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PubMed2004

Influence of thalidomide on megakaryocytes in multiple myeloma.

The aim of the study was to assess the influence of thalidomide on megakaryocytes (MK) in patients with multiple myeloma (MM). The study was based on bone marrow trephine biopsies from 12 patients with MM before initiation of thalidomide administration and after three months of its duration. The morphometric examinations were done, using image analysis (DP 12). Quantitative assessment of MK and the analysis of the morphological parameters of MK were performed. MK with features of dysplasia were more frequently observed before the treatment. Additionally, a greater number of the so-called 'naked nuclei' was noticed then. Due to the effect of thalidomide, the mean number of MK increased and so did their area. During the treatment, a more frequent presence of emperipolesis was observed. The observations confirm the fact that thalidomide may cause changes in MK.

Adult↗
PubMedDate not supplied

Complete resolution of generalized lichen planus after treatment with thalidomide.

Thalidomide has gained an infamous history due to severe birth defects observed in patients who had taken the drug to control nausea during pregnancy. The medication was withdrawn from the market because of its teratogenicity, but was approved by the FDA in 1998 for the treatment of erythema nodosum leprosum. However, thalidomide has been employed with success by dermatologists for a host of off-label uses including the treatment of lichen planus. Currently, no clinical trials or studies exist to evaluate the efficacy of using thalidomide to treat lichen planus, but case reports have been published in the medical literature supporting its therapeutic benefits. TNF-alpha is among the many cytokines that have been implicated in the pathogenicity of lichen planus. It is thought that thalidomide acts.

Adult↗
PubMed2005

[Thalidomide: new indications for an old drug].

Thalidomide has several mechanisms of action: a hypnosedative effect, several immuno-modulatory properties and an anti-angiogenic action. Thalidomide has been used in several cutaneous inflammatory disorders (such as erythema nodosum leprosum in lepromatous leprosy, cutaneous lupus erythematosus, severe aphtosis), cancers (relapsed/refractory multiple myeloma) and inflammatory conditions. Several side effects are associated with thalidomide: teratogenicity, peripheral neuropathy and deep venous thrombosis; some are minor, such as somnolence or abdominal pain and endocrinologic disturbances. Use of thalidomide is strictly controlled with close adherence to a birth control program and close monitoring for early development of peripheral neuropathy.

Humans↗
PubMed2006

Stimulation of erythropoiesis by thalidomide in multiple myeloma patients: its influence on FasL, TRAIL and their receptors on erythroblasts.

The expression of proteins of the tumor necrosis factor (TNF) family on erythroblasts was measured during thalidomide treatment in 29 patients with multiple myeloma (MM). A clinical response was observed in 17 patients (58.6%) and haemoglobin concentration increased in 22 patients (75.9%). The expression of FasL, Fas, TNF-related apoptosis-inducing ligand (TRAIL) and TRAIL-R1 on erythroblasts decreased significantly during thalidomide treatment. Additional in vitro studies revealed that the apoptosis of erythroblasts and the expression of FasL, TRAIL, TRAIL-R1 and TRAIL-R2 was lower in cultures with thalidomide than in control cultures. Altogether our results suggest that thalidomide may stimulate erythropoiesis in MM patients by decreasing the expression of TNF-like ligands/receptors on erythroblasts.

Adult↗
PubMed2003

Low-dose thalidomide plus monthly high-dose oral dexamethasone (Thali-Dexa): results, prognostic factors and side effects in eight patients previously treated with multiple myeloma.

Thalidomide is active both as single agent and in combination-therapy against refractory or relapsing multiple myeloma. Eigth patients previously treated were given Thalidomide 100mg/daily plus Dexametasone 40mg/daily for four days each month (Thali-Dexa) and followed for response, prognostic factors and side effects. Two patients had early death (one from massive cerebral ischemic stroke, the other from dementia and progressive renal failure), one patient progressed during Thali-Dexa (thalidomide 200mg) and was rescued with chemotherapy, two patients required increasing thalidomide dosage (to 200 and 400mg, respectively) because of progressive disease, three patients had stable disease remission lasting from 4m+ to 16m+. Thali-Dexa is a useful agent but age and vascular/metabolic diseases may increase the risk of severe side effects. Early decrease in erythrocyte sedimentation rate seems to correlate with better disease control.

Administration, Oral↗
PubMed2006

Successful treatment of refractory angioimmunoblastic T-cell lymphoma with thalidomide and dexamethasone.

Angioimmunoblastic T cell lymphoma (AITL) is a peripheral T-cell lymphoma characterized morphologically by lymphadenopathy with a polymorphic infiltrate, marked vascular and follicular dendritic cell proliferation. Patients usually present with advanced disease and the overall prognosis is poor. While intensive chemotherapy has been shown to induce complete remissions in 50-70% of patients, the majority of patients subsequently relapse. Herein we report the case of a 32 year old man with AITL who was refractory to conventional chemotherapy, but achieved a remarkable sustained response to treatment with thalidomide and dexamethasone. Thalidomide may be an effective therapeutic agent against AITL, and given the poor prognosis of AITL, prospective clinical studies with either thalidomide or one of the thalidomide analogues are warranted.

Adult↗
PubMed2006

Thalidomide as treatment for digestive tract angiodysplasias.

An 80-year-old man with von Willebrand's disease was admitted with severe melaena. Despite suppletion with von Willebrand concentrate he continued to be dependent on blood transfusions. Endoscopic examination did not show a bleeding focus. Video capsule endoscopy showed active bleeding from angiodysplasias in the proximal section of the small intestine. Ultimately, treatment with thalidomide was initiated at a dose of 100 mg/day. Soon after starting treatment his stools became normal and his haemoglobin level stabilised. No bleeding problems occurred for 11 months, after which the thalidomide treatment was stopped because of the potential side effects. Two months later he again developed melaena and treatment with thalidomide was restarted with a successful outcome. Trying to lower the dose to 50 mg resulted in rebleeding after three months with stabilisation after increasing the dose to 100 mg again. Monotherapy with thalidomide improves the clinical picture but may not be sufficient in the long term. Additional therapy, such as argon plasma coagulation or the use of the novel drug lenalidomide, might be necessary.

Aged, 80 and over↗
PubMed1989

Thalidomide may inhibit proliferation of mesenchyme in human limb buds.

Limb buds from 4- and 4.5-week-old human embryos were cultured on agar medium consisting of Medium 199, chick embryo extract and horse serum for 4 days with or without thalidomide (1-1.5 microgram/ml), and the direct effect of thalidomide was examined morphologically in histological preparations. In the explants treated with thalidomide, mitotic figures of mesenchymal cells were significantly decreased both in overall explant and in mesenchymal cell aggregates, but the extracellular matrix in the mesenchymal cell aggregates was seen in the experimental and control explants. These findings suggest that thalidomide affects undifferentiated and differentiated mesenchymal cell proliferation but not the chondrogenic capacity of the mesenchyme.

Cartilage↗
PubMedDate not supplied

Plasma pharmacokinetics and urinary excretion of thalidomide after oral dosing in healthy male volunteers.

The plasma pharmacokinetics and urinary excretion of thalidomide have been evaluated in eight healthy male volunteers receiving a single oral dose of 200 mg. Concentrations of thalidomide were determined by a new HPLC assay. Plasma concentration vs. time data were well fit by a one-compartment model. The mean (+/- SD) peak concentration, 1.15 +/- 0.2 microgram/ml, was achieved at 4.39 +/- 1.27 hr. Absorption and elimination half-lives were 1.70 +/- 1.05 hr and 8.70 +/- 4.11 hr, respectively, with a lag time of 0.41 +/- 0.17 hr observed in six subjects. The apparent volume of distribution and total body clearance rate, based on assumed complete bioavailability, were 120.69 +/- 45.36 liters and 10.41 +/- 2.04 liters/hr. The urinary excretion of thalidomide accounted for only 0.6 +/- 0.22% of the total dose administered over 24 hr, and the renal clearance rate was 0.08 +/- 0.03 liter/hr. This suggests that the major route of elimination of thalidomide is nonrenal.

Administration, Oral↗
PubMed1986

Thalidomide effects in Behçet's syndrome and pustular vasculitis.

Pustular vasculitis is a new disease concept that links cutaneous, and possibly systemic, aspects of Behçet's, bowel bypass, bowel-associated dermatosis-arthritis, and disseminated gonorrhea syndromes. The pathomechanism of pustular vasculitic lesion generation may relate to circulating immune complex (CIC)-mediated vessel damage and serum enhancement of neutrophil migration. Thalidomide, an oral pharmaceutical available on strict protocol, has therapeutic effects based on proposed modulation of CIC- and neutrophil-mediated cytotoxicity. Thalidomide therapy was started for four patients with significant morbidity from Behçet's syndrome and for one patient with bowel-associated dermatosis-arthritis syndrome. Clinical benefit was dramatic in all patients who completed sequential four-week "on" and "off" thalidomide therapeutic cycles. In three of four patients, in vivo testing for CIC after histamine injection immunopathology converted from positive (immunoreactant deposition in dermal vasculature [four hours after histamine] and CIC-mediated vasculitis [24 hours after histamine]) to negative during therapy. No effects were noted on neutrophil migration or on the LFA-1/Mac-1/p150,95 family of glycoproteins associated with neutrophil adherence as assessed qualitatively by tritium labelling of neutrophil cell surfaces. In this small patient group, thalidomide was a clinically effective, safe (with rigid monitoring) therapy whose mechanism of action may relate more to inhibitory effects on CIC-induced vasculitis than to effects on neutrophil-mediated cytotoxicity.

Antigen-Antibody Complex↗
PubMed1971

WHO co-ordinated short-term double-blind trial with thalidomide in the treatment of acute lepra reactions in male lepromatous patients.

The treatment of lepra reactions constitutes one of the most serious problems in leprosy. For this reason, the first reports in 1965 of the favourable results obtained with thalidomide aroused considerable interest and led WHO, in 1967, to carry out a trial with the co-operation of four centres. A short-term double-blind trial was designed to study the effect of thalidomide, in comparison with acetylsalicylic acid, in the treatment of acute lepra reactions in male lepromatous patients. Acetylsalicylic acid was used instead of a placebo because of its antipyretic and analgesic activity. Because of the severe adverse reactions that may be caused by thalidomide, mainly the teratogenic effects, only males were included in the trial.The results of this short-term study seem to confirm previous reports of the efficacy of thalidomide and indicate that acetylsalicylic acid also seems to be helpful in the management of certain symptoms of lepra reactions.

Acute Disease↗
PubMed1977

The effects of thalidomide and two analogues on the regenerating forelimb of the newt.

Oral administration (3 mg/day) of thalidomide during the dedifferentiation and early limb-bud stages of newt forelimb regeneration produced a variety of specific limb deformities. Proximal and preaxial skeletal elements were the most severely malformed, e.g. preaxial hemimelia, severe proximal deformities, and preaxial polydactyly. Likewise, oral, daily doses (3 mg) of the teratogenic analogue, EM12, on days 7 and 8 following bilateral amputation caused the same incidence and type of forelimb abnormalities as did thalidomide. Conversely, the non-teratogenic analogue, EM87, when orally administered (3 mg/day) on days 7 and 8 post-amputation resulted in a low rate of limb deformities, similar in type to those seen in control regenerates. The type of limb deformities observed in the regenerating newt forelimb following thalidomide treatment nearly mimic those seen in the human and monkey syndromes. Therefore, the newt represents a possible model for investigating some of the problems associated with thalidomide teratogenesis.

Amputation, Surgical↗
PubMed1983

[Should thalidomide be rehabilitated?].

Thalidomide (alpha-N-phtalimido-glutarimide) was withdrawn from sale in 1961 since it was held responsible for the birth of hundreds of phocomelus children. Despite this teratogenic potential, thalidomide remains a useful tool in the treatment of erythema nodosum leprosum, as well as in discoid lupus erythematosus when antimalarial drugs are ineffective or contraindicated. In addition, good results have been reported in several diseases such as actinic prurigo, polymorphous light eruption, Behçet syndrome, Weber-Christian disease, prurigo nodularis, pyoderma gangrenosum and ulcerative colitis. The mechanism of action is under debate but it is likely that thalidomide has immunomodulating properties by controlling T-suppressor lymphocytes, and anti-inflammatory effects, particularly an inhibition of neutrophil chemotaxis. Several attempts at synthesis of effective thalidomide derivatives devoid of teratogenic effects are ongoing.

Chemical Phenomena↗
PubMed1984

Thalidomide deformities and their nerve supply.

The aim of this study was to test the hypothesis that thalidomide acts upon the embryonic peripheral nervous system rather than upon mesenchyme. Pregnant rabbits were given oral thalidomide (150 mg/kg/day) on Days 7-11 of gestation. Fetuses were removed at laparotomy, under anaesthesia, on Day 29 of gestation. Seven fetuses with partial or total absence of the tibia, five treated fetuses without deformities, and four untreated controls were photographed, radiographed, killed and fixed for histological examination. Sciatic nerves were dissected and transverse sections were taken from an identical site. Total fascicular area, myelinated fibre number, fibre density and diameter distribution were obtained. There was a significant reduction in total fascicular area, and in the number of large diameter fibres in all treated animals. There was a significant depletion of total fibre numbers in deformed fetuses compared with controls. These findings are similar to the quantitative changes described in human adult subjects with thalidomide polyneuropathy, and are consistent with primary axonal degeneration in both instances. It is concluded that thalidomide acts upon embryonic nerves rather than on mesenchyme, and that dysmelic deformities of the limbs are secondary to toxic embryonic neuropathy. It is suggested that skeletal defects result when irreversible damage to the nerves reduces the transverse fascicular area below a critical minimum threshold.

Abnormalities, Drug-Induced↗
PubMed1978

On the application of thalidomide as a block of functional groups of proteins in histochemical investigations.

An attempt was made to apply thalidomide as a block of functional protein groups in histochemical investigations. It was found that thalidomide slightly oxidizes thyrosine and blocks the SH groups mainly in the cytoplasm of rat liver. Contrary to N-ethyl-maleimide, thalidomide does not block the SH groups irreversible, and they can be reactivated with BAL. It is suggested that the teratogenic effect of thalidomide can be connected with the possibility of inactivation of the SH groups by this compound.

Animals↗
PubMed1981

[PMN leukocytes chemotaxis: inhibition by thalidomide (author's transl)].

The effects of thalidomide on chemotaxis of normal human peripheral blood PMN leukocytes have been studied in vitro. Chemotaxis factor was generated by interacting normal human serum with zymosan. At concentration of 1, 10 and 100 micrograms/ml, thalidomide failed to inhibit chemotactic factor. Pre-incubation of PMNs with thalidomide caused a marked, dose-independent inhibition of chemotaxis. Random mobility did not appear to be affected. Inhibition of PMN chemotactic ability by thalidomide may account for its ability to improve skin diseases such as aphtosis, discoid lupus erythematosus and other sun-sensitive and/or inflammatory dermatoses.

Chemotaxis, Leukocyte↗
PubMed1994

Evidence for teratogenicity of thalidomide using congenic and recombinant inbred rat strains.

Teratogenic properties of thalidomide were tested in two systems of laboratory rat strains carrying the mutant lx allele that determines the polydactyly-luxate syndrome. In agreement with our previous experiments, we have confirmed that the response of foetuses basically depends on their genotype. Foetuses of LEW/BN, +/+ genotype remained unaffected following 500 or 3 x 500 mg/kg thalidomide doses (43 and 56 foetuses, respectively). In LEW/BN, +/lx foetuses these doses elicited 24% and 87% hind feet polydactyly (14/59 and 53/61 foetuses, respectively), which was highly significant when compared with 84 vehiculum-treated and 235 untreated controls (P < 0.001). However, in 48 SHR/RI 2, lx/lx foetuses both pairs of limbs were affected in an opposite way after the 500 mg/kg thalidomide dose: hind feet oligodactyly (94/96 limbs) and increased front feet polydactyly occurred (in comparison with 70 controls, P < 0.001). The mutant lx allele as well as modifying genes are involved in the response to thalidomide.

Abnormalities, Drug-Induced↗
PubMed1993

Thalidomide--the need for a new clinical evaluation of an old drug.

Thalidomide shows activity in refractory chronic graft-versus-host disease. Best responses were seen in mucocutaneous disease. The studies vary in inclusion criteria (e.g. pretreatment), time of onset of GVHD and dose given. The optimal schedule of thalidomide treatment is not defined. The role of thalidomide must be assessed in large controlled trials for treatment and prophylaxis of GvHD. Due to the variable absorption rate there is a need for an intravenous formulation of thalidomide, and in addition the search for more active and possibly less teratogenic derivatives must be intensified.

Graft vs Host Disease↗