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Thalidomide neurotoxicity.

Of six patients treated with thalidomide for either prurigo nodularis or discoid lupus erythematosus, four had paresthesias in the hands and feet and one also complained of muscular pain and stiffness. Clinical neurological findings in all four patients were normal. Subsequent electrophysiological examination disclosed a peripheral neuropathy in five of the six patients; two had electrophysiological signs of a polyneuropathy and three of a carpal tunnel syndrome. Symptoms and abnormal electrophysiological findings were still present in one patient one year after the discontinuation of thalidomide therapy. Since reports on thalidomide neurotoxicity have shown that the neurological symptoms are long standing and possibly irreversible, it is obviously important to inform patients of this possible side effect and to evaluate them closely for the symptoms and electrophysiological signs of evolving neurological changes.

Adult↗

[Decrease in the ascorbic acid content of guinea pig tissues caused by thalidomide].

It has been demonstrated that thalidomide is capable of a noticeable stabilization of the enzymes from rabbit, pig and guinea-pig liver microsomal fractions. Administration of thalidomide to guinea-pigs resulted in an increase of microsomal hydroxylase activity measured by the aniline test. The growth of the activity of microsomal enzymes led to an abrupt drop of ascorbic acid concentration in guinea-pig organs. It is suggested that thalidomide has a teratogenic action on the species which are incapable of the synthesis of ascorbic acid by making this vitamin deficiency in embryonal tissues. Probably, it is the deficiency of ascorbic acid that inhibits the synthesis of collagen in embryonal limbs and disturbs their sensory ganglia.

Adrenal Glands↗

[Studies on the CNS activity profile of thalidomide analogs (author's transl)].

CNS activity of thalidomide was compared with that of 5 analogs modified in the phthalimide or 2,6-dioxopiperidine moiety. All compounds had a qualitatively comparable profile of CNS-depressant actions. In low dosages spontaneous motor activity was depressed, threshold of barbiturate anaesthesia was lowered, and isolation-induced aggression was inhibited. All compounds suppressed tonic convulsions induced by maximum electroshock. Only at high dosages muscle tone and body temperature were lowered. Protection against nicotine lethality revealed antagonistic activity at central nicotinergic synapses. Corresponding depression of peripheral ganglionic transmission was indicated by mydriatic and antidiarrhoeal activity. While thalidomide, supidimide, EM 8, and EM 255 did not induce anaesthesia up to highest or lethal-toxic doses, EM 136 and EM 12 in accordance with common sedative-hypnotic drugs induced loss of righting reflex at high dosages. EM 136 differs from thalidomide only in that one oxygen group at the piperidine moiety is missing. This finding indicates that a minor structural change shifts CNS depression towards anaesthetic properties. A clearcut relation between structure and teratogenic activity had been established in this group of compounds, whereas CNS-depressant efficacy could not be unequivocally related to particular structural features.

Animals↗

Thalidomide in the management of chronic graft-versus-host disease in children following bone marrow transplantation.

Chronic graft-versus-host disease (GVHD) is the major complication in patients surviving > 100 days post-allogeneic bone marrow transplantation and occurs in 30% of pediatric patients. It is most prevalent 1-2 years post-transplant. Treatment involves corticosteroids and other immunosuppressive therapy which may affect growth and increase the likelihood of infectious complications. We report five children with severe corticosteroid-dependent chronic GVHD treated with thalidomide 12-25 mg/kg/day. Response to therapy was based on resolution of symptoms of chronic GVHD and withdrawal of other immunosuppressive therapy. All the children showed clinical response to thalidomide with cessation or diminution in other immunosuppressive medication. Side-effects were minimal and no patient developed peripheral neuropathy. All patients are alive 48-65 months post-transplantation. Thalidomide is a safe and effective drug for the treatment of chronic GVHD in children and may avoid the use of long-term corticosteroid therapy.

Adolescent↗

[Treatment by thalidomide of chronic multiforme erythema: its recurrent and continuous variants. A retrospective study of 26 patients].

INTRODUCTION: The objective of this study was to evaluate the efficacy of thalidomide in the treatment of chronic erythema multiforme unresponsive to usual treatments. PATIENTS AND METHODS: Twenty-six patients with chronic erythema multiforme were given thalidomide 100 mg/day after other treatments had failed, particularly acyclovir and prednisone. RESULTS: Twenty patients had recurrent erythema multiforme and were given thalidomide at the beginning of an episode. The duration of the episodes was reduced by 11 days on the average. Six of the patients had subintrant erythema multiforme and were given continuous treatment. Lesions disappeared within 5 to 8 days and remission was maintained with low dose-treatment. DISCUSSION: The spectacular results obtained here should be verified in a controlled study.

Adolescent↗

Cytokine modulation and suppression of liver injury by a novel analogue of thalidomide.

Thalidomide has been shown to reduce the production of tumor necrosis factor-alpha (TNF-alpha), a cytokine with deleterious pathophysiologic effects in various diseases. In search of thalidomide analogues with improved TNF-alpha inhibiting properties, 5-ethyl-1-phenyl-5-(3,4,5,6-tetrafluorophthalimido)barbituric acid (TFBA) was found to be superior to thalidomide. Besides TNF-alpha, TFBA also suppressed interleukin-6 and interleukin-10 production of isolated monocytes. The possibility that TFBA exerts its action by increasing levels of cAMP via inhibition of phosphodiesterase-4 activity was excluded. TFBA had no influence on T cell proliferation; neither did it inhibit TNF-alpha production in peripheral blood mononuclear cells stimulated by anti-CD3 monoclonal antibody. When applied to mice treated with D-galactosamine and lipopolysaccharide, TFBA prevented a rise in serum TNF-alpha, had no effect on interleukin-6 levels and led to an increase in interleukin-10 production. The changes in cytokine production observed in vitro and in vivo were reflected by similar changes in the mRNA expression. Moreover, TFBA significantly reduced liver transaminase levels in D-galactosamine/lipopolysaccharide-treated mice and thus efficiently protected the animals from liver injury. Thus, according to its properties, TFBA has the potential of modulating an immune response by acting as an anti-inflammatory agent.

3',5'-Cyclic-AMP Phosphodiesterases↗

Facile synthesis of an azido-labeled thalidomide analogue.

[reaction: see text] A five-step synthesis of an azido-thalidomide analogue is presented. The sequence requires cheap and readily available starting materials and reagents, and only two steps require purification. Additionally, the azido-labeled analogue possesses activity comparable to that of thalidomide in inhibiting the proliferation of human microvascular endothelial cells, thus providing impetus for its use as a potential photoaffinity label of thalidomide.

Journal Article↗

N-Alkylphthalimides: structural requirement of thalidomidal action on 12-O-tetradecanoylphorbol-13-acetate-induced tumor necrosis factor alpha production by human leukemia HL-60 cells.

Phthalimide analogs N-substituted with n-butyl, tert-butyl, hexyl and adamantyl groups were designed and prepared as simplified analogs of thalidomide and methylthalidomide. All the compounds prepared except N-n-butylphthalimide showed thalidomidal activity on 12-O-tetradecanoylphorbol-13-acetate-induced tumor necrosis factor (TNF)-alpha production by human leukemia HL-60 cells. Among the investigated compounds, including thalidomide and methylthalidomide, N-adamantylphthalimide showed the most potent TNF-alpha production-enhancing activity.

Humans↗

Docetaxel and thalidomide as a treatment option for androgen- independent, nonmetastatic prostate cancer.

Prostate cancer usually presents with early-stage disease, yet a significant proportion of patients present or will progress to androgen-independent, nonmetastatic prostate cancer (AIPC). Chemotherapy has demonstrated statistically significant improvements in palliation of AIPC. Docetaxel in particular has demonstrated high response rates as a single agent. Thalidomide is effective in treating many malignancies, including prostate cancer. Thalidomide may act synergistically with docetaxel through their antiangiogenic effects. We performed a phase II trial of docetaxel with or without thalidomide in patients with AIPC and demonstrated encouraging response rates with combination therapy. We advocate further investigation of this promising combination regimen.

Journal Article↗

Thalidomide: effect upon pregnancy in the rhesus monkey.

Thalidomide was administered to 44 female rhesus monkeys immediately after they had mated. There were no live births from these animals, whereas there were 11 live births in 57 untreated monkeys. The results are statistically significant. The hypothesis is advanced that thalidomide killed the embryo prior to implantation.

Animals↗

THALIDOMIDE SYNDROME IN MONKEYS.

Pregnant monkeys were treated with thalidomide after implantation but before formation of the fetal limbs. Two fetuses that were recovered from the treated females had congenital abnormalities. The thalidomide syndrome in the monkeys was manifested by amelia, phocomelia, internal hydrocephaly, facial capillary hemangioma, hypogenesis of the metatarsal bones, and anotia.

Abnormalities, Drug-Induced↗

Treatment of prurigo nodularis with thalidomide.

A 57-year-old man with prurigo nodularis, was unresponsive to conventional therapy, was successfully treated with thalidomide. The pharmacology and side effects of the drug are briefly reviewed. Why thalidomide is effective for prurigo nodularis is unclear, but possible mechanisms of action are discussed.

Humans↗

Thalidomide-induced peripheral neuropathy. Effect of serum factor on nerve cultures.

Sensory neuropathies developed in three of four patients with prurigo nodularis who had been treated with thalidomide. The serum samples of the patients who had neuropathy produced morphologic changes in cultured dorsal root ganglion cells. These observed changes support the postulate that thalidomide induces primary neuronal degeneration.

Adult↗

Thalidomide for the treatment of acquired immunodeficiency syndrome-associated refractory oral ulcers.

A case of severe, oral, not otherwise specified ulcers in a human immunodeficiency virus-infected patient is described. The lesions did not respond to acyclovir, prednisone, pentoxifylline, or foscarnet sodium therapy. Dramatic clinical improvement and progressive ulcer healing were observed after starting oral thalidomide therapy. Clinicians should be aware of the usefulness of thalidomide for the treatment of acquired immunodeficiency syndrome-associated not otherwise specified ulcerations.

Acquired Immunodeficiency Syndrome↗

Hypothesis: thalidomide embryopathy-proposed mechanism of action.

We propose that thalidomide affects the following pathway during limb development: Growth factors (FGF-2 and IGF-I) attach to receptors on limb bud mesenchymal cells and initiate some second messenger system (perhaps SP-1), which activates alphav and beta3 integrin subunit genes. The resulting alphav beta3 integrin proteins stimulate angiogenesis in the developing limb bud. Several steps in this pathway depend on the activation of genes with primarily GC promoters (GGGCGG). Thalidomide, or a hydrolysis or metabolic breakdown product, specifically binds to GC promoter sites and inhibits the transcription of those genes. Inhibition of the genes interferes with normal angiogenesis, which results in truncation of the limb.

Abnormalities, Drug-Induced↗

Alleviation of systemic manifestations of multicentric Castleman's disease by thalidomide.

Multicentric Castleman's disease (MCD) is a rare lymphoproliferative disorder of unknown etiology. Although HHV-8 (human herpesvirus type 8) has been suggested as a possible etiologic agent in a subpopulation of cases, appropriate treatment of the HHV-8 infection has not produced regression of the disease. Additionally, other treatment modalities, including steroids and various regimens of chemotherapy, do not consistently provide good control of the disease. Clinical signs and symptoms of the disease are primarily mediated by cytokines, especially interleukin-6 (IL-6). We report a case of multicentric Castleman's disease that responded dramatically to single agent thalidomide. A powerful cytokine disruptor, thalidomide may have good therapeutic efficacy in treating MCD and related cytokine-mediated disorders.

Adult↗

Thalidomide-dexamethasone as primary therapy for advanced multiple myeloma.

The value of thalidomide-dexamethasone was assessed in 26 consecutive, previously untreated patients with multiple myeloma of high tumor mass. All showed Hgb < 8.5 g/dL, serum calcium > 11.5 mg/dL, or both. The response rate was 73%, frequency of early death < 3 months was 5%, projected median survival was 30 months, and projected median remission time was 25 months. There were no occurrences of grade 3 or 4 neutropenia or thrombocytopenia, so that serious infection occurred in only 12% of patients. Thalidomide-dexamethasone was useful for these patients with advanced disease because of the high response rate and acceptable survival, with a low frequency of serious complications.

Adult↗

Agenesis of the vermiform appendix in a thalidomide child.

A case of congenital absence of the appendix occurring in a child with severe thalidomide deformities is described. The literature on agenesis of the appendix is reviewed. The frequency and significance of internal abnormalities in thalidomide children are discussed.

Abnormalities, Drug-Induced↗