Disease relevance of Lopac-T-144

• Thalidomide in multiple myeloma [1].
• The adverse effects noted with thalidomide included somnolence and rash (7 patients each), and 6 of the 29 patients discontinued treatment because of toxicity [2].
• Thalidomide treatment increased HIV RNA levels (median increase, 0.42 log10 copies per milliliter; increase with placebo, 0.05; P=0.04) [2].
• Thalidomide for the treatment of chronic graft-versus-host disease [3].
• METHODS: We performed a double-blind, randomized, placebo-controlled study of thalidomide as therapy for oral aphthous ulcers in HIV-infected patients [2].

Psychiatry related information on Lopac-T-144

• Thalidomide, immune modulation and narcolepsy [4].
• Thrombotic complications associated with thalidomide in multiple myeloma: an old problem with new questions and quandaries in decision-making [5].
• Thalidomide was well tolerated: Two patients developed WHO Grade 2 peripheral neuropathy and eight patients developed WHO grade 2 lethargy [6].
• Thalidomide, compared with the other groups, in addition to increasing the amount of SWS, significantly increased the total amount of REM sleep as well as REM sleep as a percent of total sleep, but did not produce ataxia or behavioral excitement [7].
• Different approaches to the monitoring of adverse reactions to drugs have been used over the years, with the aim of preventing catastrophes like the thalidomide episode and to rationalise drug usage [8].

High impact information on Lopac-T-144

• Deep venous thrombosis and thalidomide therapy for multiple myeloma [9].
• Thalidomide for malignant melanoma [10].
• Life-threatening toxic epidermal necrolysis with thalidomide therapy for myeloma [11].
• Since increased bone marrow vascularity imparts a poor prognosis in myeloma, we evaluated the efficacy of thalidomide, which has antiangiogenic properties, in patients with refractory disease [12].
• With thalidomide treatment there were unexpected increases in the plasma concentrations of TNF-alpha and soluble TNF-alpha receptors [2].

Chemical compound and disease context of Lopac-T-144

• The combination of thalidomide and intermediate-dose dexamethasone is an effective but toxic treatment for patients with primary amyloidosis (AL) [13].
• Previous studies have demonstrated the in vitro and in vivo activity of CC-5013 (Revlimid), an immunomodulatory analog (IMiD) of thalidomide, in multiple myeloma (MM) [14].
• Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis [15].
• Thalidomide, dexamethasone, and pegylated liposomal doxorubicin (ThaDD) for patients older than 65 years with newly diagnosed multiple myeloma [16].
• A phase 2 trial of combination low-dose thalidomide and prednisone for the treatment of myelofibrosis with myeloid metaplasia [17].

Biological context of Lopac-T-144

• Free radical-mediated oxidative DNA damage in the mechanism of thalidomide teratogenicity [18].
• Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation [19].
• These results suggest the use of thalidomide in a clinical setting to inhibit both virus replication and the TNF-alpha-induced systemic toxicity of HIV-1 and opportunistic infections [20].
• Median individual maximum-tolerated dose of thalidomide was 600 mg/d; 41% reached 800 mg/d. Overall RR was 28%, and 55% stable disease (SD) [21].
• In view of the heterogeneity of the antigenic phenotype of MMECs, a mixture (or a sequence) of antiangiogenic agents coupled with thalidomide would seem plausible for the biologic management of MM [22].

Anatomical context of Lopac-T-144

• CONCLUSIONS: Thalidomide is an effective treatment for aphthous ulceration of the mouth and oropharynx in patients with HIV infection [2].
• Thalidomide costimulates primary human T lymphocytes, preferentially inducing proliferation, cytokine production, and cytotoxic responses in the CD8+ subset [23].
• Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes [24].
• METHODS: By use of enzyme-linked immunosorbent assays, we measured the effects of Linomide (roquinimex), thalidomide, pentoxifylline, and genistein on TNF-alpha and GM-CSF production in vitro by virally transformed RAW 264.7 mouse macrophages and on PAI-2 production in vitro by human macrophages [25].
• The toxic metabolite of thalidomide was not produced by rat liver microsomes (the rat is not sensitive to thalidomide teratogenesis) but was produced by hepatic preparations from maternal rabbits, and rabbit, monkey, and human (all sensitive species) fetuses [26].

Associations of Lopac-T-144 with other chemical compounds

• Here, we show in rabbits that thalidomide initiates embryonic DNA oxidation and teratogenicity, both of which are abolished by pre-treatment with the free radical spin trapping agent alpha-phenyl-N-t-butylnitrone (PBN) [18].
• We have examined the mechanism of thalidomide inhibition of lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-alpha) production and found that the drug enhances the degradation of TNF-alpha mRNA [19].
• The results with thalidomide are promising but much more research into small molecules inhibiting TNF and other proinflammatory cytokines is necessary [27].
• METHODS: Eighteen subjects with chronic diarrhea caused by Enterocytozoon bieneusi that had not responded symptomatically to albendazole and 1 untreated subject with Encephalitozoon intestinalis received 1 month of thalidomide, 100 mg nocte [28].
• SAHA also enhances the anti-MM activity of other proapoptotic agents, including dexamethasone, cytotoxic chemotherapy, and thalidomide analogs [29].

Gene context of Lopac-T-144

• Thalidomide is a first-generation immuno-modulating agent that down-regulates TNF-alpha and VEGF [30].
• Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha [31].
• CC-3052: a water-soluble analog of thalidomide and potent inhibitor of activation-induced TNF-alpha production [32].
• Thalidomide abolished the NF-kappaB-dependent reporter gene expression activated by overexpression of TNFR1, TNFR-associated factor-2, and NF-kappaB-inducing kinase, but not that activated by the p65 subunit of NF-kappaB [33].
• Consistent with the observed inhibition of NF-kappaB, thalidomide blocked the cytokine-induced expression of NF-kappaB-regulated genes such as those encoding interleukin-8, TRAF1, and c-IAP2 [34].

Analytical, diagnostic and therapeutic context of Lopac-T-144

• METHODS: Eighty-four previously treated patients with refractory myeloma (76 with a relapse after high-dose chemotherapy) received oral thalidomide as a single agent for a median of 80 days (range, 2 to 465) [12].
• Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group [2].
• Thalidomide for graft-versus-host disease after bone marrow transplantation [35].
• Results of this pilot study support the need for controlled multicenter trials of thalidomide for treatment of CD [36].
• Intractable insomnia after cessation of treatment with thalidomide [37].

References