major and pustular skin lesions was treated successfully with thalidomide. Side effects have not been encountered during a 6-month symptom-free period, while he has taken 25 mg per day. The drug is currently unavailable in this country except for the treatment of leprosy. It is hoped that publication of the dramatic response to thalidomide in this one instance will encourage greater interest in this potentially useful drug.

Behcet Syndrome↗
PubMed1996

Thalidomide selectively modulates the density of cell surface molecules involved in the adhesion cascade.

The mode of action of thalidomide (THD) in clinical cases of vasculitis is still not clear. Expression of adhesion molecules on endothelial cell lines was therefore assessed in vitro. THD is capable of changing the density of tumor necrosis factor alpha (TNFalpha) induced ICAM-1 (CD54), VCAM-1 (CD106) and E-selectin antigens on HUVEC. Furthermore, modulation of L-selectin (CD62L) by THD can be demonstrated on human leukocytes in vitro. The molecules investigated are involved in the neutrophil-endothelial cell interaction and participate in the adhesion cascade. Blunting of cytokine induced up-regulation of these adhesion molecules may account at least in part for anti-vasculitic effects of thalidomide.

Cell Adhesion↗
PubMed1995

Thalidomide-resistant HIV-associated aphthae successfully treated with granulocyte colony-stimulating factor.

Thalidomide has been advocated as the treatment of choice for recalcitrant aphthae. We describe the case of patient with HIV infection and extensive aphthae whose condition failed to respond to corticosteroids, cyclosporine, and thalidomide. The patient's course was complicated by colonic aphthae. Rapid and sustained resolution was achieved through treatment with granulocyte colony-stimulating factor, a previously unreported therapeutic option.

Adult↗
PubMed1991

The thalidomide analog, EM 12, enhances 1,2-dimethylhydrazine-induction of rat colon adenocarcinomas.

Young male Sprague-Dawley rats in 3 groups were fed a basal diet supplemented with 0.10 wt. % each of thalidomide and its imide-analog of much higher teratogenicity, EM 12. Following an induction period of 17 days on the diets, all animals were injected subcutaneously with 1,2-dimethylhydrazine at 20 mg/kg for a total of 20 weekly doses and killed on week 18 after the 20th injection. The total number of colon adenocarcinomas and their occurrence in the proximal and distal portions for the thalidomide-treated rats were similar to those of the respective controls. However, the EM 12-fed group elicited statistically significant increases both in the total and ascending colon-based adenocarcinomas as compared with the control findings, in keeping with its greater teratogenicity and embryotoxicity. The numbers of small intestinal adenocarcinomas were equally higher in the imide-fed groups in contrast to the control frequency.

1,2-Dimethylhydrazine↗
PubMed1995

Exacerbation of acetaminophen hepatotoxicity by thalidomide and protection by nicotinic acid amide.

1. The effects of racemic thalidomide (D[+]/L[-] alpha-phthalimido-glutarimide) on acetaminophen (AAP)-induced hepatitis were tested in male NMRI mice (n = 133) and quantified as serum activities of glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT). 2. A 2.1-fold increase of GOT and a 1.9-fold increase of GPT activities (P < 0.001) were observed in mice treated perorally with 500 mg/kg of AAP plus 150 mg/kg of thalidomide (Thal). In the absence of AAP, Thal did not display any detectable hepatotoxic effects. 3. The Thal-induced exacerbation of AAP hepatotoxicity was completely inhibited by nicotinic acid amide, a selective inhibitor of poly(ADP-ribose) polymerase (PARP) (P < 0.0001), suggesting a possible influence of Thal on the hepatic metabolism of NAD-adenoribosylation. 4. We see the main application of nicotinic acid amide as for the combinational use in pharmaceutical preparations of AAP in order to avoid hepatic damage in patients treated with AAP and Thal.

Acetaminophen↗
PubMedDate not supplied

Mechanism of the teratogenic effect of thalidomide.

The mechanism of the teratogenic effect of thalidomide is unknown. The hypothesis that this drug acts on the sensory nerves of the embryo was derived from radiological observations of two series of thalidomide-deformed children. Supplementary evidence was found in neurological, embryological and other literature, to support the hypothesis of embryonic neuropathy. The concept can be extended to include visceral as well as skeletal deformities. Evidence for and against the hypothesis is presented, and its application to a broad spectrum of congenital deformities provides an explanation of a number of previously unrelated facts. Areas for further research are suggested.

Abnormalities, Drug-Induced↗
PubMed1989

Thalidomide--a therapy for the immunological consequences of HIV infection?

The beneficial effects of the teratogenic drug thalidomide on a variety of disorders involving the immune system have been established recently. Comparison of symptoms and immunologic abnormalities of such diseases with the acquired immunodeficiency syndrome, as well as experimentally obtained results suggest that thalidomide may be a useful agent suppressing autoaggressive reactions initiated by the human immunodeficiency virus.

Adjuvants, Immunologic↗
PubMed1989

The enantiomers of the teratogenic thalidomide analogue EM 12. 2. Chemical stability, stereoselectivity of metabolism and renal excretion in the marmoset monkey.

The rate of metabolism as well as the metabolic profiles of the enantiomers and the racemate of 2-(2,6-dioxopiperidine-3-yl)-phthalimidine (EM 12), a teratogenic thalidomide analogue, have been investigated in vitro and in the marmoset monkey in vivo. The half-life of racemic EM 12 and of the two enantiomers in vitro (phosphate buffer pH 7.4, 37 degrees C) were all in the same range (12 h). Two major hydrolysis products were found which were formed via amide cleavage of the piperidinedione ring of the molecule (EM 27 and EM 356). Their concentrations were similar. In contrast, EM 356 was the main metabolite of EM 12 present in the urine of marmoset monkeys following single i.p. or p.o. doses of 5 mg/kg b.w. About twice as much EM 356 was produced after administration of R-EM 12 than after administration of S-EM 12. The concentration ratio of the metabolites obtained after p.o. and i.p. administration of the substances were in the same range. Separation of the EM 12 enantiomers present in urine suggests that considerable racemisation took place in vivo, although at a slower rate than in vitro: about 25% of the respective optical antipodes were present 5 h after administration of the R-enantiomer and 7.5 h after administration of the S-enantiomer (compared to 1.5 h in vitro). Our results indicate that racemic EM 12 as well as its enantiomers are chemically and metabolically more stable than thalidomide; however, extensive racemisation occurs both in vivo and in vitro. The metabolism and renal excretion of the enantiomers of EM 12 in the marmoset monkey were shown to be stereoselective.

Animals↗
PubMed1990

Susceptibility to cyclophosphamide and thalidomide of fetal rat limb buds grafted in athymic (nude) mice.

Limb buds of day-14 rat fetuses were cut into pieces and transplanted into athymic (nude) mice. On the 7th and 9th days after grafting, the host nude mice were given cyclophosphamide intraperitoneally (10-120 mg/kg) or thalidomide orally (30-240 mg/kg). On the 20th day, the grafted tissue was examined macroscopically and histiologically. The grafts maintained in vehicle-treated nude mice showed considerable growth and tissue differentiation similar to in vivo. Growth and histogenesis of the grafts were significantly inhibited by treatment with cyclophosphamide (greater than or equal to 20 mg/kg). There was no indication that treatment with thalidomide (less than or equal to 240 mg/kg) adversely affects the development of grafted limbs. Thus, the susceptibility of transplanted rat limb buds to these two human teratogens was identical to the susceptibility of living rat fetuses. The heterotransplantation method of embryonic tissues may be of potential use for the study of teratogenic mechanisms and for the screening of human teratogens.

Animals↗
PubMed1990

Thalidomide in the treatment of graft-versus-host disease.

The success of allogeneic bone marrow transplantation has been restricted by the occurrence of graft-versus-host disease (GVHD). Attempts at prevention and treatment of GVHD have resulted in only a limited improvement and the morbidity and mortality rate remains high. Thalidomide has been known to have immunosuppressive properties for over 20 years, but it has only recently been used in GVHD. Evidence is now accumulating as to its value both in animal models, and in humans where most benefit has been seen in chronic GVHD. We report our experience using thalidomide in GVHD following allogeneic bone marrow transplantation and review the literature.

Bone Marrow Transplantation↗
PubMed2004

Phenylhomophthalimide-type NOS inhibitors derived from thalidomide.

Thalidomide shows moderate inhibitory activity toward neuronal nitric oxide synthase (nNOS) and inducible NOS (iNOS), but not toward endothelial NOS (eNOS). Structural development studies of thalidomide yielded novel phenylhomophthalimide-type NOS inhibitors with enhanced activity and different subtype selectivity.

Enzyme Inhibitors↗
PubMed2005

Tubulin-polymerization inhibitors derived from thalidomide.

2-(2,6-Diisopropylphenyl)-5-hydroxy-1H-isoindole-1,3-dione (5HPP-33), which was obtained during our previous structural development studies on thalidomide, was revealed to possess potent tubulin-polymerization-inhibiting activity, comparable to that of the known tubulin-polymerization inhibitors, rhizoxin and colchicine. A major metabolite of thalidomide, 5-hydroxythalidomide, which possesses a hydroxyl group at the position corresponding to that of 5HPP-33, also showed moderate inhibitory activity.

Colchicine↗
PubMed2006

Toxicity profile of the immunomodulatory thalidomide analogue, lenalidomide: phase I clinical trial of three dosing schedules in patients with solid malignancies.

Thalidomide is an anti-angiogenic agent currently used to treat patients with malignant cachexia or multiple myeloma. Lenalidomide (CC-5013) is an immunomodulatory thalidomide analogue licensed in the United States of America (USA) for the treatment of a subtype of myelodysplastic syndrome. This two-centre, open-label phase I study evaluated dose-limiting toxicities in 55 patients with malignant solid tumours refractory to standard chemotherapies. Lenalidomide capsules were consumed once daily for 12 weeks according to one of the following three schedules: (I) 25 mg daily for the first 7 d, the daily dose increased by 25 mg each week up to a maximum daily dose of 150 mg; (II) 25mg daily for 21 d followed by a 7-d rest period, the 4-week cycle repeated for 3 cycles; (III) 10 mg daily continuously. Twenty-six patients completed the study period. Two patients experienced a grade 3 hypersensitivity rash. Four patients in cohort I and 4 patients in cohort II suffered grade 3 or 4 neutropaenia. In 2 patients with predisposing medical factors, grade 3 cardiac dysrhythmia was recorded. Grade 1 neurotoxicity was detected in 6 patients. One complete and two partial radiological responses were measured by computed tomography scanning; 8 patients had stable disease after 12 weeks of treatment. Fifteen patients remained on treatment as named patients; 1 with metastatic melanoma remains in clinical remission 3.5 years from trial entry. This study indicates the tolerability and potential clinical efficacy of lenalidomide in patients with advanced solid tumours who have previously received multi-modality treatment. Depending on the extent of myelosuppressive pre-treatment, dose schedules (II) or (III) are advocated for large-scale trials of long-term administration.

Adult↗