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PubMed1992

Thalidomide and the immune system. 2. Changes in receptors on blood cells of a healthy volunteer.

Thalidomide (Thd) was given in two trials (total daily dose: 5 or 8 mg Thd/kg body weight, respectively) for five and three days to a healthy male volunteer, and various receptors were analyzed on white blood cells before, during and after (up to 30 days) the treatment period. There were neither marked deviations in the absolute number of total leukocytes nor in the percentage of total lymphocytes or monocytes throughout the study period. The most pronounced changes were observed in the surface receptors on CD4 ("helper cells") cells and leukocytes bearing the CD11b (Mac 1) and other integrin and adhesion receptors. Other changes included shifts in the ratio cytotoxic cells/suppressor cells as well as a reduction of the receptor density (passage from bright to dim) in T helper cells bearing CD45RO "memory" markers. Simultaneously, the number of B cells was found to be increased as was the percentage of some adhesion receptors on CD8+ cells. Unlike in previous experiments in which Thd was administered to marmoset monkeys, no effect could be seen in cells bearing the CD2 (LFA-2) epitope.

Antibodies, Monoclonal↗
PubMed1995

Thalidomide and the immune system. 4. Down-regulation of the CD26 receptor, probably involved in the binding of HIV components to T cells in primates.

Thalidomide (Thd) is capable of down-regulating the CD26 receptor on CD4+ lymphocytes after treatment of healthy volunteers. Similar effects are observed when marmosets (Callithrix jacchus) are treated with Thd. The Ta1 epitope of the CD26 receptor has recently been shown to bind the HIV-1 Tat trans-activating protein, and CD26 has also been suggested to be a coreceptor for the binding of the V3 loop of the gp120 HIV envelope protein. This might provide a hint for possible therapeutic interventions.

Animals↗
PubMed1994

Thalidomide and the immune system. 3. Simultaneous up- and down-regulation of different integrin receptors on human white blood cells.

Time-dependent changes in the surface receptor expression of various maturational and integrin receptors on peripheral blood cells were studied in two healthy human volunteers following oral applications of thalidomide (Thd). In each measurement the receptor density was quantified by prior calibration of the flow cytometer with latex beads bearing a determined number of fluorescence molecules. The effects observed in the course of the Thd-treatment were practically identical or at least very similar in both the volunteers during four different trials, and were in accord with previous results obtained in large-scale studies (68 treated animals) with non-human primates. It should be stressed that no clear-cut changes were observed in the percentage or absolute numbers of primary lymphocyte subsets such as CD3, CD4 and CD20. After the first two doses of 7 mg Thd/kg body wt the CD18 (the common beta-chain of the beta 2-integrins) marker already decreased in surface density or was no longer detectable on granulocytes, monocytes and lymphocytes. This effect persisted throughout the treatment period and slowly subsided after discontinuation of treatment. With a few days lag phase, the surface density of CD54 (ICAM-1) on granulocytes increased and many cells previously not bearing this receptor newly acquired such surface markers. On monocytes however, the CD54 receptor was lost on many cells. Within the lymphocyte fraction a loss of the CD54 marker could be noted on CD4 cells but not on CD8 cells, where an increase of the receptor expression could be observed. Other markers, such as the alpha chains of the beta 1 integrins CD49b (VLA alpha 2) and CD49d (VLA alpha 4) showed contrasting reactions to the Thd-treatment. Whereas a pronounced loss of the receptor density of CD49d was observed and only few cells with high epitope density were left in the blood at the end of the complete dosing schedule, no such effect was observable on cells bearing the CD49b epitope. A distinct reduction of the number of receptors was also noticeable on L-selectin (Leu8) bearing cells. On CD4 positive lymphocytes, the majority of the described effects on the integrin and adhesion receptors was seen on cells bearing the CD45R0 maturational epitope. This functional receptor is strongly down-regulated and the pathway of CD45RA to CD45R0 maturation is apparently altered by Thd-treatment. These multiple changes we observed may explain the large variety of therapeutic effects experienced in the treatment with Thd.

Carrier Proteins↗
PubMed1996

Thalidomide derivatives and the immune system. 6. Effects of two derivatives with no obvious teratogenic potency on the pattern of integrins and other surface receptors on blood cells of marmosets.

The two thalidomide (Thd) derivatives beta-EM12 and phthalimidophthalimide (Phtpht), which exhibit no obvious teratogenicity, were tested for their ability to induce changes in the pattern of lymphocyte subpopulations, and especially changes in integrin receptors, in marmosets (Callithrix jacchus). Previously, Thd and its highly teratogenic derivative alpha-EM12 had been found to alter the expression of adhesion molecules, such as CD2 (LFA-2) or CD11a/CD18 (LFA-1). None of these typical effects on adhesion receptors were observed following administration of the relatively high daily doses of 50 mg/kg body wt beta-EM12 and Phtpht. Nevertheless, there were some minor effects, such as alterations in the receptor density on peripheral blood mononuclear cells, which were often contrary to the effects induced by Thd. Mainly affected were: CD8 cells, B cells bearing the CD54 receptor and CD4 cells bearing the CD56 (NCAM) surface marker. We observed an increase in the receptor density of CD11c (p150,95) on monocytes with Phtpht but not with beta-EM12. The inability of the two substances with no obvious teratogenic potential to typically modify beta 2-integrin receptors on white blood cells at comparatively high doses is consistent with our hypothesis, that the teratogenicity of Thd may also be linked to alterations in the expression of adhesion molecules.

Animals↗
PubMed1987

Determination of thalidomide and its major metabolites by high-performance liquid chromatography.

A rapid and sensitive isocratic high-performance liquid chromatography assay for the simultaneous and quantitative determination of thalidomide (alpha-phthalimidoglutarimide) and its major metabolites from human serum has been developed. The parent compound and the metabolites can be efficiently separated by reversed-phase chromatography using tetramethylammonium bromide as an ion-pair-forming reagent.

Biotransformation↗
PubMed2005

Design and synthesis of subtype-selective cyclooxygenase (COX) inhibitors derived from thalidomide.

A series of substituted indoline and indole derivatives with cyclooxygenase (COX)-inhibitory activity was prepared during our structural development studies based on thalidomide as a multi-template lead compound. Structure-activity relationship studies indicated that the nature of the substituent introduced at the benzene ring of the indoline (indole) backbone, and the length and type of the linking group between the nitrogen atom of indoline (indole) and the N-substituent are important for the activity. This study has led to the identification of COX-1-selective inhibitors, and these should be useful not only as pharmacological tools to investigate the physiology and pathophysiology of COX, but also as sophisticated leads for the development of novel drugs to treat COX-associated diseases, such as inflammatory diseases, and cancer.

Cyclooxygenase 1↗
PubMed2005

Design, synthesis and antiinflammatory activity of novel phthalimide derivatives, structurally related to thalidomide.

As part of an ongoing effort to develop new thalidomide analogues as antiinflammatory lead-candidates, this paper describes the synthesis and antiinflammatory activity of novel N-phenyl-phthalimide functionalized derivatives (4a-d, 5a,b, 6a,b). The target compounds were assayed in an acute lung inflammatory model and all compounds were able to inhibit TNF-alpha production and subsequent neutrophil recruitment in the LPS-acute lung inflammatory model.

Animals↗
PubMed2005

An intriguing case of primary amyloidosis with cardiac involvement: symptomatic and echocardiographic improvement with thalidomide treatment.

Patients with primary amyloidosis (AL) have poor prognosis with a median survival of one to two years. In patients with symptomatic cardiac involvement, prognosis is even worse with the reported median survival of 6 months. One patient, diagnosed as AL amyloidosis with cardiac involvement, was treated with thalidomide and showed remarkable improvement in functional capacity, cardiac function, and various laboratory parameters without any significant adverse effect and, therefore, we report the case with the review of literatures.

Amyloidosis↗
PubMedDate not supplied

Maternal administration of thalidomide or valproic acid causes abnormal serotonergic neurons in the offspring: implication for pathogenesis of autism.

Embryonic exposure to thalidomide (THAL) or valproic acid (VPA) before neural tube closure has been demonstrated as a useful model for human autism in rats. Abnormalities of the serotonergic system which are often observed in human autism have been shown in these rats. Thus, we examined whether early serotonergic neuronal development is perturbed by THAL/VPA. When pregnant rats were exposed to THAL or VPA on embryonic day 9, a dramatic shift of the distribution of serotonergic neurons in the dorsal raphe nucleus was observed on postnatal day 50. This alteration is thought to reflect abnormality of serotonergic neuronal differentiation and migration. In vitro studies revealed that VPA retards the maturation of serotonergic neuron from ES cell-derived neuronal progenitors, whereas exogenously added Sonic hedgehog, a morphogen that has been implicated in serotonergic cell fate, partially prevented this retardation. These results indicate that disruption of early serotonergic neuronal development might be involved in the etiology of autism.

Analysis of Variance↗
PubMed2006

The neutropenia induced by the thalidomide analogue CC-4047 in patients with multiple myeloma is associated with an increased percentage of neutrophils bearing CD64.

A major limitation to the treatment of multiple myeloma by the thalidomide analogue CC-4047 (Actimid) is the development of a severe neutropenia. We investigated the hypothesis that this effect may have been due to CC-4047 enhancing the removal of neutrophils from the circulation by altering the expression of surface adhesion molecules required for endothelial binding, by binding to platelets, or by enhancing apoptosis. Flow cytometric analysis was used to examine the expression of neutrophil surface molecules, platelet binding and apoptosis in whole blood samples from 19 patients with multiple myeloma who were assigned to receive either 1, 2, 5 or 10 mg of CC-4047 every other day (e.o.d.) for 28 days. CC-4047 induced dose-related decreases in neutrophil numbers and increases in the percentage of CD64-positive neutrophils, but had little, or no effect on the expression of CD11b, CD62L or CD162, neutrophil-platelet binding, or apoptosis. Relative decreases in the neutrophil count were inversely associated with relative increases in the intensity of CD64 expression on neutrophils (r=- 0.307; p=0.028). Although seven patients developed severe neutropenia, none suffered severe or recurrent bacterial infections. The percentage of CD64-positive neutrophils was still increased in eight patients who continued receiving 1-5 mg CC-4047 e.o.d. for several months afterwards, but neutrophil counts were similar to pre-treatment values.

Adult↗
PubMed2004

Treatment of recalcitrant scleromyxedema with thalidomide in 3 patients.

Scleromyxedema is a generalized, papular, and sclerodermoid form of lichen myxedematosus associated with monoclonal gammopathy and systemic changes. Despite anecdotal reports of success with various agents, no satisfactory treatments are currently available. We report 3 adult patients with recalcitrant scleromyxedema associated with paraproteinemia who were treated with thalidomide. All 3 patients had marked improvement of the skin lesions and joint mobility after the first 2 months of therapy, with further amelioration after 4 months, and reduction in paraprotein levels.

Aged↗
PubMed2005

Complex aphthosis: a large case series with evaluation algorithm and therapeutic ladder from topicals to thalidomide.

BACKGROUND: Recurrent aphthous stomatitis is a common problem with 20% to 50% of the population having experienced simple aphthous lesions (ie, canker sores). Complex aphthosis is the diagnosis given to patients with almost constant >3 oral aphthae or recurrent oral and genital aphthae in the absence of Behcet's disease. METHODS: Eighty-one patients were referred to the Wake Forest University School of Medicine, Department of Dermatology from 1995 to 2001 with the diagnosis of presumptive Behcet's disease. After exclusion of patients with simple recurrent aphthous stomatitis or non-aphthous oral disease, 64 patients remained. Ten of the patients met criteria for Behcet's disease. The remaining 54 patients were evaluated and treated as patients with the diagnosis of complex aphthosis. RESULTS: The 54 patients with complex aphthosis became the subject of this study. Twelve patients had secondary complex aphthosis with 10/12 having inflammatory bowel disease. The remaining 42 patients had primary (ie, idiopathic) complex aphthosis. The therapeutic ladder for these patients ranged from topical therapy through oral colchicine and combination oral colchicine and oral dapsone therapy to oral thalidomide therapy. CONCLUSION: Complex aphthosis is an important condition to distinguish from Behcet's disease. Appropriate patient evaluation algorithms and treatment therapeutic ladders are proposed.

Adult↗
PubMed2005

Thalidomide in the treatment of recalcitrant Sweet's syndrome associated with myelodysplasia.

Sweet's syndrome is a neutrophilic dermatosis characterized by tender, erythematous, pseudovesicular plaques that can be associated with hematologic malignancy. We report a patient with recalcitrant Sweet's syndrome that preceded the development of myelodysplastic syndrome by 30 months. The delay between the onset of Sweet's syndrome and the subsequent diagnosis of myelodysplasia highlights the need for thorough and repeated evaluation for underlying malignancy in patients with such a course. Although corticosteroids are the initial treatment of choice, this patient's eruption was only partially responsive to high-dose prednisone and was refractory to metronidazole, dapsone, and methotrexate. Treatment with thalidomide resulted in complete resolution of the cutaneous lesions within one month of therapy.

Humans↗
PubMed2006

Carpal tunnel syndrome accompanying radial dysplasia due to thalidomide embryopathy.

We performed endoscopic carpal tunnel release in four hands in three patients suffering from radial dysplasia due to thalidomide embryopathy. Carpal canal pressure measurements results confirmed the diagnoses. All operations were successfully performed and resulted in no complications. Tingling sensation and sensory disturbances of the hands subsided.

Abnormalities, Drug-Induced↗
PubMed2004

Thalidomide for severe systemic onset juvenile rheumatoid arthritis: A multicenter study.

Thirteen children with difficult systemic onset juvenile rheumatoid arthritis were treated with thalidomide. At 6 months, 11 of the 13 were able to reduce their use of prednisone ( P < .002), with a concurrent improvement in erythrocyte sedimentation rate ( P < .0001) and an increase in hemoglobin level ( P < 0.005). Juvenile rheumatoid arthritis improvement scores >/=50% were obtained by 10 of the 13 children.

Arthritis, Juvenile↗
PubMed2004

Arsenic trioxide and thalidomide combination produces multi-lineage hematological responses in myelodysplastic syndromes patients, particularly in those with high pre-therapy EVI1 expression.

Twenty-eight myelodysplastic syndromes (MDS) patients were treated with arsenic trioxide (ATO) and thalidomide. Seven patients responded including one complete hematologic and cytogenetic response and one with regression in spleen size. Two trilineage responses were seen in patients with inv(3)(q21q26.2). Three of five patients who had high pre-therapy EVI1 levels showed unexpectedly good responses while two died early in the first cycle. In vitro studies using 32Dcl3 cells forced to express EVI1 confirmed increased sensitivity of these cells to ATO. Both low/high risk MDS may benefit significantly from therapy with ATO/thalidomide, and those with high pre-therapy EVI1 expression may be uniquely sensitive.

Aged↗
PubMed2006

Differential surface expression of CD18 and CD44 by neutrophils in bone marrow and spleen contributed to the neutrophilia in thalidomide-treated female B6C3F1 mice.

Previously, we have reported that thalidomide (Thd) can enhance neutrophil function in female B6C3F1 mice. The present study was intended to evaluate the mechanisms underlying the enhanced neutrophil responses following Thd treatment intraperitoneally (100 mg/kg) for 14 or 28 days. Treatment with Thd increased the numbers of neutrophils in the spleen, peripheral blood, bone marrow, peritoneal cavity and lungs of female B6C3F1 mice when compared to the vehicle control mice. Thd treatment for 14 days increased the percentage and the number of neutrophils in the spleen in the first 8 h (peaking at 2 h) after the last Thd treatment, and it returned to the baseline after 24 h. However, Thd treatment for 28 days increased the percentage and number of neutrophils in the spleen even at the 24-h time point after the last Thd treatment. These neutrophils were demonstrated to be functional by the myeloperoxidase activity assay. Further studies have ruled out the possibility of an increased bone marrow granulopoiesis following Thd treatment. Flow cytometric analysis of the surface expression of adhesion molecules suggested that Thd treatment for either 14 or 28 days decreased the surface expression of either CD18 or CD44 by bone marrow neutrophils. On the other hand, the surface expression of both CD18 and CD44 by splenic neutrophils was increased following Thd treatment for 28 days but not for 14 days. No effect was produced for other cell surface molecules such as CD62L and CD11a. It was possible that decreased surface expressions of CD18 and CD44 facilitated neutrophils' release from the bone marrow; increased surface expressions of CD44 and CD18 by splenic neutrophils after 28 days of Thd treatment increased their ability to remain in the periphery. Taken together, Thd treatment increased neutrophils in female B6C3F1 mice, at least partially, through differentially modulating the surface expression of CD18 and CD44 by the neutrophils in the bone marrow and spleen.

Animals↗
PubMedDate not supplied

The use of thalidomide in androgen-independent prostate cancer.

More than 200,000 men will be diagnosed with prostate cancer during the year 2006. Approximately 20% to 30% of these cases may develop advanced disease, for which there currently is no cure. Although therapy for this disease has improved significantly over the past few years, with docetaxel treatment showing improved survival times in metastatic disease, there remains the need for improved treatment options. Dr. Folkman put forth the idea of angiogenesis in 1971, and, since that time, researchers have been trying to determine the best possible way to inhibit blood vessel formation. This review summarizes the use of thalidomide in androgen-independent prostate cancer and the results of trials conducted at the National Cancer Institute.

Angiogenesis Inhibitors↗