Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “THALIDOMIDE”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 793 records · Page 44Linked to original sources
PubMed1996

Selection of novel analogs of thalidomide with enhanced tumor necrosis factor alpha inhibitory activity.

BACKGROUND: Tumor necrosis factor alpha (TNF alpha) is thought to mediate both protective and detrimental manifestations of the inflammatory response. Recently, thalidomide (alpha-N-phthalimidoglutarimide) was shown to partially inhibit monocyte TNF alpha production (by 50-70%) both in vivo and in vitro. More efficient inhibition of TNF alpha may, however, be necessary to rescue the host from more acute and extensive toxicities of TNF alpha-mediated inflammation. MATERIALS AND METHODS: Three structural analogues of thalidomide were selected for study based on increased activity against TNF alpha production. The parent drug and the analogs were tested in vitro in human peripheral blood mononuclear cell cultures for their effects on lipopolysaccharide (LPS) induced cytokine protein and mRNA production using ELISAs and Northern blot hybridization. The in vitro effects of the drugs were then confirmed in vivo in a mouse model of LPS induced lethality. RESULTS: The new compounds (two esters and one amide) showed increased inhibition of TNF alpha production by LPS-stimulated human monocytes, relative to the parent drug thalidomide. The analogs and the parent drug enhanced the production of interleukin 10 (IL-10), but had little effect on IL-6 and IL-1 beta protein and mRNA production. When tested in vivo, the amide analog protected 80% of LPS-treated mice against death from endotoxin induced shock. CONCLUSIONS: Analogs of thalidomide designed to better inhibit TNF alpha production in vitro have correspondingly greater efficacy in vivo. These finding may have therapeutic implication for the treatment of human diseases characterized by acute and extensive TNF alpha production such as tuberculous meningitis or toxic shock.

Animals↗
PubMedDate not supplied

Failure of thalidomide to inhibit tumor growth and angiogenesis in vivo.

Thalidomide was recently suggested to be angiogenesis-inhibitor following the demonstration of its activity in a rabbit cornea micropocket model. The purpose of the present study was to test its efficacy in solid tumors in mice. B16-F10 melanoma and CT-26 colon carcinoma cells were injected subcutaneously, intravenously and intraperitoneally, and mice received daily gavage of 0.3-1.0 mg thalidomide starting either two or 10 days following tumor cell injection. The tumors were measured and compared with controls. There was no growth retardation in CT-26 bearing mice nor in mice with pulmonary or peritoneal metastases of B16-F10 melanoma. In 3/7 groups of mice with SC B16-F10 tumors, growth retardation was demonstrated, however the difference was not statistically significant. All tumors eventually reached maximal size, similar to controls. Morphological evaluation of the blood vessels oriented towards the tumor revealed that in both thalidomide and control groups, all mice had developed an intact network of new blood vessels. In our model for the oral administration of thalidomide inhibition of tumor growth and angiogenesis did not occur. We hypothesize that the lack of sustained antiangiogenic response was either due to immune modulation or to tumor heterogeneity and adaptation.

Animals↗
PubMedDate not supplied

Thalidomide. A surprising recovery.

The epidemic of birth defects in Europe in the early 1960s attributed to thalidomide led to stringent and unprecedented drug safety requirements in many countries. No definitive mechanism of action has been determined for the biological activities associated with thalidomide. Food and Drug Administration and congressional concerns about the handling of clinical investigations of thalidomide led to sweeping new regulations for clinical trials. Thalidomide is currently being used clinically to treat such conditions as cachexia associated with HIV and cancer, mycobacterial disease, and autoimmune diseases.

Autoimmune Diseases↗
PubMed1998

Thalidomide reduces vascular density in granulation tissue of subcutaneously implanted polyvinyl alcohol sponges in guinea pigs.

The efficacy of thalidomide in the treatment of erythema nodosum leprosum is a well established fact; there is also accumulating evidence of its therapeutic value in a number of other inflammatory and immune-mediated conditions. In addition, thalidomide has been shown to be an inhibitor of angiogenesis induced by basic fibroblast growth factor (bFGF). Nevertheless, its mechanism of action remains speculative. Using guinea pigs, orally administered thalidomide significantly enhanced the response of multinucleated foreign body giant cells (p<0.05) in subcutaneously implanted polyvinyl alcohol sponges. Furthermore, the drug exerted a dual effect in that it reduced vascular density (p<0.05), which was not abolished by recombinant human bFGF, and at the same time amplified the granulomatous response with and without bFGF (p<0.05 and p<0.01, respectively). The results of our experiments represent a further step toward understanding the mechanism of action of thalidomide, with implications for its potential use in wound healing and scar formation as well as in the control of tumorigenesis.

Animals↗
PubMed1998

CC-3052: a water-soluble analog of thalidomide and potent inhibitor of activation-induced TNF-alpha production.

The immunomodulatory drug thalidomide has been shown to be clinically useful in a number of situations due to its ability to inhibit TNF-alpha synthesis. However, its use is restricted by potentially serious side effects, including teratogenicity and neuorotoxicity; furthermore, insolubility may present problems in terms of systemic bioavailability. Recently, structural modifications of thalidomide have been designed enabling greatly enhanced anti-TNF-alpha activity in LPS-treated mice. In contrast to thalidomide (LPS-induced TNF-alpha IC50 approximately 200 microM in DMSO) and other analogs tested, one of these compounds, CC-3052 (IC50 approximately 1 microM in water), is water soluble. Furthermore, this analog exhibits increased stability in human plasma (t(1/2) approximately 17.5 vs 1.5 h for thalidomide) and appears to be nontoxic, nonmutagenic, and nonteratogenic. At pharmacologically active levels, cellular proliferation and LPS-induced IL-6 mRNA and IL-12p40 mRNA (as well as IL-1beta and IL-6 protein levels) in whole blood cultures were not affected; apparent inhibition of NK activity by CC-3052 was reversed upon addition of exogenous rTNF-alpha. In addition, IL-10 mRNA and protein levels were increased. These properties are consistent with results indicating inhibition of phosphodiesterase type IV activity by CC-3052. Furthermore, CC-3052 did not increase the degradation rate of macrophage TNF-alpha transcripts nor inhibit LPS-induced primary macrophage NF-kappaB activation. Taken together, the potency of selective TNF-alpha inhibition, water solubility, and increased plasma stability make CC-3052 an excellent candidate for further development and clinical evaluation for the treatment of TNF-alpha-mediated disease.

Adjuvants, Immunologic↗
PubMed2001

Three-step synthesis of (R)- and (S)-thalidomides from ornithine.

Three-step synthesis of enantiomerically pure thalidomide is described. D-Ornithine (2) reacted with thionyl chloride in methanol followed by treatment with triethylamine to give the (R)-3-amino-piperidin-2-one hydrochloride (3) in good yield. Protection of amino moiety by the use of N-carboethoxyphtalimide in DMSO furnished (R)-N-phtaloylpiperidin-2-one (4) as colorless crystals. Finally, the oxidation using a catalytic amount of RuO2 in the presence of excess sodium metaperiodate in a two-phase system gave (R)-thalidomide (1) in good yield without racemization. (S)-Thalidomide (1) was also synthesized from L-ornithine (2) in good overall yield. Since all the intermediates to thalidomide are easily recrystallized, the present method can be performed on a large scale without purification by column chromatography.

Journal Article↗
PubMed1997

Interaction of [glutarimide-2-14C]-thalidomide with rat embryonic DNA in vivo.

We have investigated the possibility of [phthalimide carbonyl-14C]thalidomide and [glutarimide-2-14C]thalidomide interaction with DNA. In each experiment, groups of pregnant Wistar rats were treated with a labeled compound on day 12 of gestation. The embryos were harvested 24 h later, and dimethlformamide-treated control groups and groups treated with the same labeled compound and with the same radioactive doses were pooled respectively and analyzed. The DNA from each group was purified and monitored for 14C radioactivity. Low but statistically significant radioactivity was detected in only the DNA samples prepared from the [glutarimide-2-14C]thalidomide-treated embryos. This result demonstrates the binding of the glutarimide moiety, or its reactive intermediates, with rat embryonic DNA in vivo.

Animals↗
PubMed1998

5'-Substituted thalidomide analogs as modulators of TNF-alpha.

The synthesis of 5'-substituted thalidomide analogs is described. The amino acids 2 necessary to synthesize the target compounds were prepared by Michael reaction. Condensation of 2 with phthalic anhydrides followed by reaction with urea yielded 4 as diastereomeric mixtures. Furthermore glutethimide (5) was brominated by an improved method and the resulting compound 6 was reacted in several steps with sodium azide, hydrogen, and phthalic anhydride to give 8. In a similar manner, 6 was reacted with sodium azide and various phthalic anhydrides to give 9, 10, and 11. All final compounds were tested in vitro for their inhibitory activity on the release of TNF-alpha, using stimulated peripheral mononuclear blood cells (PBMCs). Compounds with an additional aromatic substituent in position 5' of the thalidomide molecule were more active than thalidomide. Compound 11 was able to reduce increased levels of IL-2 in vitro.

Humans↗
PubMed2003

Thalidomide and dexamethasone therapy of myeloma in a patient with previously untreated B-chronic lymphocytic leukemia.

A 67-year-old woman with previously untreated lambda-positive B-chronic lymphocytic leukemia (CLL) had kappa-positive myeloma develop that was treated with daily thalidomide and intermittent dexamethasone. After 4 months, there was a marked reduction in marrow plasmacytosis, urine kappa chains, and peripheral blood and marrow lymphocytosis. She reduced her thalidomide (but not dexamethasone) doses after 6 months, because she had symptoms of peripheral neuropathy. Although blood lymphocyte concentrations remained normal, she had progression of myeloma and died. Thalidomide and dexamethasone therapy similar to that administered for myeloma alone may be effective treatment for myeloma in patients with preexisting B-CLL and may also have anti-B-CLL activity.

Aged↗
PubMed2005

Temozolomide plus thalidomide in patients with brain metastases from melanoma: a phase II study.

BACKGROUND: Temozolomide plus thalidomide is a promising oral combination regimen for the treatment of metastatic melanoma. The current Phase II study examined the efficacy and safety of this combination in chemotherapy-naive patients with brain metastases. METHODS: Patients with histologically confirmed metastatic melanoma and measurable brain metastases received temozolomide (75 mg/m2 per day for 6 weeks with a 2-week break between cycles) plus concomitant thalidomide (200 mg/day escalating to 400 mg/day for patients < 70 years or 100 mg/day escalating to 250 mg/day for patients > or = 70 years). The primary end point was tumor response in the brain assessed every 8 weeks. RESULTS: Twenty-six patients with a median age of 60 years were treated. All patients had progressive brain metastases: 16 were symptomatic and 25 had extensive extracranial metastases. Eight patients had received whole-brain radiotherapy, 4 had received stereotactic radiotherapy, and 8 had received craniotomy with resection of hemorrhagic lesions. Fifteen patients completed > or = 1 cycle (median, 1 cycle; range, 0-4 cycles), and 11 discontinued treatment before completing 1 cycle (7 for intracranial hemorrhage, 2 for pulmonary embolism, 1 for deep vein thrombosis, and 1 for Grade 3 rash). Of 15 patients assessable for response, 3 had a complete or partial response (12% intent to treat) and 7 had minor response or stable disease in the brain. However, 5 of these 10 patients had disease progression at extracranial sites. The median survival period was 5 months for all 26 patients and 6 months for the 15 assessable patients. CONCLUSIONS: Temozolomide plus thalidomide was an active oral regimen for patients with brain metastases from malignant melanoma.

Adult↗
PubMed2005

Oral melphalan, prednisone, and thalidomide for newly diagnosed patients with myeloma.

BACKGROUND: Thalidomide is an immunomodulatory drug with strong antimyeloma activity. It is an effective treatment for multiple myeloma at disease recurrence and at diagnosis, both as a single agent and in combination with steroids or chemotherapy. No data are available on the association of thalidomide with oral melphalan and prednisone, still considered the standard treatment for elderly patients. METHODS: The feasibility and efficacy of the combination of melphalan, prednisone, and thalidomide (MPT) have been valuated in 49 newly diagnosed patients with multiple myeloma. RESULTS: According to European Bone Marrow Transplantation/ International Bone Marrow Transplantation Registry (EBMT/IBMTR) criteria, 18% of patients achieved immunofixation-negative complete disease remission (CR), 6% achieved immunofixation-positive near CR, 4% achieved a very good partial response, and 45% achieved a partial response, with a 50-89% reduction in monoclonal paraprotein. Six percent did not respond and 10% showed progressive disease. The median time to maximum response was 4 months. The Kaplan-Meier estimates of event-free survival and overall survival at 2 years were 64% and 91%, respectively. The major acute adverse events (National Cancer Institute Common Toxicity Criteria Grade III-IV) included thrombosis (20%), infections (12%), constipation (6%), and hematologic (22%) and neurologic (8%) toxicities. One patient died of pulmonary thromboembolism. CONCLUSIONS: These data suggested that MPT induced rapid and durable tumor responses with CR rates similar to those observed after autologous transplantation. Administration of prophylactic anticoagulant was required to prevent thromboembolism. MPT merits further investigation in randomized clinical trials.

Administration, Oral↗
PubMed2006

Pilot trial of bone-targeted therapy with zoledronate, thalidomide, and interferon-gamma for metastatic renal cell carcinoma.

BACKGROUND: The purpose of the study was to evaluate the efficacy and safety of a bone-targeted regimen consisting of zoledronate, thalidomide, and interferon-gamma in patients with renal cell carcinoma and bone metastases. METHODS: Eligible patients had radiographic evidence of bone metastasis. Impending pathologic fractures or spinal cord compressions must have been controlled by surgery or radiation therapy before enrollment. Zoledronate (4 mg) was given intravenously every 4 weeks, thalidomide (300 mg) was given orally once a day, and interferon-gamma (100 microg) was given subcutaneously once a week. Patients were evaluated for time to skeletal-related events, the appearance of calcification in osteolytic metastases, and levels of the bone formation/resorption markers. RESULTS.: Fifteen patients were treated between November 2002 and November 2003; 12 had previously undergone surgery, radiation, or embolization for their bone metastases; 11 had more than 3 sites of bone involvement; and 9 also had nonosseous metastases in the lung, liver, lymph node, pancreas, or adrenal gland. The median time to progression was 8.3 weeks (range, 2.1-48 weeks). The median time to a skeletal-related event was 12.0 weeks (range, 3.9-46.4 weeks). Two patients discontinued treatment because of adverse drug reactions (1 deep venous thrombosis and 1 myocardial infarction). Two patients experienced pain improvement and developed calcification in osseous metastases; these patients also showed favorable changes in bone marker levels. CONCLUSIONS: In this pilot study a bone-targeted regimen combining zoledronate, thalidomide, and interferon-gamma was well tolerated and might provide clinical benefit for a small subset of patients with renal cell carcinoma and bone metastases.

Adult↗
PubMed1984

Rabbit sural nerve responses to chronic treatment with thalidomide and supidimide.

Chronic treatment of rabbits with thalidomide (3-(N-phthalimido) glutarimide) produced progressive decrements in sural nerve conduction velocity (NCV) that were unassociated with qualitative or quantitative morphological changes of nervous tissue. Three groups of eight rabbits received 100 mg/kg/day thalidomide (group I), 200 mg/kg/day supidimide (a related drug) (group II), or a carboxymethylcellulose vehicle (group III) 5 days/week for 40 weeks. At 6 months of treatment, a noninvasive determination of the mean maximum sural NCV for group I was significantly reduced relative to the conduction velocities of groups II and III. Direct measurement of conduction velocity when treatment was terminated confirmed these findings and demonstrated similar conduction deficits in proximal and distal portions of the sural nerve in group I animals. At 6 months, rabbits in group II showed a significant reduction in mean conduction velocity, and, at the termination of treatment, they displayed mean values similar to that of group III and significantly greater than that of group I. Morphological findings were unremarkable in 20 regions of the central nervous system (CNS) and the peripheral nervous system (PNS) known to display changes early in toxic neuropathies. Morphometric estimation of unmyelinated and myelinated fibers in the sural nerve at the heel revealed no between-group differences in axon diameter, fiber diameter, g-ratio (the ratio of inside/outside diameters), or internodal length. In conclusion, chronic treatment with thalidomide produces selected decrements in sural nerve function that have an unknown relationship to the poorly reversible sensory neuropathy reported in humans receiving this drug.

Animals↗
PubMed2007

A phase II trial of thalidomide and cyclophosphamide in patients with recurrent or refractory pediatric malignancies.

BACKGROUND: Previous clinical and pre-clinical research has demonstrated synergy between anti-angiogenic agents and cytotoxic chemotherapy. This trial was undertaken to investigate whether the combination of cyclophosphamide and thalidomide would be active against pediatric tumors. PROCEDURE: Patients with pediatric malignancies who had no remaining conventional therapeutic options were recruited from January 1999 to May 2001. They received thalidomide (6-12 mg/kg po every day; maximum daily dose 800 mg) and cyclophosphamide (1,200 mg/m2 IV every 28 days). RESULTS: Twenty-seven patients were enrolled on the study. Seventeen were male and 10 were female. Median age at the time of registration was 15 years (range 1-54 years). The median number of prior treatment regimens was four. Twenty-one patients were evaluable for response; 1 had a partial response (Hodgkin disease), 1 demonstrated stable disease (neuroendocrine tumor), and 19 had progressive disease. The most common toxicities were hematological (leukocytopenia and neutropenia) and gastrointestinal. One patient experienced a grade 3 rash. Fatigue and daytime somnolence were variable. No peripheral neuropathy was observed. CONCLUSION: The combination of thalidomide and cyclophosphamide as described herein has a modest and tolerable toxicity profile but little evidence of efficacy.

Adolescent↗
PubMed1976

Studies of the etiology of thalidomide dysmorphogenesis.

Thalidomide was administered to pregnant rabbits in dosages of 150-250 mg/kg/day on days 8-12 of gestation. These females produced 40 offspring, 21 of which were deformed. Four control females produced 34 offspring, none of which was deformed. The C6 and C7 ganglia of day-13, -15, -17, and -21 control and experimental embryos and fetuses were examined electron microscopically. Degenerative changes were found in the neurons and axons of dorsal root ganglia in day-13 experimental embryos, i.e., at least 16h before the earliest signs of thalidomide dysmelia have been reported in rabbits (Vickers, '67). Since the dorsal root ganglia form in rabbits on days 11 and 12 the changes evident at day 13 indicate that degeneration of neurons and axons may be a pathogenetic factor in thalidomide-induced peripheral deformities.

Abnormalities, Drug-Induced↗
PubMed1979

The teratogenic activity of a thalidomide analogus EM12 in rats on a low-zinc diet.

The relationship between the teratogenicity of EM12, 2-(2,6-dioxopiperiden-3'-yl) phthalimidine, a stable analogue of thalidomide, and zinc status in the maternal animal was investigated using pregnant rats on a low-zinc diet (1 ppm zinc, days 0--14 gestation) as the experimental model. Previous studies with this compound in rats fed a commercial diet at oral doses up to 250 mg/kg per day for three days and intravenous doses up to 10 mg/kg per day for three days failed to produce "typical" thalidomide malformations. However, when a dose of 150 mg/kg was given intraperitoneally to rats on a low-zinc diet, typical thalidomide malformations occurred with an incidence of 57.5%.

Abnormalities, Drug-Induced↗
PubMed1995

Thalidomide-induced neuropathy and genetic differences in drug metabolism.

A pharmacogenetic predisposition to thalidomide-induced neuropathy has been investigated. Differences of drug metabolism were examined in 16 patients with severe orogenital ulceration, who were treated with thalidomide (< or = 200 mg/day) for 0.3-5.0 years. Eight had evidence of early peripheral neuropathy according to nerve conduction studies. Rates of C-hydroxylation, N-acetylation, and conjugation reactions with sulphate, glucuronide and glycine, were tested with the probe compounds debrisoquine, sulphadimidine, paracetamol and aspirin, respectively. Urinary drug metabolites were analysed by high pressure liquid chromatography. Results were compared with 16 healthy age- and sex-matched volunteers. Of the patients 6.25% and 13.3% of the controls had a poor Debrisoquine Hydroxylator Ratio (DMR); none of the patients with neuropathy had a poor DMR as compared to 12.5% without neuropathy. Of the patients 40.0% and 35.7% of the controls were slow acetylators; 28.6% with neuropathy were slow acetylators as opposed to 50% without neuropathy. Similarly, there were no significant differences in rates of conjugation between groups. All unaffected patients were active smokers, whereas only two of those with neuropathy smoked. Cumulative dose or duration of therapy were unrelated to risk of neuropathy. In conclusion, changes of nerve conductivity are a frequent and unpredictable adverse effect of thalidomide (< or = 200 mg/day), although smoking may have a protective action against their development. Nerve conduction studies are required before and during treatment, irrespective of the prescribed dose.

Acetylation↗
PubMed1977

[Teratologic-neurotoxicologic studies on biglumide (K-2004) and thalidomide].

Comparison of the teratogenic and neurotoxic influence of thalidomide with the new hypnosedative preparation Biglumide (K-2004) revealed significant differences. Malformations could be seen only after treatment with thalidomide. Some results concerning the thalidomide-treated group of animals could be interpreted as a retardation of development in the posterior root ganglia.

Animals↗