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Re: Reversible thalidomide neuropathy

Dear Editor

Thank you very much for an excellent review of thalidomide. It really made an interesting reading.

I would like to describe a case of thalidomide-induced peripheral neuropathy that I came across. A 58-year old man was diagnosed to have multiple myeloma three years ago and was treated with a combination of melphalan and steroids. He responded well to that treatment protocol. He presented eight months ago with features of a myeloma relapse. He was started on thalidomide. While on thalidomide, he developed numbness of feet and hands associated with paresthesias. He also had weakness of his lower limbs. Clinical examination revealed a glove and stocking distribution of sensory impairment. Deep tendon reflexes were sluggish. Nerve conduction studies showed features of axonal length-dependent sensori more than motor neuropathy. He was investigated for possible causes of neuropathy including diabetes mellitus, Hansen's disease, vasculitis and paraneoplastic aetiology. All investigations were normal. A possible diagnosis of thalidomide-induced peripheral neuropathy was made. Thalidomide could not be stopped as his myeloma would have worsened. Therefore, the dose of thalidomide was reduced. Within a week, the patient noted an improvement in his symptoms with disappearance of paresthesias. At three-month follow up, he was asymptomatic with normal power and sensations. His myeloma was also in remission.

This report thus highlights that thalidomide-induced peripheral neuropathy is reversible with no residual deficits. Similar results were observed in two patients in an earlier report, though the severity of neuropathy was mild.[1]

Previous reports have found the neuropathy to be related to the initial thalidomide dose, with negligible risks at doses below 25 mg per day.[2,3] Older age has also been found to be a risk factor for this condition.[3]

References

(1) Gupta A, Cohen BH, Ruggieri P, Packer RJ, Phillips PC. Phase I study of thalidomide for the treatment of plexiform neurofibroma in neurofibromatosis 1. Neurology 2003; 60(1):130-2.

(2) Bastuji-Garin S, Ochonisky S, Bouche P, Gherardi RK, Duguet C, Djerradine Z, Poli F, Revuz J; Thalidomide Neuropathy Study Group.Incidence and risk factors for thalidomide neuropathy: a prospective study of 135 dermatologic patients. J Invest Dermatol 2002;119(5):1020 -6.

(3) Molloy FM, Floeter MK, Syed NA, Sandbrink F, Culcea E, Steinberg SM, Dahut W, Pluda J, Kruger EA, Reed E, Figg WD.Thalidomide neuropathy in patients treated for metastatic prostate cancer. Muscle Nerve 2001;24(8):1050-7.

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Re: Old drugs – new uses

Dear Editor

The review on thalidomide in a fine way illustrates how different diseases may respond to the same drug, and why.[1] In addition to the conditions discussed in the review, thalidomide has also been evaluated in patients with cardiac congestion.[2] The rationale behind that is that TNF-a and other cytokines are involved in the pathogenesis for this condition too, however, the picture is complex and we have to learn more about these mechanisms.[3] In line with this, digitalis, such as in the form of digitoxin and oleandrin, have recently been shown to target the transcription factor NF-kB and modulate pro-inflammatory cytokines.[4,5] Probably these molecular effects of digitalis contribute to the impact of the drug on cardiac conditions, in addition to its well known inhibition of the Na+/K+ATPase. Digitalis, especially in the form of digitoxin, also induces apoptosis in an array of cancer cells in concentrations that are non-toxic in vivo, and posses several other features that makes it a drug of potential use in oncology.[6-8] Actually, the recent elucidated mechanisms of action of digitoxin are similar to the thalidomide effects; inhibition of angiogenesis, inhibition of NF-kB and modulation of cytokine responses. In addition, digitoxin targets tyrosine kinases in a complex way and triggers apoptotic pathways in diverse malignant cells.[9] Pro-inflammatory cytokines are involved in the pathogenesis of multiple sclerosis, rheumatoid arthritis, Crohn's disease, atherosclerosis and several other diseases, including cancer.[1,10] Evidently, drugs that modulate these cytokines can be beneficial. Now, more than 200 years after William Withering tracked the valuable effects of digitalis for dropsy, digitalis in the form of digitoxin and its derivatives may have a renaissance for other diseases, such as cancer, inflammatory bowel diseases and perhaps cystic fibrosis, at least if some of the effects detected in the laboratory will be present in vivo.

References

1. Gordon JN, Goggin PM. Thalidomide and its derivatives: emerging from the wilderness. Postgrad Med J 2003;79:127-32.

2. Gullestad L, Semb AG, Holt E, et al. Effect of thalidomide in patients with chronic heart failure. Am Heart J 2002;144:847-50.

3. Aukrust P, Yndestad A, Damas JK, et al. Therapeutic potential of anticytokine therapy in congestive heart failure. Am J Cardiovasc Drugs 2004;4:169-77

4. Manna SK, Sah NK, Newman RA, et al. Oleandrin suppresses activation of nuclear transcription factor-kappaB, activator protein-1, and c-Jun NH2-terminal kinase. Cancer Res 2000;60:3838-47.

5. Srivastava M, Eidelman O, Zhang J, et al. Digitoxin mimics gene therapy with CFTR and suppresses hypersecretion of IL-8 from cystic fibrosis lung epithelial cells. Proc Natl Acad Sci U S A. 2004;101:7693-8.

6. Haux J. Digitoxin is a potential anticancer agent for several types of cancer. Med Hypotheses. 1999;53:543-8.

7. Johansson S, Lindholm P, Gullbo J, et al.Cytotoxicity of digitoxin and related cardiac glycosides in human tumor cells. Anticancer Drugs 2001;12:475-83.

8. Haux J, Klepp O, Spigset O, et al. Digitoxin medication and cancer; case control and internal dose-response studies. BMC Cancer 2001;1:11.

9. Haux J. Digitalis; impinges on more than just the (ion-) pump. Med Hypotheses. 2002;59:781-2.