Longitudinal limb deficiencies and the sclerotomes. An analysis of 378 dysmelic malformations induced by thalidomide.
The pathogenesis of longitudinal reduction deformities of the limbs, or dysmelia, is still a matter of debate. Their morphological pattern was defined from a large collection of radiographs of children with dysmelia following the thalidomide disaster. We compared radiographs of 378 of these limbs with the sclerotomes which are areas of segmental sensory innervation of the limb skeleton defined by the radiation of referred pain. The pattern of dysmelia matched the sclerotomes closely in 279 limbs (73.5%). The principles of skeletal reduction in dysmelia are explained by the arrangement of the sclerotomes. The congruence between two separate and independent data sets shows that both patterns are expressions of the underlying segmental sensory innervation of the skeleton, and that the sensory nervous system is involved in the process of limb morphogenesis and teratogenesis. (+info)
Thalidomide for the treatment of esophageal aphthous ulcers in patients with human immunodeficiency virus infection. National Institute of Allergy and Infectious Disease AIDS Clinical Trials Group.
A multicenter, double-blind, randomized, placebo-controlled clinical trial was conducted to determine the safety and efficacy of thalidomide for treating esophageal aphthous ulceration in persons infected with human immunodeficiency virus (HIV). Twenty-four HIV-infected patients with biopsy-confirmed aphthous ulceration of the esophagus were randomly assigned to receive either oral thalidomide, 200 mg/day, or oral placebo daily for 4 weeks. Eight (73%) of 11 patients randomized to receive thalidomide had complete healing of aphthous ulcers at the 4-week endoscopic evaluation, compared with 3 (23%) of 13 placebo-randomized patients (odds ratio, 13.82; 95% confidence interval, 1.16-823.75; P=.033). Odynophagia and impaired eating ability caused by esophageal aphthae were improved markedly by thalidomide treatment. Adverse events among patients receiving thalidomide included somnolence (4 patients), rash (2 patients), and peripheral sensory neuropathy (3 patients). Thalidomide is effective in healing aphthous ulceration of the esophagus in patients infected with HIV. (+info)
Protein kinase C-dependent effects on leukocyte migration of thalidomide.
Thalidomide is effective in the treatment of some tumor necrosis factor-related diseases, but its cellular target is not known. Effects of thalidomide were investigated on lymphocytes and monocytes. Cell migration was examined in a Boyden chamber. Effects on protein kinase C (PKC) were investigated functionally by use of PKC inhibitor and in purified enzyme preparations. Thalidomide itself showed no direct chemotactic effect on lymphocytes or monocytes. Preincubation with the drug significantly enhanced random migration of both cell types. This effect was bisindolylmaleimide-reversible, suggesting involvement of PKC. Preincubation with thalidomide diminished the chemotactic response of monocytes towards formyl peptide but failed to influence lymphocyte chemotaxis towards RANTES or interleukin-8. In a cell-free assay, inhibition of PKC activation by bisindolylmaleimide could be reversed by thalidomide, indicating direct interactions of thalidomide with PKC. Results suggest that effects of thalidomide in chronic inflammation may be related to actions on leukocyte functions. (+info)
The puzzle of autism: an ophthalmologic contribution.
PURPOSE: A previous study of 86 thalidomide-affected subjects with ophthalmic manifestations revealed the unexpected finding of autism in 4 of the 5 severely retarded individuals. The subjects had anomalies associated with an early gestational effect of thalidomide, including facial nerve palsy and incomitant strabismus. Because autism has been observed in a few cases of Mobius sequence (Mobius syndrome), a condition characterized by involvement of the sixth and seventh cranial nerves, the similarity to early thalidomide embryopathy suggested a relation between cranial nerve involvement and autism. The present study was undertaken to further evaluate the association of autism with patients manifesting findings of Mobius syndrome. METHODS: A prospective study of 25 Swedish patients with Mobius sequence was conducted. The patients had a complete multidisciplinary evaluation, including ophthalmologic and psychiatric examinations and standard testing for autism. Findings associated with autism were compared with the ocular and systemic anomalies of the 4 thalidomide-affected subjects. RESULTS: In the Mobius group 6 patients had autism, achieving the criteria for autism according to all the diagnostic manuals that were used. One patient showed autistic-like conditions meeting fewer numbers of the criteria. A few were too young to be meeting evaluated. Incomitant strabismus ranging from primary abduction defects alone to a horizontal gaze paresis pattern was noted in these patients, in addition to characteristic findings of seventh nerve paresis. Aberrant lacrimation was observed in many cases, especially often associated with autism. CONCLUSION: The common group of anomalies noted in both cases of thalidomide embryopathy and Mobius sequence suggests that brain-stem damage probably early in embryogenesis can sometimes be associated with autism. (+info)
Thalidomide increases both intra-tumoural tumour necrosis factor-alpha production and anti-tumour activity in response to 5,6-dimethylxanthenone-4-acetic acid.
5,6-Dimethylxanthenone-4-acetic acid (DMXAA), synthesized in this laboratory and currently in phase I clinical trial, is a low molecular weight inducer of tumour necrosis factor-alpha (TNF-alpha). Administration of DMXAA to mice with established transplantable tumours elicits rapid vascular collapse selectively in the tumour, followed by extensive haemorrhagic necrosis mediated primarily through the production of TNF-alpha. In this report we have investigated the synthesis of TNF-alpha mRNA in hepatic, splenic and tumour tissue. Co-administration of thalidomide with DMXAA increased anti-tumour activity and increased intra-tumoural TNF-alpha production approximately tenfold over that obtained with DMXAA alone. Thalidomide increased splenic TNF-alpha production slightly but significantly decreased serum and hepatic levels of TNF-alpha induced with DMXAA. Lipopolysaccharide (LPS) induced 300-fold higher serum TNF-alpha than did DMXAA at the maximum tolerated dose, but induced similar amounts of TNF-alpha in spleen, liver and tumour. Splenic TNF-alpha activity induced with LPS was slightly increased with thalidomide, but serum and liver TNF-alpha levels were suppressed. Thalidomide did not increase intra-tumoural TNF-alpha production induced with LPS, in sharp contrast to that obtained with DMXAA. While thalidomide improved the anti-tumour response to DMXAA, it had no effect on the anti-tumour action of LPS that did not induce a significant growth delay or cures against the Colon 38 tumour. The increase in the anti-tumour action by thalidomide in combination with DMXAA corresponded to an increase in intra-tumoural TNF-alpha production. Co-administration of thalidomide may represent a novel approach to improving selective intra-tumoural TNF-alpha production and anti-tumour efficacy of DMXAA. (+info)
Protective effect of pentoxifylline plus thalidomide against septic shock in mice.
Mortality caused by septic shock in experimental animals is reduced by thalidomide, an inhibitor of tumour necrosis factor alpha. Another drug that could act on the pathophysiological mechanisms of septic shock is pentoxifylline, an inhibitor of platelet aggregation that increases the flexibility of the erythrocyte membrane and has fibrinolytic activity. We studied the effect of pentoxifylline alone and combined with thalidomide in septic shock; 97 NIH mice were injected with lipopolysaccharides of Salmonella abortus equi and D galactosamine. Animals were separated in 4 groups; group A (n = 20) was used as control, group B (n = 15) received thalidomide 50 mg/kg, group C (n = 20) received pentoxifylline 40 mg/kg, and group D (n = 15) received thalidomide plus pentoxifylline. Mortality was recorded every hour. Additionally, 5 animals from each group were sacrificed 8 h after the induction of septic shock for histological analysis of heart, lung, brain, kidney, small intestine, adrenal glands and liver. Microscopic findings were rated as absent, mild, moderate and severe damage. In control animals histological analysis showed intense haemorrhage and necrosis in all organs studied. When compared with controls, treatment with pentoxifylline plus thalidomide reduced mortality (P < 0.03). The tissue damage was less severe in animals from the groups that received pentoxifylline or pentoxifylline plus thalidomide (P < 0.05). Pentoxifylline seems to potentiate the beneficial effects of thalidomide, reducing mortality and attenuating the pathological changes produced by septic shock. (+info)
Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha.
TNF-alpha mediates both protective and detrimental manifestations of the host immune response. Our previous work has shown thalidomide to be a relatively selective inhibitor of TNF-alpha production in vivo and in vitro. Additionally, we have recently reported that thalidomide exerts a costimulatory effect on T cell responses. To develop thalidomide analogues with increased anti-TNF-alpha activity and reduced or absent toxicities, novel TNF-alpha inhibitors were designed and synthesized. When a selected group of these compounds was examined for their immunomodulatory activities, different patterns of cytokine modulation were revealed. The tested compounds segregated into two distinct classes: one class of compounds, shown to be potent phosphodiesterase 4 inhibitors, inhibited TNF-alpha production, increased IL-10 production by LPS-induced PBMC, and had little effect on T cell activation; the other class of compounds, similar to thalidomide, were not phosphodiesterase 4 inhibitors and markedly stimulated T cell proliferation and IL-2 and IFN-gamma production. These compounds inhibited TNF-alpha, IL-1beta, and IL-6 and greatly increased IL-10 production by LPS-induced PBMC. Similar to thalidomide, the effect of these agents on IL-12 production was dichotomous; IL-12 was inhibited when PBMC were stimulated with LPS but increased when cells were stimulated by cross-linking the TCR. The latter effect was associated with increased T cell CD40 ligand expression. The distinct immunomodulatory activities of these classes of thalidomide analogues may potentially allow them to be used in the clinic for the treatment of different immunopathological disorders. (+info)
Combination oral antiangiogenic therapy with thalidomide and sulindac inhibits tumour growth in rabbits.
Neovascularization facilitates tumour growth and metastasis formation. In our laboratory, we attempt to identify clinically available oral efficacious drugs for antiangiogenic activity. Here, we report which non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit corneal neovascularization, induced by basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF). This antiangiogenic activity may contribute to the known effects of NSAIDs on gastric ulcers, polyps and tumours. We found that sulindac was one of the most potent antiangiogenic NSAIDs, inhibiting bFGF-induced neovascularization by 50% and VEGF-induced neovascularization by 55%. Previously, we reported that thalidomide inhibited growth factor-induced corneal neovascularization. When we combined sulindac with thalidomide, we found a significantly increased inhibition of bFGF- or VEGF-induced corneal neovascularization (by 63% or 74% respectively) compared with either agent alone (P < 0.01). Because of this strong antiangiogenic effect, we tested the oral combination of thalidomide and sulindac for its ability to inhibit the growth of V2 carcinoma in rabbits. Oral treatment of thalidomide or sulindac alone inhibited tumour growth by 55% and 35% respectively. When given together, the growth of the V2 carcinoma was inhibited by 75%. Our results indicated that oral antiangiogenic combination therapy with thalidomide and sulindac may be a useful non-toxic treatment for cancer. (+info)