Therapeutic Effects Of Thalidomide Research Articles

Therapeutic effects of thalidomide on patients with systemic sclerosis-associated interstitial lung disease.

To evaluate the clinical efficacy of thalidomide in patients with systemic sclerosis-associated interstitial lung disease. Ninety-six systemic sclerosis-associated interstitial lung disease patients who received basic glucocorticoid treatment and admitted between 2016 and 2020 were included in this study, including 48 cases in the thalidomide group (combination of thalidomide and cyclophosphamide) and 48 cases in control group (cyclophosphamide monotherapy). Evaluation items included clinical symptoms, modified Rodnan skin score, pulmonary function test, chest high-resolution computed tomography scores, and adverse effects between two groups after 24 weeks of treatment. Remarkable improvements in several aspects were found in the thalidomide group, including modified Rodnan skin score, expiratory dyspnea score, cough visual analog scale score, total ground-glass opacity score, and total interstitial lung disease score. Compared to the control group, improvements in the thalidomide group were found, such as significantly decreased cough visual analog scale score and expectoration; increased number of platelets; improved pulmonary fibrosis (p = 0.056), and reduced carbon monoxide diffusing capacity (p = 0.053). There were no statistically significant differences in the expiratory dyspnea score and predicted forced vital capacity between the two groups. Patients who experienced at least one adverse event in the control group and thalidomide group were 33.3% and 64.6% (p = 0.002); while those with serious adverse events were 8.3% versus 12.5% (p = 0.504). Venous thrombosis was found in one case in the thalidomide group. Thalidomide combined with cyclophosphamide can improve the symptoms of cough and expectoration in patients with systemic sclerosis-associated interstitial lung disease, and may slightly delay the progression of pulmonary fibrosis, but with the possibility of an increased risk of adverse events.

Therapeutic effects of thalidomide in hematologic disorders: a review

The extensive autoimmune, anti-inflammatory, and anticancer applications of thalidomide have inspired a growing number of studies and clinical trials. As an inexpensive agent with relatively low toxicity, thalidomide is regarded as a promising therapeutic candidate, especially for malignant diseases. We review its therapeutic effects in hematology, including those on multiple myeloma, Waldenstroem macroglobulinemia, lymphoma, mantle-cell lymphoma, myelodysplastic syndrome, hereditary hemorrhagic telangiectasia, and graftversus-host disease. Most studies have shown satisfactory results, although several have reported the opposite. Aside from optimal outcomes, the toxicities and adverse effects of thalidomide should also be examined. The current work includes a discussion of the mechanisms through which the novel biological effects of thalidomide occur, although more studies should be devoted to this aspect. With appropriate safeguards, thalidomide may benefit patients suffering from a broad variety of disorders, particularly refractory and resistant diseases.

Thalidomide inhibits fibronectin production in TGF-β1-treated normal and keloid fibroblasts via inhibition of the p38/Smad3 pathway

Keloids are characterized by the vigorously continuous production of extracellular matrix protein and aberrant cytokine activity in the dermis. There is a growing body of evidence that thalidomide, α-N-phthalimidoglutarimide, has anti-fibrotic properties. The aims were to examine possible therapeutic effects of thalidomide on fibronectin expression in transforming growth factor-β1 (TGF-β1)-treated normal fibroblasts (NFs) and keloid-derived fibroblasts (KFs) and the underlying mechanism of action, especially the involvement of mitogen-activated protein kinase (MAPKs) and Sma- and Mad-related family (Smads) pathways. In surgically removed human tissues, TGF-β1 and fibronectin immunoreactivity was high in keloid tissue, but barely detectable in normal tissue. TGF-β1 induced significant fibronectin expression in NFs and KFs and the effect was inhibited by pretreatment with thalidomide. TGF-β1 also induced phosphorylation of MAPKs (ERK1/2, p38, and JNK) and Smad2/3 and pretreatment with PD98059 (an ERK1/2 inhibitor), SB203580 (a p38 inhibitor), or SP600125 (a JNK inhibitor) inhibited TGF-β1-induced fibronectin expression. Furthermore, pretreatment with thalidomide inhibited the TGF-β1-induced phosphorylation of p38 and Smad3, but not that of ERK1/2, JNK, and Smad2. In addition, thalidomide pretreatment inhibited the TGF-β-induced DNA binding activity of AP-1 and Smad3/4, caused fibronectin degradation by increasing the activity of matrix metalloproteinase 9, and decreased production of TGF-β1 and fibronectin and the number of fibroblasts in an in vivo keloid model. These results show that thalidomide has an antifibrotic effect on keloid fibroblasts that is caused by suppression of TGF-β1-induced p38 and Smad3 signaling. Our findings indicate that thalidomide may be a potential candidate drug for the treatment and prevention of keloids.

Effective Treatment of Erythema Nodosum Leprosum with Thalidomide Is Associated with Immune Stimulation

The immunomodulatory drug thalidomide is the treatment of choice for erythema nodosum leprosum (ENL), an inflammatory cutaneous and systemic complication of multibacillary leprosy. To elucidate the mechanism of action of thalidomide in this syndrome, we prospectively investigated 20 patients with ENL who were treated with thalidomide for 21 days. All patients responded to treatment, with the majority of them having complete resolution of cutaneous lesions within 7 days. This response was associated with a marked but transient increase in ex vivo mitogen-induced expression of interleukin (IL)-2 and interferon- gamma by CD4(+) and CD8(+) T cells that was observed on treatment day 7, but these returned to pretreatment levels by day 21. Plasma tumor necrosis factor- alpha levels were not high at baseline, and they increased modestly during treatment. Plasma levels of IL-12 increased steadily during thalidomide treatment. Hence, the therapeutic effect of thalidomide in ENL appears to be associated with transient immune stimulation, which suggests that the drug may promote an active immunoregulatory response.

Therapeutic effect of thalidomide through cytokine and chemokine regulation in herpes simplex virus-induced Behçet's disease-like animal model.

These results suggest that thalidomide can modulate both cytokine and chemokine expression and also induce death in cells involved in producing excessive inflammatory reactions in order to produce measurable improvements in the symptoms of BD-like mice.

Theoretical basis for the activity of thalidomide.

The revival of thalidomide began shortly after the drug was withdrawn from the market because of its teratogenic properties. Therapeutic effects of thalidomide were found accidentally in leprosy patients with erythema nodosum leprosum (ENL). Subsequent research widened the understanding of the activity of thalidomide, and with improved methodology and the augmented background knowledge of immunology it was possible to interpret the properties of thalidomide more coherently. Effects on tumour necrosis factor-alpha (TNFalpha) release play an important role in the ability of thalidomide to affect the immune system. Alteration of synthesis and release of cytokines such as interleukin (IL)-1, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12 and interferon-gamma is involved in the complex mechanisms of thalidomide. Thalidomide targets leucocytes, endothelial cells and keratinocytes, affecting them in a different manner and at different cellular levels. Changes in the density of adhesion molecules alter leucocyte extravasation and the inflammatory response in the tissue involved. Several mechanisms for the teratogenic action of thalidomide are currently under review, but this mode of action of the drug still remains unclear and we review evidence-based hypotheses for the teratogenicity of thalidomide. Thalidomide shows significant clinical impact in several diseases such as ENL in lepromatous leprosy, chronic graft-versus-host disease, systemic lupus erythematosus, sarcoidosis, aphthous lesions in HIV infection, wasting syndrome in chronic illness, inflammatory bowel disease, multiple myeloma and some solid tumours. In 1998 the US Food and Drug Administration approved thalidomide exclusively for the treatment of ENL, and strict conditions were stipulated for its use in order to prevent teratogenic adverse effects. However, despite the promising findings of thalidomide at the molecular level, namely its anti-TNFalpha properties and its intercalation with DNA, and activity in clinical trials, there is still a great need for more intensive research.

Thalidomide in the treatment of sixty cases of chronic discoid lupus erythematosus.

The therapeutic effect of thalidomide in chronic discoid lupus erythematosus (CDLE) was studied in sixty patients who were followed up for 2 years. In fifty-four patients (90%) a complete or marked regression of the disease was observed, but when the thalidomide was stopped, thirty out of forty-one (71%) patients relapsed. Patients undergoing a second course of thalidomide treatment again responded well. Nine of the patients in whom the disease recurred after successful treatment with thalidomide and who had been unresponsive to intermittent treatment with antimalarials, showed a good response to a second or third course with thalidomide. Mild side-effects were common and 25% of patients complained of slight to moderate polyneuritic symptoms. Since electroneurological examinations had not been performed before the thalidomide therapy, the frequency of neurological side-effects cannot be accurately calculated but we recommend neurological examinations before and periodically during thalidomide treatment. Thalidomide is a very effective drug in CDLE, but in most cases it exerts its effect only whilst treatment is continued. Its use should be restricted to patients resistant to topical steroids and systemic antimalarials.

Treatment of chronic discoid lupus erythematosus with thalidomide

In an uncontrolled study the therapeutic effect of thalidomide on chronic discoid lupus erythematosus was investigated. In 24 patients (17 women, 7 men) with a history ranging from 0.5–32 years and unresponsive to any previous therapeutic measures, complete or substantial regression of the disease was observed in 19 cases (80%) after treatment with thalidomide. Side effects were somnolence, constipation, exanthema, oral dryness, and circulatory disturbances. None of these effects were serious.

Significance of Neutrophil Activation in Reactional Lepromatous Leprosy: Effects of Thalidomide <i>in vivo</i> and <i>in vitro</i>. Activation in Adjuvant Disease

A proportion of circulating neutrophils is able to reduce nitroblue tetrazolium (NBT) <i>in vitro</i>. Such cells show blue formazan precipitates in their cytoplasm (FP cells). The proportion of FP cells is raised in many bacterial infections because of increased oxido-reductive activity (activation). This may also be induced <i>in vitro</i> by incubation with endo-toxin. We have previously reported that, while in lepromatous leprosy (LL) there was no activation, a significant elevation in proportion of FP cells took place in reactional lepromatous leprosy (RLL). RLL is reported to be a form of immune complex disease, therefore, neutrophils would be involved in tissue damage. Signs and symptoms of RLL are dramatically improved by thalidomide. We have now studied neutrophil activation in patients with RLL just before and during treatment with thalidomide. Clinical improvement produced by this drug took place before lowering the proportion of FP cells. Concomitant infectious processes induced activation even if patients were under thalidomide treatment. Thalidomide, tested <i>in vitro</i>, did not affect spontaneous reduction of NBT by neutrophils, nor did it block endotoxin-induced activation. The therapeutic effect of thalidomide is not related to properties inhibiting neutrophil activation. RLL has features that resemble those of adjuvant disease (ADJ). The latter is induced in the rat by injecting killed mycobacteria suspended in an oily vehicle. Inflammatory lesions, owing mainly to delayed hypersensitivity, appear in joints, skin and eyes. Thalidomide has suppressive properties concerning the signs of ADJ. We now studied neutrophil activation in rats of two strains: one susceptible to ADJ and the other refractory. Neutrophils from rats of both strains were able to become activated by <i>in vitro</i> incubation with endotoxin, latex particles and <i>Staphylococcus aureus</i> suspensions. After injection of mycobacteria, rats from the refractory strain showed little or no ADJ or neutrophil activation, despite the presence of inflammation at the injected site and gross enlargement of draining lymph nodes. Susceptible rats had a very intense ADJ. There was also a significant increase in proportion of FP cells, but this took place shortly after injection of mycobacteria and before signs of ADJ or acme of local inflammation had taken place. Activation disappeared by the time that ADJ became apparent. Significant neutrophil activation did not occur when susceptible rats received the oily vehicle alone. Our findings do not support the hypothesis that tissue damage in RLL is due <i>solely</i> to neutrophil action by a mechanism similar to that of immune complex disease. Activation may be in RLL as in ADJ a specific phenomenon induced by a lymphokine.