Revisiting thalidomide: Fighting with caution against idiopathic pulmonary fibrosis
Thalidomide is an infamous drug whose use by pregnant women in the middle of last century tragically resulted in serious birth defects. However, as a result of its potent immunomodulatory, anti-inflammatory and antiangiogenic properties, thalidomide may be a potential therapy in many diseases. In recent years, thalidomide has been used effectively to treat various malignancies, including multiple myeloma, myelodysplastic syndromes, renal cell cancer, glioblastoma multiforme and prostate cancer. In addition, thalidomide has also proven effective against other immune-related diseases, including erythema nodosum leprosum and sarcoidosis. Idiopathic pulmonary fibrosis (IPF) is a deadly fibrotic disease with no effective treatment options. However, there is data to suggest that thalidomide may be useful in treating the chronic, disabling cough that accompanies IPF. It remains to be seen whether the immunomodulatory and antiangiogenic properties of thalidomide will also make it a potential therapy against the clinical progression of IPF.
Available from: Neil Vargesson
- "renal cell cancer, prostate cancer, and Karposi's sarcoma)   . Recently thalidomide has been shown to be effective in relieving the clinical symptoms of hereditary hemorrhagic telangiectasia (HHT), a bleeding disorder  and idiopathic pulmonary fibrosis  . Clearly thalidomide has some very beneficial clinical uses. "
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ABSTRACT: Thalidomide remains one of the world’s most notorious drugs due to the severe birth defects it induced in children between 1957 and 1962. Yet, to some this drug is a lifesaver, as it now enjoys renaissance in the treatment for a wide range of conditions including leprosy, multiple myeloma, Behcet’s disease, and some cancers. However, thalidomide has also been linked to causing a new generation of thalidomide survivors in Brazil, where the drug is used to treat leprosy. Surprisingly how thalidomide causes birth defects and how it acts in the treatment of clinical conditions are still far from clear. In the past decade great strides in our understanding of the actions of the drug, as well as molecular targets, have been made. The purpose of this review is to look at the recent work carried out into understanding how thalidomide causes birth defects, it’s molecular targets and the challenges that remain to be elucidated. These challenges include identifying clinically relevant but nonteratogenic forms of the drug, and the mechanisms underlying phocomelia and species specificity.
10/2013; 2013(3). DOI:10.1155/2013/241016
Available from: PubMed Central
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ABSTRACT: The aims of this study were to observe the effects of thalidomide on a rat model of pulmonary fibrosis, to determine the protein expression levels of phosphorylated c-Jun N-terminal kinase (p-JNK) and α-smooth muscle actin (α-SMA) and to explore the mechanism underlying the preventive effect of thalidomide on pulmonary fibrosis. Ninety healthy male Wistar rats (200±20 g) were randomly divided into control (N), model (M), SP600125 (SP), thalidomide (T) and SP600125 plus thalidomide (SP + T) groups. Pulmonary fibrosis models were established in groups M, SP, T and SP + T by the intratracheal instillation of bleomycin (BLM). A gavage of thalidomide was administered to the rats in groups T and SP + T once daily, whereas normal saline was administered to the rats in the other groups. The rats in the SP and SP + T groups were injected intraperitoneally with SP600125 following BLM administration, whereas the rats in the other groups received dimethyl sulfoxide. Rats were randomly sacrificed on days 7, 14 and 28. Pathological changes were examined by light microscopy using hematoxylin and eosin staining. Hydroxyproline (HYP) levels in the lung tissues were detected using alkaline hydrolysis. The protein expression levels of p-JNK and α-SMA were measured by immunohistochemical staining and western blot analysis. In group M, alveolitis was most serious on day 7 and then eased on day 14; marked pulmonary fibrosis was observed on day 28. The fibrosis was markedly attenuated in the SP + T group compared with that in group M. The HYP content increased gradually with time after BLM administration and peaked on day 28. On days 14 and 28, the HYP content was lower in groups T and SP than in group M (P<0.05). The expression levels of p-JNK protein and α-SMA were significantly lower in groups SP, T and SP + T than those in group M on day 14 (P<0.05). The expression level of α-SMA was lower in group SP + T than those in groups SP and T on days 14 and 28 (P<0.05). The expression level of p-JNK protein in group T was higher than those in groups SP and SP + T on days 14 and 28 (P<0.05). Thus, thalidomide eased the degree of BLM-induced pulmonary fibrosis in rats by downregulating p-JNK and α-SMA expression.
Experimental and therapeutic medicine 03/2014; 7(3):669-674. DOI:10.3892/etm.2013.1457 · 1.27 Impact Factor
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We studied the effect of thalidomide on NFκB-induced TNF-α in acute pancreatitis-associated lung injury in the rat.
Rats were intragastrically administered thalidomide (100 mg/kg) daily for 8 days and then acute pancreatitis was induced by retrograde infusion of 5% sodium taurocholate into the rat biliopancreatic duct. Serum amylase (AMY), blood oxygen partial pressure (PaO2), ratios of lung wet/dry weight, and cytoplasmic IκBα and TNF-α protein and nuclear NFκBp65 protein were measured. Also, lung NFκBp65 and TNF-α mRNA were measured.
Compared with the model group, pathological score of the pancreas and lung, serum AMY, ratios of lung wet/dry weight, and lung NFκBp65 and TNF-α mRNA and protein of rats given thalidomide were decreased significantly (P < 0.01), but PaO2 and IκBα protein was elevated significantly (P < 0.01).
Thalidomide may inhibit TNF-α expression via down-regulation of the NFκB signaling pathway to alleviate acute pancreatitis-associated lung injury in rats.
Pathology - Research and Practice 09/2014; 210(9). DOI:10.1016/j.prp.2014.04.022 · 1.40 Impact Factor
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