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PubMed1977

[Fixed lupus erythematosus (its treatment with thalidomide)].

The results obtained from the first 20 cases of Discoid Lupus Erithematosus treated with Thalidomide showed evidence of its great efficacy, evident from the first 15 days of treatment. In the incipient cases the results were even spectacular. 2. The minimum dosage used by the authors seems to be adequate on the basis of the results obtained. 3. The precise mode of action of thalidomide but it is thought that in acts on the hypothalamus. 4. The intolerance to Thalidomide and its undesireable side effects consisted slight somnolence; only one case had fever, cephalea, arthralgia, vertigo, nausea and urticaria which is unknown made it necessary to discontinue the medication. 5. The teratogenic effect of thalidomide obliges us to redouble the vigilance in women in age of reproduction by using of parenteral contraceptives applied by or in presence of the investigator. This study included one case that started treatment during the 7th month of pregnancy, without any problem and with an excellent result. The patient gave birth to a healthy full term infant. 6. It is recognized that this preliminary study should be continued with a greater number of cases and that these should be continued for a longer follow-up evaluation. At the present time, the authors believe that thalidomide is the best treatment for Discoid Lupus Erythematosus.

Adolescent↗
PubMed1985

Thalidomide--effect on T cell subsets as a possible mechanism of action.

Thalidomide is the drug of choice in the erythema nodosum leprosum (ENL) type of lepra reaction. Lately it has been used successfully in other diseases, such as discoid lupus erythematosus, actinic prurigo, Behcet's disease, etc. However, its mechanism of action remains unknown. In patients for whom thalidomide provided relief in their disorder, the proportions of T lymphocytes and their subsets in peripheral blood were assessed by means of monoclonal antibodies. Three lepromatous leprosy patients with ENL had their T helper populations significantly increased after thalidomide therapy. A 14-year-old girl with Behcet's syndrome showed a consistent decrease in Ia+ cells throughout her three-month course of thalidomide therapy. The same findings were observed in two patients with the actinic prurigo type of polymorphous light eruption. From these results, we conclude that thalidomide may act as an immunomodulating agent on T cell subsets.

Adolescent↗
PubMed1984

[Treatment of aphthosis with thalidomide and with colchicine].

Thalidomide alone (200-300 mg daily) or associated with colchicine (2-3 mg daily) was given orally to 25 patients with aphthosis: 8 patients with recurrent oral aphthae; 4 patients with recurrent mucocutaneous aphthosis, without visceral involvement, and 13 patients with Behçet's disease (Touraine's aphthosis). A major improvement was noted in all groups, with a rapid healing of mucous lesions and a rapid reduction of pain and burning as compared to prior spontaneous regressions. No new outbreaks were noted at a dose of 50-100 mg thalidomide and 1 mg colchicine daily. Under oral administration of the drugs, thrombophlebitis was noted in 1 case (third group) only. In the other patients with Behçet's disease, skin aphthae, ocular symptoms, arthritis, superficial nodular phlebitis quickly disappeared with treatment. The efficiency of the drugs is only temporary, since new lesions usually appeared a few weeks after the end of treatment. Due to the relatively small number of cases studied in each group, no conclusions can be drawn concerning the efficiency of thalidomide alone compared to the association of the two drugs. However, this open trial does support the usefulness of thalidomide, or thalidomide and colchicine, in recurrent mucocutaneous aphthae, aphthosis and Behçet's disease.

Adult↗
PubMed1983

[Thalidomide in dermatology].

Based on present publications we review indications of the therapy of dermatoses with thalidomide as well as possible mechanisms of action and side effects of this drug. In reactional states of leprosy the use of thalidomide is established. Further indications are chronic cutaneous lupus erythematosus, prurigo nodularis, and eventually recurrent aphthosis and certain photodermatoses not responding to usual treatment. Therapeutical trials of thalidomide in diseases in which such a treatment is only occasionally or not at all mentioned in the literature will be reported. Concerning the mechanisms of action emphasis is put on a possible immunosuppression by thalidomide. Among the side effects the thalidomide neuropathy is stressed.

Animals↗
PubMed1995

Thalidomide as salvage therapy for chronic graft-versus-host disease.

Thalidomide has been reported to be an effective agent for treatment of chronic graft-versus-host disease (CGVHD). To determine the efficacy of this agent in patients with refractory CGVHD a total of 80 patients who failed to respond to prednisone (PSE) or PSE and cyclosporine (CSA) were treated with thalidomide. Sixteen patients (20%) had a sustained response, 9 with a complete remission and 7 with a partial response. Twenty-nine patients (36%) had thalidomide discontinued because of side effects, which included sedation, constipation, neuritis, skin rash, and neutropenia. Side effects were reversible with drug discontinuation except for mild residual neuritis in one case. Rashes and neutropenia have not previously been reported as thalidomide side effects when used for CGVHD treatment. We conclude thalidomide is immunosuppressive and active in the treatment of CGVHD. A high incidence of reversible side effects limited dose intensity and reduced the number of patients who could benefit from treatment.

Adolescent↗
PubMed1995

[Melkersson-Rosenthal syndrome treated by thalidomide. 2 cases].

INTRODUCTION: Treatment of Melkersson-Rosenthal syndrome (MRS) remains uncertain. Two cases of MRS treated with thalidomide are described. CASE REPORT: Two patients with cheilitis granulomatosa and recurrent facial edema have been treated with thalidomide (100 mg daily) for 3 and 6 months respectively. The efficacy of thalidomide was complete clinically and histologically in one case. In the second one, thalidomide suppressed attacks of facial edema and reduced lip swelling. COMMENTS: These cases suggest a therapeutic effect of thalidomide in MRS.

Adult↗
PubMed1998

Novel biological response modifiers derived from thalidomide.

Thalidomide (N-alpha-phthalimidoglutarimide) was used widely as a hypnotic/sedative agent in the late 1950s and the early 1960s, but had to be withdrawn from the market because of its severe teratogenicity. In spite of this, there has been a resurgence of interest in the drug in recent years due to its potential usefulness for the treatment of various diseases, including acquired immunodeficiency syndrome (AIDS) and graft-versus-host disease (GVHD). The effectiveness of the drug in these diseases has been attributed to its specific inhibitory activity on tumor necrosis factor-alpha (TNF-alpha) production. Because TNF-alpha, a cytokine mediating host defence and immune regulation, with a wide range of activities, has deleterious pathophysiological effects in various diseases, including AIDS, tumors, rheumatoid arthritis and diabetes, its production-regulators are attractive lead compounds for novel biological response modifiers. The regulatory effect of thalidomide on TNF-alpha production has been found to be bidirectional, depending on both the cell-type and the TNF-alpha production-inducer; i.e., thalidomide possesses both enhancing and inhibiting activities on TNF-alpha production. Structural modification of thalidomide aiming at the creation of superior TNF-alpha production-regulators has afforded a number of phenyl- and benzylphthalimide analogs possessing more potent activity than thalidomide itself. The structure-activity relationships of these analogs has been investigated. The bidirectional TNF-alpha production-regulating activity is electronic state- and enantio-dependent, and both pure inhibitors and pure enhancers of TNF-alpha production has been obtained. Further structural development of the phthalimide analogs has yielded potent non-steroidal androgen antagonists.

Androgen Antagonists↗
PubMed2000

[Thalidomide as a new treatment option in patients with multiple myeloma]

Thalidomide as a new treatment option in patients with multiple myeloma. HISTORYAND ADMISSION FINDINGS: In a 56 year old woman the diagnosis of multiple myeloma of subtype IgG kappa led to the performance of an autologous stem cell transplantation. After initial partial remission the disease became refractory to standard chemotherapy requiring repeated plasmaphereses due to hyperproteinemia. INVESTIGATIONS: Before application of thalidomide the patient had a serum protein of 12 g/dl and a paraprotein of 4.4 g/dl. Bone marrow histology revealed a 40 % infiltration of the marrow by differentiated plasma cells. On neurologic examination a slightly diminished nerve conduction speed of the right median nerve due to carpal tunnel syndrome was diagnosed. TREATMENT AND COURSE: Treatment with thalidomide in a dosage of 400 mg p. o. was initiated and led to a partial remission with a > 50 % reduction of the paraprotein within four weeks. Due to a neuropathy (WHO grade 1) a dose reduction to 200 mg per day was performed after seven weeks of treatment. 48 weeks after initiation of treatment the patient remains in a stable partial remission with a paraprotein of 1.4 g/dl. After 20 weeks of treatment 5 % of the bone marrow remained infiltrated by monoclonal plasma cells. CONCLUSION: Monotherapy with thalidomide led to a stable partial remission in a patient with refractory multiple myeloma. In vitro thalidomide is a potent inhibitor of angiogenesis. Besides, a reduction of TNFalpha as well as an inhibition of cytokines have been described. The exact mechanism of the drug in multiple myeloma remains elusive. However several phase II trials have demonstrated a beneficial effect in relapsed or refractory disease. The optimal dosage and timing have to be studied in further trials.

Journal Article↗
PubMed2002

The History of Thalidomide.

The first paper describing the pharmacological actions of thalidomide was published in 1956. The drug, then designated as K17, was thought to have sedative effects superior to those of comparator drugs and was thought to be virtually nontoxic. Only 2 years after thalidomide's launch as Contergan in Germany, it's alleged lack of toxicity came into question, with reports of the drug causing numerous side effects. Shortly thereafter, thalidomide was connected with an epidemic of horrific deformities in children whose mothers had taken the drug during pregnancy. This disaster brought on by thalidomide's teratogenic effects was responsible for the institution of some regulatory bodies, such as the United Kingdom's Committee on the Safety of Drugs, and for the strengthening of others, such as the U.S. Food and Drug Administration. An objective examination of published papers and contemporary accounts confirms that the preclinical tests on thalidomide were superficial, and there is no doubt that it was never administered to pregnant animals prior to its use in patients. Within a short time after its withdrawal from the market due to its suspected association with fetal abnormalities, the drug was shown to produce fetal toxicity in laboratory animals. Had there been more extensive testing on laboratory animals before the drug was launched, the disaster could have been avoided. (c) 2002 Prous Science. All rights reserved.

Journal Article↗
PubMed1998

Thalidomide revisited: pharmacology and clinical applications.

Thalidomide is attracting new interest. Since the discovery of its remarkable efficacy in erythema nodosum leprosum, the drug has been used successfully in a variety of dermatologic and other diseases whose apparent common thread is immune dysregulation. Meanwhile, immunomodulatory and anti-inflammatory activities of thalidomide, particularly its inhibition of tumour necrosis factor alpha (TNF-alpha), have been identified and elucidated. The drug has also been found to inhibit angiogenesis. Recent clinical trials have shown thalidomide effective in graft-versus-host disease, Behçet's syndrome and aphthous ulcers and wasting associated with HIV infection. Provocative findings in other diseases, including primary HIV infection, HIV-associated diarrhoea, inflammatory bowel disease, cancer and sepsis, have suggested additional clinical applications. Use of thalidomide in women capable of childbearing is controversial. However, guidelines have emerged for prevention of teratogenicity and peripheral neuropathy, the drug's other major adverse effect. With appropriate safeguards, thalidomide may hold benefit for patients with a broad variety of disorders in which existing treatments are inadequate. Its current use may represent only a small part of its therapeutic potential.

Journal Article↗
PubMed1964

THALIDOMIDE: EFFECTS ON EHRLICH ASCITES TUMOR CELLS IN VITRO.

Thalidomide did not inhibit dehydrogenase activity or growth of Ehrlich ascites tumor cells in agar. When mixed with Ehrlich ascites tumor cells in vitro, thalidomide increased the mitotic activity. The effect of the thalidomide was not altered by the addition of nicotinic or folic acid, or by vitamin B(1) or B(6). Oxygen uptake by the tumor cells was not affected by thalidomide.

Animals↗
PubMed2003

Low-dose thalidomide therapy for refractory cutaneous lesions of lupus erythematosus.

BACKGROUND: Thalidomide is an anti-inflammatory agent and an immunomodulator that inhibits the production of tumor necrosis factor alpha. It has shown promise as a treatment option for the cutaneous manifestations of lupus erythematosus (LE). OBJECTIVE: To assess the degree of clinical response per subtype of cutaneous lupus, the duration of therapy before documented clinical improvement, and the incidence of adverse effects, including peripheral neuropathy, with low-dose thalidomide therapy at 100 mg daily in the treatment of refractory cutaneous lesions of LE. METHODS: This retrospective medical record review of patients with refractory cutaneous manifestations of LE is one of the largest modern series in the literature. There were 29 patients seen at the Department of Dermatology, Wake Forest University School of Medicine (Winston-Salem, NC), who were unresponsive to conventional agents including antimalarial agents, and who started treatment between 1998 and 2000. Twenty-three patients who took the drug for 1 month or more were included in the analysis. Clinical responses were assessed by the investigators based on statements of improvement listed in the clinic notes and were categorized as "no response," "partial response," and "complete response." Partial response was classified as either 75% or greater or less than 75% improvement. The incidence of adverse effects including peripheral neuropathy was determined. RESULTS: Of the 23 patients, 17 (74%) demonstrated complete resolution of the cutaneous manifestations of LE, whereas 3 patients (13%) demonstrated 75% or greater partial improvement; 3 patients (13%) had less than 75% partial clinical improvement; and 21 patients (91%) who demonstrated a complete or partial response did so within 8 weeks of initiating thalidomide therapy. CONCLUSIONS: Based on the results of this case series, we believe that thalidomide should be given prime consideration as a treatment for antimalarial drug-resistant interface lesions of LE. The design of prospective, randomized, double-blind, placebo-controlled trials for this indication is warranted.

Adult↗
PubMed1996

Mesonephros has a role in limb development and is related to thalidomide embryopathy.

Recent studies have demonstrated a link between limb reduction defects and mesonephros removal [Geduspan and Solursh, 1992) Dev. Biol., 151:242-250]. However, there is some question as to whether the limb-reduction defects seen in that study resulted from the removal of mesonephros or from the formation of scar tissue medial to the limb territory. The current study was conducted to test the hypothesis that elimination of the mesonephros without producing scar tissue adjacent to the limb will adversely affect limb morphogenesis. The hypothesis was tested by the insertion of tantalum foil barriers into various levels of the intermediate mesoderm of developing chick embryos to prevent the caudal elongation of the mesonephros. Limb reduction defects were obtained when the mesonephros was prevented from forming caudal to somite 14. No limb defects were seen when a foil barrier was placed into the intermediate mesoderm at the level of somite 21 or 25. Our results support the notion that a signal from the mesonephros is necessary for normal limb development. In addition, it appears that a craniocaudal factor emanating from the mesonephros plays a role in limb development. The limb reduction defects obtained in this study were also compared to the pattern of thalidomide embryopathy in humans. There is a close correspondence between the types of limb reduction anomalies seen with thalidomide and mesonephric blocks and between the severity of defects vs. the timing of thalidomide intake or mesonephric blockage. A model for possible thalidomide embryopathy is presented.

Animals↗
PubMed2000

Evaluation of the developmental toxicity of thalidomide using frog embryo teratogenesis assay-xenopus (FETAX): biotransformation and detoxification.

The developmental toxicity of thalidomide was evaluated using FETAX (Frog Embryo Teratogenesis Assay - Xenopus). Young X. Laevis embryos were exposed to this compound in each of two concentration-response experiments with and without differently induced exogenous metabolic activation systems (MASs) and/or inhibited MASs. Young male Sprague-Dawley rats were treated with either isoniazid or Aroclor 1254 to induce cytochrome P-450. Several of the rats were subsequently treated with diethyl maleate (DM) to deplete glutathione reserves. Specific aliquots of rat liver microsomes were treated with 3-amino-1,2,4-triazole (ATZ) or alpha-napthoflavone (alpha-N) to selectively inhibit P-450 activity. Bioactivation was indicated by increased developmental toxicity observed in MAS tests. Results obtained indicated that thalidomide was predominantly activated by P-450 isozyne CYP2E1, although weak cross-specificity between CYP1A1/A2 may have existed. Detoxification pathways for thalidomide were investigated by treatment of the MAS with cyclohexene oxide (CHO) and DM to inhibit the epoxide hydrolase and glutathione conjugation pathways, respectively. Results indicated that epoxide hydrolase was primarily responsible for the detoxification of bioactivated thalidomide. Teratogenesis Carcinog. Mutagen. 20:35-47, 2000.

Amitrole↗
PubMed2001

Determination of the enantiomerization barrier of thalidomide by dynamic capillary electrokinetic chromatography.

Enantioselective chromatographic methods, representing the most commonly used techniques for the determination of enantiomeric ratios, can also be used for the evaluation of stereochemical integrity. In the present study, dynamic capillary electrokinetic chromatography (DEKC) was employed to determine the enantiomerization barrier of thalidomide. In the presence of the chiral mobile phase additive carboxymethyl-beta-cyclodextrin, the interconverting enantiomers of thalidomide produced characteristic elution profiles exhibiting plateaus and/or peak broadening between 25 and 55 degrees C at pH 8. To obtain the enantiomerization barrier of thalidomide from experimental data, the fast and efficient simulation program ChromWin was used to simulate the experimental interconversion profiles and to obtain the apparent rate constants k1app(T). Additionally, these values were compared with the novel approximation function for the direct calculation of enantiomerization barriers from chromatographic parameters of elution profiles. From the rate constants k1app(T) of temperature-dependent measurements the kinetic activation parameters deltaG(T)#,deltaH#, and deltaS# of the enantiomerization of thalidomide were obtained. At 25 degrees C, the enantiomerization barrier deltaG# was determined to be 102 +/- 1 kJ/mol at pH 8 in the dynamic electrokinetic chromatographic experiment.

Chromatography↗
PubMed2002

One-year open-label trial of thalidomide in ankylosing spondylitis.

OBJECTIVES: To test in a large open study whether thalidomide is potentially useful in treating ankylosing spondylitis, and to see if thalidomide induces any change in expression of genes in peripheral blood mononuclear cells (PBMC). METHODS: Thirty male patients with treatment-refractory ankylosing spondylitis were recruited into a 12-month open study using thalidomide at a dosage of 200 mg/day. Seven indices were measured as primary outcome measures, and 6 other indices as secondary outcome measures. Transcripts in the PBMC of some of these patients were first screened with microarray, and then measured with reverse transcriptase-polymerase chain reaction. RESULTS: Twenty-six patients completed the study. Of these, 80% showed a >20% improvement in 4 of 7 primary indices. Sharp declines in several parameters were noticed at 3-6 months. Nine patients became pain-free. There was also a statistically significant decrease in tumor necrosis factor alpha transcripts in the PBMC. CONCLUSION: Thalidomide is a reasonably promising drug in treatment-resistant ankylosing spondylitis.

Adult↗
PubMed2002

A high rate of venous thromboembolism in a multi-institutional phase II trial of weekly intravenous gemcitabine with continuous infusion fluorouracil and daily thalidomide in patients with metastatic renal cell carcinoma.

BACKGROUND: The objective of this study was to determine the clinical response rate of the combination of weekly intravenous (IV) gemcitabine with continuous infusion fluorouracil (5-FU) and daily oral thalidomide in patients with metastatic renal cell carcinoma (RCC). METHODS: Between June, 2000 and January, 2001, 21 patients with metastatic RCC were enrolled onto this multi-institutional Phase II study of gemcitabine at 600 mg/m(2) per day on Days 1, 8, and 15; 5-FU at 150 mg/m(2) per day by continuous IV infusion through a permanent catheter on Days 1-21; and oral thalidomide on Days 1-28 starting at a dose of 200 mg daily. After the first 2 weeks of therapy, the thalidomide dose was escalated by 100 mg per day every week to a maximum dose of 400 mg per day unless it was precluded by toxicity. Treatment cycles were repeated every 28 days. RESULTS: A high rate of venous thromboembolism (VTE) was observed. Five patients developed deep vein thrombosis (DVT), three patients developed pulmonary embolization (PE), and one patient suffered a fatal cardiac arrest preceded by hemoptysis, for an overall VTE rate of 43%. Of the 18 assessable patients, there were no complete responses and 2 partial responses (objective response rate, 10%; 95% confidence interval, 1-30%). CONCLUSIONS: The addition of thalidomide to gemcitabine and 5-FU did not improve the objective response rate previously observed with gemcitabine and 5-FU alone and added significant vascular toxicity. The authors recommend against further development or use of this three-drug regimen.

Administration, Oral↗
PubMed2003

A randomized trial of liposomal daunorubicin and cytarabine versus liposomal daunorubicin and topotecan with or without thalidomide as initial therapy for patients with poor prognosis acute myelogenous leukemia or myelodysplastic syndrome.

BACKGROUND: Because angiogenesis may play a role in the pathogenesis of acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), and thalidomide (Th) has shown significant anti-angiogenic activity, this study was designed to investigate the potential role of Th in the treatment of patients with AML and MDS and the possible role of a non-ara-C-containing regimen. METHODS: Adults with AML or high-risk MDS and cytogenetic abnormalities other than inv (16), t(8;21), -Y or -X were randomized to receive liposomal daunorubicin (DNX) and ara-C (DA) or DNX and topotecan (DT). Within each arm, patients were randomized to receive chemotherapy alone (DA or DT) or with thalidomide (DATh or DTTh). Vascular endothelial growth factor (VEGF) plasma levels and microvascular density was measured before and after therapy. Eighty-four patients (median age, 65 years; range, 27-84 years) were treated. RESULTS: None of 11 patients treated with DT or DTTh responded and these arms were closed. Seventeen of 37 patients treated with DA and 15 of 36 treated with DATh achieved an early complete remission. Median complete response duration was 38 and 34 weeks (P = 0.57) and median survival 35 and 28 weeks (P = 0.15), respectively. Patients with high pretreatment VEGF levels had an inferior survival. There was no significant difference in the changes in VEGF levels or microvascular density after treatment in patients who did versus those who did not receive thalidomide. CONCLUSIONS: The authors concluded that thalidomide in combination with chemotherapy does not result in clinical benefit in patients with AML or high-risk MDS.

Adult↗