Thalidomide reduces tumour necrosis factor α and interleukin 12 production in patients with chronic active Crohn's disease

PubMed Central

Bauditz, J; Wedel, S; Lochs, H

2002-01-01

Background: Thalidomide improves clinical symptoms in patients with therapy refractory Crohn's disease, as shown in two recent studies. The mechanism of this effect however is still unknown. Suppression of tumour necrosis factor α (TNF-α) by thalidomide has been suggested as a possible mechanism. However, effects on other cytokines have not been adequately investigated. Aim: The aim of our study was to investigate the effects of thalidomide on cytokine production in patients with inflammatory bowel disease (IBD). Methods: Ten patients with therapy refractory IBD (nine Crohn's disease, one ulcerative colitis) received thalidomide 300 mg daily in a 12 week open label study. Production of TNF-α, interleukin (IL)-1β, IL-6, and IL-12 was investigated in short term cultures of stimulated colonic lamina propria mononuclear cells (LPMC) and peripheral blood monocytes (PBMC) before and after 12 weeks of treatment. LPMC were also cultured with graded doses of thalidomide. Results: Three patients discontinued treatment because of sedative side effects. In the other patients, disease activity decreased significantly, with four patients achieving remission. Production of TNF-α and IL-12 decreased during treatment with thalidomide: LPMC (TNF-α: 42.3 (8.3) pg/ml v 16.4 (6.3); IL-12: 9.7 (3.3) v 5.0 (2.5); p<0.04) and PBMC (TNF-α: 62.8 (14.6) v 22.5 (9.2); p<0.02). Production of IL-1β and IL-6 did not change significantly. Culturing of LPMC with thalidomide showed a dose dependent decrease in TNF-α and IL-12 production. Conclusion: The clinical effects of thalidomide in Crohn's disease may be mediated by reduction of both TNF-α and IL-12. PMID:11788559

Teratogen metabolism: activation of thalidomide and thalidomide analogues to products that inhibit the attachment of cells to concanavalin A coated plastic surfaces.

PubMed

Braun, A G; Weinreb, S L

1984-05-01

Thalidomide metabolites inhibited the attachment of tumor cells to concanavalin A coated polyethylene surfaces. Thalidomide, itself, was non-inhibitory. Thalidomide activation to inhibitory products required hepatic microsomes, an NADPH-generating system, and molecular oxygen. Production of inhibitory metabolites was unaffected by either epoxide hydrolase or 1,2-epoxy-3,3,3-trichloropropane (TCPO), an inhibitor of epoxide hydrolase endogenous to hepatic S9 fraction. Therefore, the attachment inhibitor was probably not an arene oxide. Inhibition was not accompanied by cytotoxicity, as judged by trypan blue exclusion. Although uninduced hepatic microsomes from mice, rats and dogs had similar abilities to activate thalidomide, microsomes from Aroclor 1254 induced rats were relatively inactive in the system. Inhibitory metabolites were generated from the thalidomide analogues EM8 , EM12 , EM16 , EM87 , EM136 , EM255 , E350 , phthalimide, phthalimido-phthalimide, indan, 1- indanone and 1,3- indandione . Glutarimide , glutamic acid and phthalic acid did not activate to inhibitory products.

Identification of a primary target of thalidomide teratogenicity.

PubMed

Ito, Takumi; Ando, Hideki; Suzuki, Takayuki; Ogura, Toshihiko; Hotta, Kentaro; Imamura, Yoshimasa; Yamaguchi, Yuki; Handa, Hiroshi

2010-03-12

Half a century ago, thalidomide was widely prescribed to pregnant women as a sedative but was found to be teratogenic, causing multiple birth defects. Today, thalidomide is still used in the treatment of leprosy and multiple myeloma, although how it causes limb malformation and other developmental defects is unknown. Here, we identified cereblon (CRBN) as a thalidomide-binding protein. CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cul4A that is important for limb outgrowth and expression of the fibroblast growth factor Fgf8 in zebrafish and chicks. Thalidomide initiates its teratogenic effects by binding to CRBN and inhibiting the associated ubiquitin ligase activity. This study reveals a basis for thalidomide teratogenicity and may contribute to the development of new thalidomide derivatives without teratogenic activity.

The effects of thalidomide on the stimulation of NF-kappaB activity and TNF-alpha production by lipopolysaccharide in a human colonic epithelial cell line.

PubMed

Kim, You Sun; Kim, Joo Sung; Jung, Hyun Chae; Song, In Sung

2004-04-30

The immunomodulatory and anti-inflammatory effects of thalidomide are associated with inhibition of TNF-alpha levels. However, the mechanism by which thalidomide reduces TNF-alpha production remains elusive. NF-kappaB is known to play a central role in regulating inflammatory responses in patients with inflammatory bowel disease (IBD). We tested whether thalidomide acts through inhibiting NF-kappaB activity. HT-29 cells were stimulated with LPS (1 microg/ml) alone, or after pretreatment with thalidomide (100 microg/ml), and NF-kappaB activity was determined by gel mobility shift assays. RT-PCR was used to measure expression of the proinflammatory cytokine genes TNF-alpha, IL-1beta and IL-8. The level of TNF-alpha mRNA was also analyzed by real-time quantitative RT-PCR, and TNF-alpha protein was measured by ELISA. Thalidomide pretreatment did not affect NF-kappaB activity in HT-29 cells stimulated with LPS but production of TNF-alpha was depressed. Thalidomide was found to accelerate the degradation of TNF-alpha mRNA, but had little effect on IL-1beta or IL-8. These observations suggest that the immunomodulatory effect of thalidomide in colonic epithelial cells is associated with inhibition of TNF-alpha. However, it does not act by inhibiting NF-kappaB but rather by inducing degradation of TNF-alpha mRNA.

Effect of thalidomide on endotoxin-induced decreases in activity and expression of hepatic cytochrome P450 3A2.

PubMed

Ueyama, Jun; Nadai, Masayuki; Zhao, Ying Lan; Kanazawa, Hiroaki; Takagi, Kenji; Kondo, Takaaki; Takagi, Kenzo; Wakusawa, Shinya; Abe, Fumie; Saito, Hiroko; Miyamoto, Ken-Ichi; Hasegawa, Takaaki

2008-08-01

Thalidomide has been reported to inhibit the production of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) that are involved in the down-regulation of hepatic cytochrome P450 (CYP) induced by endotoxin. In the present study, we investigated the effects of thalidomide on endotoxin-induced decreases in the activity and expression of hepatic CYP3A2 in rats. Thalidomide (50 mg/kg) was administered orally 22 h and 2 h before intraperitoneal injection of endotoxin (1 mg/kg). Twenty-four hours after the injection of endotoxin, antipyrine clearance experiments were conducted, in which the rats were sacrificed and protein levels of hepatic CYP3A2 were measured. There were no significant differences in the histopathological changes in the liver between the endotoxin-treated and endotoxin plus thalidomide-treated rats. Thalidomide had no effect on the systemic clearance of antipyrine, which is a proper indicator for hepatic CYP3A2 activity, whereas it enhanced endotoxin-induced decrease in the systemic clearance of antipyrine. Western blot analysis revealed that thalidomide had no effect on the protein levels of hepatic CYP3A2, whereas it enhanced the down-regulation of hepatic CYP3A2 by endotoxin. However, there were no significant differences in the concentrations of TNF-alpha and NO in plasma between the endotoxin-treated and endotoxin plus thalidomide-treated rats. The present findings suggest that thalidomide enhances endotoxin-induced decreases in the activity and expression of hepatic CYP3A2.

Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results

PubMed Central

Morgan, Gareth J.; Davies, Faith E.; Gregory, Walter M.; Bell, Sue E.; Szubert, Alexander J.; Navarro Coy, Nuria; Cook, Gordon; Feyler, Sylvia; Johnson, Peter R.E.; Rudin, Claudius; Drayson, Mark T.; Owen, Roger G.; Ross, Fiona M.; Russell, Nigel H.; Jackson, Graham H.; Child, J. Anthony

2012-01-01

Background Thalidomide is active in multiple myeloma and is associated with minimal myelosuppression, making it a good candidate for induction therapy prior to high-dose therapy with autologous stem-cell transplantation. Design and Methods Oral cyclophosphamide, thalidomide, and dexamethasone was compared with infusional cyclophosphamide, vincristine, doxorubicin, and dexamethasone in patients with newly diagnosed multiple myeloma. Results The post-induction overall response rate (≥ partial response) for the intent-to-treat population was significantly higher with cyclophosphamide-thalidomide-dexamethasone (n=555) versus cyclophosphamide-vincristine-doxorubicin-dexamethasone (n=556); 82.5% versus 71.2%; odds ratio 1.91; 95% confidence interval 1.44–2.55; P<0.0001. The complete response rates were 13.0% with cyclophosphamide-thalidomide-dexamethasone and 8.1% with cyclophos-phamide-vincristine-doxorubicin-dexamethasone (P=0.0083), with this differential response being maintained in patients who received autologous stem-cell transplantation (post-transplant complete response 50.0% versus 37.2%, respectively; P=0.00052). Cyclophosphamide-thalidomide-dexamethasone was non-inferior to cyclophosphamide-vincristine-doxorubicin-dexamethasone for progression-free and overall survival, and there was a trend toward a late survival benefit with cyclophosphamide-thalidomide-dexamethasone in responders. A trend toward an overall survival advantage for cyclophosphamide-thalidomide-dexamethasone over cyclophosphamide-vincristine-doxorubicin-dexamethasone was also observed in a subgroup of patients with favorable interphase fluorescence in situ hybridization. Compared with cyclophosphamide-vincristine-doxorubicin-dexamethasone, cyclophosphamide-thalidomide-dexamethasone was associated with more constipation and somnolence, but a lower incidence of cytopenias. Conclusions The cyclophosphamide-thalidomide-dexamethasone regimen showed improved response rates and was not inferior in terms of survival outcomes to the standard infusional regimen of cyclophosphamide-vincristine-doxorubicin-dexamethasone. Based on its oral administration and the reduced incidence of infection and cytopenia, cyclophosphamide-thalidomide-dexa-methasone may be considered an effective induction therapy option for patients with newly diagnosed multiple myeloma. (ISRCTN: 68454111) PMID:22058209

Thalidomide inhibits lipopolysaccharide-induced tumor necrosis factor-alpha production via down-regulation of MyD88 expression.

PubMed

Noman, Abu Shadat M; Koide, Naoki; Hassan, Ferdaus; I-E-Khuda, Imtiaz; Dagvadorj, Jargalsaikhan; Tumurkhuu, Gantsetseg; Islam, Shamima; Naiki, Yoshikazu; Yoshida, Tomoaki; Yokochi, Takashi

2009-02-01

The effect of thalidomide on lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-alpha production was studied by using RAW 264.7 murine macrophage-like cells. Thalidomide significantly inhibited LPS-induced TNF-alpha production. Thalidomide prevented the activation of nuclear factor (NF)-KB by down-regulating phosphorylation of inhibitory KB factor (IKB), and IKB kinase (IKK)-alpha and IKK-beta Moreover, thalidomide inhibited LPS-induced phosphorylation of AKT, p38 and stress-activated protein kinase (SAPK)/JNK. The expression of myeloid differentiation factor 88 (MyD88) protein and mRNA was markedly reduced in thalidomide-treated RAW 264.7 cells but there was no significant alteration in the expression of interleukin-1 receptor-associated kinase (IRAK) 1 and TNF receptor-associated factor (TRAF) 6 in the cells. Thalidomide did not affect the cell surface expression of Toll-like receptor (TLR) 4 and CD14, suggesting the impairment of intracellular LPS signalling in thalidomide-treated RAW 264.7 cells. Thalidomide significantly inhibited the TNF-alpha production in response to palmitoyl-Cys(RS)-2,3-di(palmitoyloxy) propyl)-Ala-Gly-OH (Pam(3)Cys) as a MyD88-dependent TLR2 ligand. Therefore, it is suggested that thalidomide might impair LPS signalling via down-regulation of MyD88 protein and mRNA and inhibit LPS-induced TNF-alpha production. The putative mechanism of thalidomide-induced MyD88 down-regulation is discussed.

[Effect of thalidomide in a mouse model of paraquat-induced acute lung injury and the underlying mechanisms].

PubMed

Li, Dong; Xu, Li-yan; Chang, Zi-juan; Zhao, Guang-ju; Nan, Chao; Lu, Zhong-qiu

2013-03-01

To investigate the intervention effect of thalidomide on paraquat-induced acute lung injury in mice and its mechanism. Male ICR mice were randomly allocated to negative control group (n = 30), thalidomide control group (n = 30), paraquat poisoning group (n = 30), 50 mg/kg thalidomide treatment group (n = 30), 100 mg/kg thalidomide treatment group (n = 30), and 150 mg/kg thalidomide treatment group (n = 30). The negative control group was intraperitoneally injected with the same volume of saline; the thalidomide control group was intraperitoneally injected with thalidomide (150 mg/kg); the paraquat poisoning group was intraperitoneally injected with diluted paraquat solution (22 mg/kg); each thalidomide treatment group was intraperitoneally injected with the same volume of paraquat solution (22 mg/kg) and was injected with thalidomide (50, 100, or 150 mg/kg) 1 h later. All mice were anesthetized and sacrificed at 1, 3, or 7 d after paraquat poisoning, and their lung tissue was collected. The levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in lung tissue were measured by double-antibody sandwich ELISA; the mRNA expression of nuclear factor-kappa B (NF-κB) was measured by RT-PCR; the protein expression of nuclear NF-kgr;B p65 was measured by Western blot. The pathological changes of lung tissue were observed under light microscope; the wet/dry ratio of the lung was calculated. Compared with the negative control group, the paraquat poisoning group had significantly increased levels of TNF-α, IL-1β, IL-6, NF-κB mRNA, and nuclear NF-κB p65 and wet/dry ratio of the lung (P < 0.05). Compared with the paraquat poisoning group, the thalidomide treatment groups had significantly decreased levels of TNF-α, IL-1β, IL-6, NF-κB mRNA, and nuclear NF-κB p65 and wet/dry ratios of the lung (P < 0.05), and the 150 mg/kg thalidomide treatment group showed the most significant decrease in the levels of TNF-α, IL-1β, IL-6, NF-κB mRNA, and nuclear NF-κB p65. The observation of pathological changes showed that the paraquat poisoning group had the most marked lung tissue damage at 3 d after poisoning, and the lung tissue damage was lessened in the thalidomide treatment groups. Thalidomide can reduce paraquat-induced acute lung injury and lung edema. The mechanism may include inhibition of NF-κB activation and expression and downregulation of TNF-α, IL-1β, and IL-6.

Thalidomide analogues: Tumor necrosis factor-alpha inhibitors and their evaluation as anti-inflammatory agents.

PubMed

Casal, Juan José; Bollini, Mariela; Lombardo, María Elisa; Bruno, Ana María

2016-02-15

A series of related thalidomide derivatives (2-9) were synthesized by microwave irradiation and evaluated for anti-inflammatory activity. Such activity was assessed in vivo and ex vivo. Compounds 2, 8 and 9 showed the highest levels of inhibition of TNF-α production. On rat paw edema and hyperalgesia assays, compound 9, (1,4-phthalazinedione) demonstrated the highest in vivo anti-inflammatory activity. Thus, compound 9 can be considered as a promising compound to be subjected to further modification to obtain new agents for the treatment of inflammatory diseases.

Immunomodulatory effects of thalidomide analogs on LPS-induced plasma and hepatic cytokines in the rat.

PubMed

Fernández-Martínez, Eduardo; Morales-Ríos, Martha S; Pérez-Alvarez, Víctor; Muriel, Pablo

2004-10-01

Thalidomide has shown to inhibit, selectively and mainly the cytokine tumor necrosis factor-alpha (TNF-alpha), thus, thalidomide has inhibitory consequences on other cytokines; this is ascribed as an immunomodulatory effect. Novel thalidomide analogs are reported with immunomodulatory activity. The aim of this work was to synthesize some of these analogs and to assess them as immunomodulatory agents in an acute model of LPS-induced septic challenge in rat. Animal groups received orally twice a day vehicle carboxymethylcellulose (0.9%), or thalidomide in suspension (100mg/kg), or analogs in an equimolar dose. Two hours after last dose, rats were injected with saline (NaCl, 0.9%, i.p.) or LPS (5mg/kg, i.p.). Groups were sacrificed 2h after injection and samples of blood and liver were obtained. TNF-alpha, interleukin-6, -1beta, and -10 (IL-6, IL-1beta, IL-10) were quantified by enzyme linked immunosorbent assay (ELISA) and studied in plasma and liver. After 2h of LPS-induction, different patterns of measured cytokines were observed with thalidomide analogs administration evidencing their immunomodulatory effects. Interestingly, some analogs decreased significantly plasma and hepatic levels of LPS-induced proinflammatory TNF-alpha and others increased plasma concentration of anti-inflammatory IL-10. Thalidomide analogs also showed slight effects on the remaining proinflammatory cytokines. Differences among immunomodulatory effects of analogs can be related to potency, mechanism of action, and half lives. Thalidomide analogs could be used as a pharmacological tool and in therapeutics in the future.

Modulation of thalidomide pharmacokinetics by cyclophosphamide or 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in mice: the role of tumour necrosis factor.

PubMed

Chung, Francisco; Wang, Liang-Chuan S; Kestell, Philip; Baguley, Bruce C; Ching, Lai-Ming

2004-05-01

There is considerable current interest in the use of thalidomide as a single agent or in combination with drugs such as cyclophosphamide in the treatment of multiple myeloma and other cancers. Our previous work has shown that thalidomide potentiates the antitumour activity of both cyclophosphamide and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) against murine Colon 38 tumours. In both of these cases, thalidomide extends the half-life (t(1/2)) of the other drug. We wished to determine whether cyclophosphamide and DMXAA altered the t(1/2) of thalidomide. Since both thalidomide and DMXAA modulate tumour necrosis factor (TNF), we also wished to determine the role of TNF in this interaction. Mice with Colon 38 tumours were treated with cyclophosphamide (220 mg/kg) and/or thalidomide (20 mg/kg) or DMXAA (25 mg/kg) and thalidomide (100 mg/kg), combinations that have previously demonstrated synergistic activity. Plasma and tumour tissue drug concentrations were analysed by high-performance liquid chromatography. To determine the role of TNF, similar experiments were performed using mice defective in the TNF gene (TNF(-/-)) or the TNF receptor-1 gene (TNFR1(-/-)). Coadministration of cyclophosphamide increased the thalidomide t(1/2) by 3.9- and 3.6-fold, respectively, in plasma and tumour tissue, with a corresponding increase in the concentration-time curve (AUC). The corresponding values following coadministration of DMXAA were 3.0- and 4.6-fold, respectively. Coadministration of cyclophosphamide had similar effects on thalidomide t(1/2) in C57Bl/6, TNF(-/-) and TNFR1(-/-) mice, while coadministration of DMXAA did not alter the t(1/2) or AUC in TNF(-/-) and TNFR1(-/-) mice. Both cyclophosphamide and DMXAA have a pharmacokinetic interaction with thalidomide, increasing t(1/2) and AUC. TNF mediates the effect of DMXAA on thalidomide pharmacokinetics but not that of cyclophosphamide.

Anti-nociceptive effect of thalidomide on zymosan-induced experimental articular incapacitation.

PubMed

Vale, Mariana L; Cunha, Fernando Q; Brito, Gerly A C; Benevides, Verônica M; Ferreira, Sérgio H; Poole, Stephen; Ribeiro, Ronaldo A

2006-05-01

The anti-nociceptive effect of thalidomide on zymosan-induced articular knee joint incapacitation in rats was investigated. Thalidomide (5-45 mg/kg), given 30 min before but not 2 h after the intra-articular injection of zymosan, inhibited the nociceptive response in a dose-dependent manner. Furthermore, thalidomide pretreatment significantly reduced the concentration of tumor necrosis factor-alpha (TNF-alpha, -68.4%) in the exudate of zymosan-injected joints, but not those of interleukin-1beta, interleukin-6, CINC-1 or interleukin-10. The expression of TNF-alpha, determined by immunohistochemical staining, in synovial tissues obtained from articular joints injected with zymosan was also inhibited by thalidomide pretreatment. The anti-nociceptive effect of thalidomide was not reversed by the co-administration of an opioid receptor antagonist, naloxone, suggesting that endogenous opioids do not mediate the anti-nociceptive effect of thalidomide in this model. In conclusion, the anti-nociceptive activity of thalidomide in zymosan-induced articular incapacitation is associated with the inhibition of TNF-alpha by resident synovial cells.

Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha.

PubMed

Corral, L G; Haslett, P A; Muller, G W; Chen, R; Wong, L M; Ocampo, C J; Patterson, R T; Stirling, D I; Kaplan, G

1999-07-01

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.

The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis.

PubMed

Morgan, Gareth J; Gregory, Walter M; Davies, Faith E; Bell, Sue E; Szubert, Alexander J; Brown, Julia M; Coy, Nuria N; Cook, Gordon; Russell, Nigel H; Rudin, Claudius; Roddie, Huw; Drayson, Mark T; Owen, Roger G; Ross, Fiona M; Jackson, Graham H; Child, J Anthony

2012-01-05

Thalidomide maintenance has the potential to modulate residual multiple myeloma (MM) after an initial response. This trial compared the effect of thalidomide maintenance and no maintenance on progression-free survival (PFS) and overall survival (OS) in MM patients. After intensive or nonintensive induction therapy, 820 newly diagnosed MM patients were randomized to open-label thalidomide maintenance until progression, or no maintenance. Interphase FISH (iFISH) analysis was performed at study entry. Median PFS was significantly longer with thalidomide maintenance (log-rank P < .001). Median OS was similar between regimens (log-rank P = .40). Patients with favorable iFISH showed improved PFS (P = .004) and a trend toward a late survival benefit. Patients with adverse iFISH receiving thalidomide showed no significant PFS benefit and worse OS (P = .009). Effective relapse therapy enhanced survival after progression, translating into a significant OS benefit. Meta-analysis of this and other studies show a significant late OS benefit (P < .001, 7-year difference hazard ratio = 12.3; 95% confidence interval, 5.5-19.0). Thalidomide maintenance significantly improves PFS and can be associated with improved OS. iFISH testing is important in assessing the clinical impact of maintenance therapy. Overview analysis demonstrated that thalidomide maintenance was associated with a significant late OS benefit. This trial was registered at www.isrctn.org as #ISRCTN68454111.

High-dose thalidomide increases the risk of peripheral neuropathy in the treatment of ankylosing spondylitis.

PubMed

Xue, Hong-Xia; Fu, Wen-Yi; Cui, Hua-Dong; Yang, Li-Li; Zhang, Ning; Zhao, Li-Juan

2015-05-01

Thalidomide is an effective drug for the treatment of ankylosing spondylitis but might induce peripheral neuropathy. This major adverse reaction has attracted much concern. The current study aimed to observe the incidence of thalidomide-induced peripheral neuropathy among ankylosing spondylitis patients for 1 year after treatment. In this study, 207 ankylosing spondylitis cases received thalidomide treatment, while 116 ankylosing spondylitis cases received other treatments. Results showed that the incidence of thalidomide-induced peripheral neuropathy in the thalidomide group was higher than that in the non-thalidomide group. There was no significant difference in the incidence of neuropathy between the < 6 months medication and ≥ 6 months medication groups. There were no differences in the mean age, gender, or daily dose between the two groups. The incidence of peripheral neuropathy among patients receiving 25, 50, 75, or 100 mg thalidomide per day was 4.6%, 8.5%, 17.1%, 21.7%, respectively. The incidence was significantly different between the groups receiving 25 mg and 100 mg thalidomide. In conclusion, thalidomide can induce peripheral neuropathy within 1 year after treatment of ankylosing spondylitis; however, age and gender have no obvious impact on the incidence of peripheral neuropathy. The incidence of peripheral neuropathy is associated with increasing daily doses of thalidomide.

High-dose thalidomide increases the risk of peripheral neuropathy in the treatment of ankylosing spondylitis

PubMed Central

Xue, Hong-xia; Fu, Wen-yi; Cui, Hua-dong; Yang, Li-li; Zhang, Ning; Zhao, Li-juan

2015-01-01

Thalidomide is an effective drug for the treatment of ankylosing spondylitis but might induce peripheral neuropathy. This major adverse reaction has attracted much concern. The current study aimed to observe the incidence of thalidomide-induced peripheral neuropathy among ankylosing spondylitis patients for 1 year after treatment. In this study, 207 ankylosing spondylitis cases received thalidomide treatment, while 116 ankylosing spondylitis cases received other treatments. Results showed that the incidence of thalidomide-induced peripheral neuropathy in the thalidomide group was higher than that in the non-thalidomide group. There was no significant difference in the incidence of neuropathy between the < 6 months medication and ≥ 6 months medication groups. There were no differences in the mean age, gender, or daily dose between the two groups. The incidence of peripheral neuropathy among patients receiving 25, 50, 75, or 100 mg thalidomide per day was 4.6%, 8.5%, 17.1%, 21.7%, respectively. The incidence was significantly different between the groups receiving 25 mg and 100 mg thalidomide. In conclusion, thalidomide can induce peripheral neuropathy within 1 year after treatment of ankylosing spondylitis; however, age and gender have no obvious impact on the incidence of peripheral neuropathy. The incidence of peripheral neuropathy is associated with increasing daily doses of thalidomide. PMID:26109960

Thalidomide analogue CC-3052 reduces HIV+ neutrophil apoptosis in vitro

PubMed Central

Guckian, M; Dransfield, I; Hay, P; Dalgleish, A G

2000-01-01

Thalidomide has significant immunomodulatory properties and has been used successfully in the treatment of oral ulcers and wasting in HIV patients. However, its use is limited by its poor bioavailability due to low solubility and short half life in solution, and teratogenic and neurotoxic side-effects. Recently, water-soluble analogues of thalidomide with significantly greater immunomodulatory activity and reduced side-effects have become available. We examined the effect of thalidomide and one analogue, CC-3052, on neutrophil apoptosis following culture for 20 h in vitro. Apoptosis was assessed by reduced CD16 expression and Annexin V binding using flow cytometry. Thalidomide or CC-3052 alone had no effect on neutrophil apoptosis when used at physiological levels. However, when used together with prostaglandin E2 (10−7 m), a potent adenylate cyclase activator, CC-3052 but not thalidomide (both 10−5 m) reduced apoptosis in neutrophils from normal and HIV+ donors. The reduced apoptosis could not be attributed to the ability of CC-3052 to reduce tumour necrosis factor-alpha (TNF-α) production, but may be due to its PDE4 inhibitor properties, as it increased [cAMP]i, and mimicked the effect of increasing [cAMP]i using dibutryl cAMP, a membrane-permeable analogue of cAMP. The results suggest a role for thalidomide analogue CC-3052 in reducing persistent activation of the TNF-α system in HIV without markedly impairing neutrophil viability. PMID:10971513

Protective effect of thalidomide against N-methyl-D-aspartate-induced retinal neurotoxicity.

PubMed

Takada, Kazuhide; Munemasa, Yasunari; Kuribayashi, Junko; Fujino, Hiromi; Kitaoka, Yasushi

2011-10-01

Thalidomide, an inhibitor of tumor necrosis factor-α (TNF-α) production, has been indicated to be useful for many inflammatory and oncogenic diseases. In the present study, we examined whether thalidomide (50 mg/kg/day, p.o.) has a protective effect against N-methyl-D-aspartate (NMDA)-induced retinal neurotoxicity in rats. A morphometric analysis showed that systemic administration of thalidomide protects neural cells in the ganglion cell layer (GCL) in a dose-dependent manner and significantly decreases the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells in GCL and in the inner nuclear layer (INL). ELISA showed that thalidomide significantly suppressed the elevation of TNF-α 6 and 24 hr after an NMDA injection. Western blot analysis revealed a significant increase in nuclear factor-κB (NF-κB) p65 level in the retinas treated with NMDA at 24 hr after the injection, but not at 6 or 72 hr. Furthermore, an increase in p-JNK and p-p38 levels was also observed in the retina after NMDA injection. Thalidomide suppressed the increased expressions of NF-κB p65, p-JNK, and p-p38 after NMDA injection. Immunohistochemical analysis showed that thalidomide attenuated NF-κB p65 immunoreactivity in the GCL induced by NMDA treatment. In the NMDA-treated group, translocation of NF-κB p65 from the cytoplasm to the nucleus was detected in TUNEL-positive cells exposed to NMDA treatment. These results suggest new indications for thalidomide against neurodegenerative diseases. Copyright © 2011 Wiley-Liss, Inc.

Effect of combination of thalidomide and sulfasalazine in experimentally induced inflammatory bowel disease in rats.

PubMed

Prakash, O; Medhi, B; Saikia, U N; Pandhi, P

2011-09-01

Thalidomide provided significant protection against tri nitro benzene sulfonic acid induced colitis. Combination therapy also reduced colonic inflammation and all the biochemical parameters (myeloperoxidase assay, malondialdehyde assay and tumor necrosis factor-alpha, estimation) were significant as compared to control as well as thalidomide alone treated group. Combination therapy showed additive effect of thalidomide which restored lipid peroxidation as well as reduced myeloperoxidase and TNF-a towards the normal levels. Morphological and histological scores were significantly reduced in combination groups. In experimental model of colitis, oral administration of thalidomide (150 mg/kg) alone as well as its combination with sulfasalazine (360 mg/kg) significantly reduced the colonic inflammation. The results indicate the additive effect of thalidomide with sulfasalazine in rat colitis model which requires further confirmation in human studies.

Thalidomide suppresses sclerosing encapsulating peritonitis in a rat experimental model.

PubMed

Mondello, Stefania; Mazzon, Emanuela; Di Paola, Rosanna; Crisafulli, Concetta; Mondello, Paolo; Buemi, Michele; Aloisi, Carmelo; Cuzzocrea, Salvatore

2009-09-01

Peritoneal dialysis is an alternative treatment of patients with end-stage renal disease. Sclerosing encapsulating peritonitis is a life-threatening complication of continuous ambulatory peritoneal dialysis. The aim of the present study was to evaluate the effect of thalidomide, which is used for the treatment of various inflammatory and autoimmune diseases, on the development of sclerosing encapsulating peritonitis induced by chlorhexidine gluconate (CG). A peritoneal fibrosis model was established using rats treated intraperitoneally with injections of CG. Thalidomide was administered orally at a dose of 100 mg/kg three times per week. When compared with CG-treated rats, thalidomide (100 mg/kg orally)-treated mice subjected to CG-induced peritoneal fibrosis experienced a significantly lower rate in the extent and severity of histological signs of peritoneal injury. Thalidomide also caused a substantial reduction of 1) the rise in myeloperoxidase activity (mucosa); 2) the expression in the tissue of TNF-alpha, IL-1beta, transforming growth factor-beta, and vascular endothelial growth factor; 3) the increase in staining (immunohistochemistry) for nitrotyrosine and for poly(ADP ribose), as well as 4) the nuclear factor-kappaB activation caused by CG in the peritoneum. Thus, thalidomide treatment reduces the degree of peritoneal fibrosis caused by CG. We propose that this evidence may help clarify the potential therapeutic actions of thalidomide in patients with peritoneal fibrosis.

Thalidomide distinctly affected TNF-α, IL-6 and MMP secretion by an ovarian cancer cell line (SKOV-3) and primary ovarian cancer cells.

PubMed

Piura, Benjamin; Medina, Liat; Rabinovich, Alex; Dyomin, Victor; Huleihel, Mahmoud

2013-01-01

Thalidomide inhibits TNF-α production in lipopolysaccharide-stimulated monocytes. The aim of this study was to evaluate the effect of thalidomide on TNF-α, IL-6 and MMP secretion in epithelial ovarian carcinoma cells. SKOV-3 cells and primary epithelial ovarian carcinoma cells were cultured in the presence of various concentrations of thalidomide. Cell proliferation was examined by MTT proliferation assay. TNF-α and IL-6 levels were determined in the supernatants of the cell cultures by ELISA, and MMP activity was examined by gelatin zymography. Thalidomide did not significantly affect the proliferation and growth of SKOV-3 cells. However, it decreased significantly the capacity of SKOV-3 cells and primary epithelial ovarian carcinoma cells to secrete TNF-α. Thalidomide also significantly decreased the capacity of SKOV-3 cells, but not primary epithelial ovarian carcinoma cells, to secrete MMP-9 and MMP-2. However, thalidomide did not affect IL-6 secretion in SKOV-3 cells or primary epithelial ovarian carcinoma cells. Our study suggests that thalidomide distinctly affected TNF-α, IL-6 and MMPs secretion by an ovarian carcinoma cell line (SKOV-3) and primary ovarian cancer cells. This might suggest a different susceptibility of these two types of cells to thalidomide, and/or that the mechanisms of secretion of the factors examined are differently regulated in these cells. Our results may deepen our understanding the mechanism/s of action of thalidomide in ovarian carcinoma cells. The results might have important implications in future therapeutic strategies that will incorporate thalidomide and other cytokine inhibitors in the treatment of epithelial ovarian carcinoma.

Inhibitory effects of thalidomide on bleomycin-induced pulmonary fibrosis in rats via regulation of thioredoxin reductase and inflammations.

PubMed

Dong, Xiaoying; Li, Xin; Li, Minghui; Chen, Ming; Fan, Qian; Wei, Wei

2017-01-01

In this study, the potential clinical effects of thalidomide on bleomycin-induced pulmonary fibrosis were investigated. A Sprague-Dawley rats' model of pulmonary fibrosis induced by an intratracheal instillation of bleomycin was adopted. The rats in thalidomide treated groups were intraperitoneally injected with thalidomide (10, 20, 50 mg/kg) daily for 28 days, while the rats in control and bleomycin treated groups were injected with a saline solution. The effects of thalidomide on pulmonary injury were evaluated by the lung wet/dry weight ratios, cell counts, and histopathological examination. Inflammation of lung tissues was assessed by measuring the levels of interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β in bronchoalveolar lavage fluid (BALF). Oxidative stress was evaluated by detecting the levels of reactive oxygen species (ROS), superoxide dismutase (SOD), total antioxidant capacity (T-AOC), and malondialdehyde (MDA) in lung tissue. The results indicated that thalidomide treatment remarkably attenuated bleomycin-induced pulmonary fibrosis, oxidative stress and inflammation in rats' lung. The anti-inflammatory and anti-oxidative effects of thalidomide were also found in human lung fibroblasts. Thalidomide administration significantly stimulated the activity of thioredoxin reductase, while other enzymes or proteins involved in biologic oxidation-reduction equilibrium were not affected. Our findings indicate that thalidomide-mediated suppression of fibro-proliferation may contribute to the anti-fibrotic effect against bleomycin-induced pulmonary fibrosis. The mechanisms are related to the inhibition of oxidative stress and inflammatory response. In summary, these results may provide a rationale to explore clinical application of thalidomide for the prevention of pulmonary fibrosis.

Thalidomide analogue CC1069 inhibits development of rat adjuvant arthritis

PubMed Central

Oliver, S J; Freeman, S L; Corral, L G; Ocampo, C J; Kaplan, G

1999-01-01

The cytokine tumour necrosis factor-alpha (TNF-α) has been implicated in the aetiology of rheumatoid arthritis in humans as well as of experimental arthritis in rodents. Thalidomide, and to a greater extent the new thalidomide analogue CC1069, inhibit monocyte TNF-α production both in vitro and in vivo. The aim of the present study is to establish whether these drugs block production of TNF-α as well as IL-2 by rat leucocytes and whether this inhibition affects the development of rat adjuvant arthritis (AA). Cultured splenocytes were stimulated with either lipopolysaccharide (LPS) or concanavalin A (Con A) in the presence of thalidomide, CC1069, or solvent, and the production of TNF-α and IL-2 were compared. Next, adjuvant was injected into the base of the tail of rats without or with daily intraperitoneal injections with 100–200 mg/kg per day thalidomide or 50–200 mg/kg per day CC1069. Disease activity, including ankle swelling, hind limb radiographic and histological changes, weight gain, and ankle joint cytokine mRNA levels, were monitored. CC1069, but not the parent drug thalidomide, inhibited in vitro production of TNF-α and IL-2 by stimulated splenocytes in a dose-dependent manner. In vivo, a dose-dependent suppression of AA disease activity occurred in the CC1069-treated animals. In contrast, thalidomide-treated rats experienced comparable arthritis severity to placebo-treated animals. There was also a reduction in TNF-α and IL-2 mRNA levels in the ankle joints of CC1069-treated rats compared with thalidomide- and placebo-treated arthritic rats. Early initiation of CC1069 treatment suppressed AA inflammation more efficiently than delayed treatment. We conclude that thalidomide, which did not suppress TNF-α or IL-2 production in vitro by Lewis rat cells, did not suppress development of rat AA. However, the development of rat AA can be blocked by the thalidomide analogue CC1069, which is an efficient inhibitor of TNF-α production and IL-2 in vitro. PMID:10540197

Thalidomide treatment in cutaneous lesions of systemic lupus erythematosus: a multicenter study in China.

PubMed

Wang, Dandan; Chen, Haifeng; Wang, Shiying; Zou, Yaohong; Li, Jing; Pan, Jieping; Wang, Xiangdang; Ren, Tianli; Zhang, Yu; Chen, Zhiwei; Feng, Xuebing; Sun, Lingyun

2016-06-01

Thalidomide is effective for treating severe cutaneous lupus patients. The aim of this study was to observe the optimum effective and maintenance doses of thalidomide to maximize clinical benefit and minimize side effects for patients with cutaneous lupus in China. Sixty-nine patients with lupus rash from eight hospitals in China were enrolled and treated with different doses of thalidomide. We started the dose of thalidomide at 25 mg daily and gradually increased administration dose once a week until erythema was markedly improved. The effective and maintenance doses were documented. The size of skin lesions was noted once a week. Systemic lupus erythematosus disease activity index (SLEDAI) score, levels of erythrocyte sedimentation rate (ESR), and serum TNF-α were measured before and after treatment. The remission rates were evaluated weekly until 8 weeks. Sixty-eight percent of patients showed an effective dose of 50 mg daily; another 13, 10, and 9 % of patients had an effective dose of 100, 75, and 25 mg daily, respectively. The maintenance dose was 50 mg daily for 71 % of the patients, and 100, 75, and 25 mg daily for 9, 14, and 6 % of the patients. SLEDAI score and serum ESR levels significantly decreased 4 weeks after thalidomide treatment. At the end of the fourth week, the rates of complete remission, partial remission, and no response were 56 % (n = 39), 41 % (n = 28), and 3 % (n = 2). At the eighth week, the rate of total remission rose up to 100 %. The most common side effects were drowsiness and constipation. No peripheral neuropathy was observed in these patients. Thalidomide at a dose of 50 mg daily may offer a better benefit to risk ratio in the treatment of Chinese cutaneous lupus patients.

LPS-induced knee-joint reactive arthritis and spinal cord glial activation were reduced after intrathecal thalidomide injection in rats.

PubMed

Bressan, Elisângela; Mitkovski, Mišo; Tonussi, Carlos Rogério

2010-10-09

Thalidomide is thought to prevent TNF-α production, and such mechanism could be useful in a spinally delivered drug approach for the control of peripheral inflammation. This study aimed to evaluate the effect of intrathecal thalidomide, in comparison with that of intraperitoneal treatment, on articular incapacitation, edema, synovial leukocyte content, and spinal cord glial activation in a model of Escherichia coli lipopolysaccharide (LPS)-induced reactive arthritis in rats. LPS (30ng) was injected into a knee-joint previously primed with carrageenan (300μg). Systemic (30 and 100mg/kg; intraperitoneal, i.p.) and intrathecal (10 and 100μg; i.t.) thalidomide were given 1h or 20min before LPS injection, respectively. Articular incapacitation and edema were evaluated hourly. After 6h, synovial fluid and lumbar spinal cords were collected for subsequent evaluations of cell migration and expression of CD11b/c and GFAP markers, respectively. Systemic (30 and 100mg/kg) or intrathecal (10 and 100μg) thalidomide reduced articular incapacitation, edema, and polymorphonuclear migration. In addition, i.p. and i.t. thalidomide reduced the expression of CD11b/c and GFAP markers in the lumbar spinal cord. These results suggest that thalidomide can also produce peripheral anti-inflammatory effects through action in the spinal cord that may involve glia inhibition. This study provides new evidence that the direct spinal delivery of immunomodulators may be an alternative for the treatment of arthritic diseases, which require long systemic treatment with drugs associated with undesirable side effects. Copyright © 2010 Elsevier Inc. All rights reserved.

Anti-Cancer Properties of a Novel Class of Tetrafluorinated Thalidomide Analogs

PubMed Central

Beedie, Shaunna L.; Peer, Cody J.; Pisle, Steven; Gardner, Erin R.; Mahony, Chris; Barnett, Shelby; Ambrozak, Agnieszka; Gütschow, Michael; Chau, Cindy H.; Vargesson, Neil; Figg, William D.

2015-01-01

Thalidomide has demonstrated clinical activity in various malignancies affecting immunomodulatory and angiogenesis pathways. The development of novel thalidomide analogs with improved efficacy and decreased toxicity is an ongoing research effort. We recently designed and synthesized a new class of compounds, consisting of both tetrafluorinated thalidomide analogs (Gu973 and Gu998) and tetrafluorobenzamides (Gu1029 and Gu992). In this study, we demonstrate the anti-angiogenic properties of these newly synthesized compounds. We examined the specific anti-angiogenic characteristics in vitro using rat aortic rings with carboxyamidotriazole as a positive control. Additionally, further in vitro efficacy was evaluated using HUVECs and PC3 cells treated with 5μM and 10μM doses of each compound. All compounds were seen to reduce microvessel outgrowth in rat aortic rings as well as inhibit HUVECs to a greater extent, at lower concentrations than previously tested thalidomide analogs. The anti-angiogenic properties of the compounds was also examined in vivo in fli1:EGFP zebrafish embryos, where all compounds were seen to inhibit the extent of outgrowth of newly developing blood vessels. In addition, Gu1029 and Gu973 reduced the anti-inflammatory response in mpo:GFP zebrafish embryos, while Gu998 and Gu992 showed no difference. The compounds anti-tumor effects were also explored in vivo using the human prostate cancer PC3 xenograft model. All four compounds were also screened in vivo in chicken embryos to investigate their teratogenic potential. This study establishes these novel thalidomide analogs as a promising immunomodulatory class with anti-cancer effects that warrant further development to characterize their mechanisms of action. PMID:26269604

The effect of thalidomide on vascular endothelial growth factor and tumor necrosis factor-alpha levels in retinal ischemia/reperfusion injury.

PubMed

Aydoğan, Semih; Celiker, Ulkü; Türkçüoğlu, Peykan; Ilhan, Nevin; Akpolat, Nusret

2008-03-01

To evaluate the effects of thalidomide treatment on the temporal course of TNF-alpha, VEGF production and the histopathological changes in ischemia/reperfusion (I/R) injured guinea pigs retina. Control, ischemia, and thalidomide/ischemia groups including seven animals each were formed. Retinal ischemia was induced in male guinea pigs by cannulating anterior chambers and lifting the bottle to a height of 205 cm for 90 min in the ischemia and thalidomide/ischemia groups. The thalidomide/ischemia group received thalidomide (300 mg/kg/day) via nasogastric tube 24 h before ischemia and during 7 days of reperfusion. Guinea pigs were sacrificed for histopathological examination to evaluate the mean thickness of the inner plexiform layer (IPL), polymorphonuclear leukocyte (PMNL) infiltration, and biochemical analysis of retinal VEGF and TNF-alpha levels by ELISA. The mean retinal VEGF and TNF-alpha levels of the control, ischemia, and thalidomide/ischemia groups were 10.22 +/- 2.58 and 270.41 +/- 69.77 pg/ml; 35.80 +/- 5.97 and 629.93 +/- 146.41 pg/ml; 19.01 +/- 3.01 and 340.93 +/- 158.26 pg/ml, respectively. The retinal VEGF levels were significantly higher in I/R injured groups. The thalidomide/ischemia group retinal VEGF level was significantly lower versus the ischemia group. The retinal TNF-alpha levels were significantly elevated in the ischemia group, but no difference was observed between the thalidomide/ischemia and control groups. Also, the retinal TNF-alpha level was significantly lower in the thalidomide/ischemia group versus the ischemia group. The mean thickness of IPL and PMNL infiltration showed no difference between the control and thalidomide/ischemia groups. However, there was a significant difference between the control and ischemia groups. Thalidomide treatment decreases PMNL infiltration, retinal edema, VEGF, and TNF-alpha synthesis following I/R injury to the guinea pig retina.

Protective effect of thalidomide on endotoxin-induced liver injury.

PubMed

Enomoto, Nobuyuki; Takei, Yoshiyuki; Hirose, Miyoko; Kitamura, Tsuneo; Ikejima, Kenichi; Sato, Nobuhiro

2003-08-01

Activation of Kupffer cells by lipopolysaccharide (LPS) plays a pivotal role in the onset of pathophysiological events that occur during endotoxemia, and intracellular calcium concentration ([Ca2+]i) is involved in LPS-stimulated cytokine production. Tumor necrosis factor (TNF)-alpha is produced exclusively by the monocyte-macrophage lineage, which is mostly made up of Kupffer cells, and thalidomide has been shown to reduce TNF-alpha production from macrophages. However, there is increasing evidence that TNF-alpha may play a role in the initiation or progression of multiple organ failure syndrome. Therefore, the purpose of this work was to determine whether thalidomide could prevent LPS-induced liver injury. Rats were given a single oral dose of thalidomide (5 mg/kg). To assess the sensitization of Kupffer cells, LPS (5 or 10 mg/kg) was administered intravenously, and mortality, liver histology, and transaminases were evaluated 24 hr later. Kupffer cells were isolated 2 hr after thalidomide treatment. After the addition of LPS, [Ca2+]i was measured by using a microspectrofluorometer with the fluorescent indicator fura-2, and TNF-alpha was measured by enzyme-linked immunosorbent assay. LPS caused focal necrosis with neutrophil infiltration in the liver. Moreover, LPS dramatically increased transaminases. These pathologic parameters and increases of serum transaminases were diminished markedly by thalidomide. In isolated Kupffer cells, LPS-induced increases in [Ca2+]i and TNF-alpha production were suppressed by treatment with thalidomide. To further explore the mechanism by which thalidomide directly abrogated Kupffer cell sensitivity to LPS, we determined the effect of thalidomide (5 microM) in vitro on LPS-induced [Ca2+]i response and TNF-alpha production. With the addition of thalidomide (5 microM) in vitro to the culture media for 2 hr before LPS, these parameters were suppressed. Thalidomide prevents LPS-induced liver injury via mechanisms dependent on the suppression of TNF-alpha production from Kupffer cells.

Pomalidomide is nonteratogenic in chicken and zebrafish embryos and nonneurotoxic in vitro

PubMed Central

Mahony, Chris; Erskine, Lynda; Niven, Jennifer; Greig, Nigel H.; Figg, William Douglas; Vargesson, Neil

2013-01-01

Thalidomide and its analog, Lenalidomide, are in current use clinically for treatment of multiple myeloma, complications of leprosy and cancers. An additional analog, Pomalidomide, has recently been licensed for treatment of multiple myeloma, and is purported to be clinically more potent than either Thalidomide or Lenalidomide. Using a combination of zebrafish and chicken embryos together with in vitro assays we have determined the relative anti-inflammatory activity of each compound. We demonstrate that in vivo embryonic assays Pomalidomide is a significantly more potent anti-inflammatory agent than either Thalidomide or Lenalidomide. We tested the effect of Pomalidomide and Lenalidomide on angiogenesis, teratogenesis, and neurite outgrowth, known detrimental effects of Thalidomide. We found that Pomalidomide, displays a high degree of cell specificity, and has no detectable teratogenic, antiangiogenic or neurotoxic effects at potent anti-inflammatory concentrations. This is in marked contrast to Thalidomide and Lenalidomide, which had detrimental effects on blood vessels, nerves, and embryonic development at anti-inflammatory concentrations. This work has implications for Pomalidomide as a treatment for conditions Thalidomide and Lenalidomide treat currently. PMID:23858438

A novel effect of thalidomide and its analogs: suppression of cereblon ubiquitination enhances ubiquitin ligase function

PubMed Central

Liu, Yaobin; Huang, Xiangao; He, Xian; Zhou, Yanqing; Jiang, Xiaogang; Chen-Kiang, Selina; Jaffrey, Samie R.; Xu, Guoqiang

2015-01-01

The immunomodulatory drug (IMiD) thalidomide and its structural analogs lenalidomide and pomalidomide are highly effective in treating clinical indications. Thalidomide binds to cereblon (CRBN), a substrate receptor of the cullin-4 really interesting new gene (RING) E3 ligase complex. Here, we examine the effect of thalidomide and its analogs on CRBN ubiquitination and its functions in human cell lines. We find that the ubiquitin modification of CRBN includes K48-linked polyubiquitin chains and that thalidomide blocks the formation of CRBN-ubiquitin conjugates. Furthermore, we show that ubiquitinated CRBN is targeted for proteasomal degradation. Treatment of human myeloma cell lines such as MM1.S, OPM2, and U266 with thalidomide (100 μM) and its structural analog lenalidomide (10 μM) results in stabilization of CRBN and elevation of CRBN protein levels. This in turn leads to the reduced level of CRBN target proteins and enhances the sensitivity of human multiple myeloma cells to IMiDs. Our results reveal a novel mechanism by which thalidomide and its analogs modulate the CRBN function in cells. Through inhibition of CRBN ubiquitination, thalidomide and its analogs allow CRBN to accumulate, leading to the increased cullin-4 RING E3 ligase-mediated degradation of target proteins.—Liu, Y., Huang, X., He, X., Zhou, Y., Jiang, X., Chen-Kiang, S., Jaffrey, S. R., Xu, G. A novel effect of thalidomide and its analogs: suppression of cereblon ubiquitination enhances ubiquitin ligase function. PMID:26231201

A framework to identify gene expression profiles in a model of inflammation induced by lipopolysaccharide after treatment with thalidomide

PubMed Central

2012-01-01

Background Thalidomide is an anti-inflammatory and anti-angiogenic drug currently used for the treatment of several diseases, including erythema nodosum leprosum, which occurs in patients with lepromatous leprosy. In this research, we use DNA microarray analysis to identify the impact of thalidomide on gene expression responses in human cells after lipopolysaccharide (LPS) stimulation. We employed a two-stage framework. Initially, we identified 1584 altered genes in response to LPS. Modulation of this set of genes was then analyzed in the LPS stimulated cells treated with thalidomide. Results We identified 64 genes with altered expression induced by thalidomide using the rank product method. In addition, the lists of up-regulated and down-regulated genes were investigated by means of bioinformatics functional analysis, which allowed for the identification of biological processes affected by thalidomide. Confirmatory analysis was done in five of the identified genes using real time PCR. Conclusions The results showed some genes that can further our understanding of the biological mechanisms in the action of thalidomide. Of the five genes evaluated with real time PCR, three were down regulated and two were up regulated confirming the initial results of the microarray analysis. PMID:22695124

Thalidomide Prevents the Progression of Peritoneal Fibrosis in Mice

PubMed Central

Arai, Hideyuki; Furusu, Akira; Nishino, Tomoya; Obata, Yoko; Nakazawa, Yuka; Nakazawa, Masayuki; Hirose, Misaki; Abe, Katsushige; Koji, Takehiko; Kohno, Shigeru

2011-01-01

Thalidomide is clinically recognized as a therapeutic agent for multiple myeloma and has been known to exert anti-angiogenic actions. Recent studies have suggested the involvement of angiogenesis in the progression of peritoneal fibrosis. The present study investigated the effects of thalidomide on the development of peritoneal fibrosis induced by injection of chlorhexidine gluconate (CG) into the mouse peritoneal cavity every other day for 3 weeks. Thalidomide was given orally every day. Peritoneal tissues were dissected out 21 days after CG injection. Expression of CD31 (as a marker of endothelial cells), proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor (VEGF), α-smooth muscle actin (as a marker of myofibroblasts), type III collagen and transforming growth factor (TGF)-β was examined using immunohistochemistry. CG group showed thickening of the submesothelial zone and increased numbers of vessels and myofibroblasts. Large numbers of VEGF-, PCNA-, and TGF-β-positive cells were observed in the submesothelial area. Thalidomide treatment significantly ameliorated submesothelial thickening and angiogenesis, and decreased numbers of PCNA- and VEGF-expressing cells, myofibroblasts, and TGF-β-positive cells. Moreover, thalidomide attenuated peritoneal permeability for creatinine, compared to the CG group. Our results indicate the potential utility of thalidomide for preventing peritoneal fibrosis. PMID:21614166

Thalidomide ameliorates cisplatin-induced nephrotoxicity by inhibiting renal inflammation in an experimental model.

PubMed

Amirshahrokhi, Keyvan; Khalili, Ali-Reza

2015-04-01

Cisplatin is a platinum-based chemotherapy drug. However, its chemotherapeutic use is restricted by serious side effects, especially nephrotoxicity. Inflammatory mechanisms have a significant role in the pathogenesis of cisplatin-induced nephrotoxicity. Thalidomide is an immunomodulatory and anti-inflammatory agent and is used for the treatment of various inflammatory diseases. The purpose of this study was to investigate the potential nephroprotective effect of thalidomide in a mouse model of cisplatin-induced nephrotoxicity. Nephrotoxicity was induced in mice by a single injection of cisplatin (15 mg/kg, i.p.) and treated with thalidomide (50 and 100 mg/kg/day, orally) for 4 days, beginning 24 h prior to the cisplatin injection. Renal toxicity induced by cisplatin was demonstrated by increasing plasma levels of creatinine and blood urea nitrogen (BUN). Cisplatin increased the renal production of the proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and transforming growth factor (TGF)-β1. In addition, kidney levels of malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) were increased by cisplatin. Biochemical results showed that thalidomide reduced cisplatin-induced increase in plasma creatinine and BUN. Thalidomide treatment also significantly reduced tissue levels of the proinflammatory cytokines, MDA, MPO, and NO and increased anti-inflammatory cytokine IL-10. Furthermore, histological examination indicated that thalidomide ameliorated renal damage caused by cisplatin. These data suggest that thalidomide attenuates cisplatin-induced nephrotoxicity possibly by inhibition of inflammatory reactions. Taken together, our findings indicate that thalidomide might be a valuable candidate for the prevention of nephrotoxicity in patients receiving cisplatin.

The thalidomide analog 3-phthalimido-3-(3,4-dimethoxyphenyl)-propanoic acid improves the biliary cirrhosis in the rat.

PubMed

Fernández-Martínez, Eduardo; Pérez-Hernández, Nury; Muriel, Pablo; Pérez-Alvarez, Víctor; Shibayama, Mineko; Tsutsumi, Víctor

2009-09-01

Chronic cholestasis and cholangitis may lead to the last phase known as biliary cirrhosis, characterized by cellular necrosis, apoptosis, tissue damage, local regeneration, inflammation and fibrosis. Such events are mediated by cytokines. Thalidomide and its analogs have shown to be effective immunomodulatory and hepatoprotective agents. The aim of this work was to evaluate the hepatoprotective properties of a thalidomide analog, the 3-phthalimido-3-(3,4-dimethoxyphenyl)-propanoic acid (PDA), on bile duct obstruction-induced cirrhosis. Vehicle or PDA (67 mg/kg) was orally administered twice a day to sham (Sham) or bile duct-ligated (BDL) male Wistar rats. The animals were sacrificed 28 days after treatments. Alkaline phosphatase (AP), gamma-glutamyl transpeptidase (GGTP) and alanine aminotransferase (ALT) enzyme activities as well as direct and total bilirubins concentration were determined in plasma. Lipid peroxidation (LP), glycogen and collagen were quantified in liver; in addition, histopathology was performed. PDA improved cholestasis, necrosis and fibrosis by significantly diminishing most of liver injury markers (P<0.05). Histopathology also showed remarkable liver damage amelioration. PDA effectiveness may be due to its water-solubility, stability, phosphodiesterase-4 inhibitory and immunomodulatory actions. Thalidomide and its analogs seem to be promising drugs for further treatment of biliary cirrhosis.

Thalidomide inhibits adipogenesis of orbital fibroblasts in Graves' ophthalmopathy.

PubMed

Zhang, Chu; Zhang, Xianfeng; Ma, Lizhen; Peng, Fengying; Huang, Jiao; Han, Hui

2012-04-01

The expansion of orbital adipose tissue is a main pathophysiology of Graves' ophthalmopathy (GO), which is an inflammatory autoimmune disease in the orbital region. The effects of immunosuppressive drugs on adipogenesis of orbital fibroblasts have not been determined. Thalidomide, as an immunosuppressive drug, has recently been used in the therapy of many autoimmune diseases. In this study, we analyzed the effects of thalidomide on adipogenesis and found that adipocyte differentiation from preadipocytes in the orbital region was enhanced, which was demonstrated by enhanced expression of peroxisome proliferator activated receptor γ (PPARγ), ap2, and thyroid-stimulating hormone receptor (TSHR). The expression of inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin 6 (IL-6) was also increased in GO. Thalidomide dose-dependently inhibited adipogenesis of 3T3-L1 preadipocytes and orbital fibroblasts from GO patients. Along with the inhibited adipogenesis, the expression of TSHR, TNFα, and IL-6 was also down-regulated. We discovered that the mechanism for thalidomide inhibiting adipogenesis was the down-regulation of PPARγ, rather than C/EBPβ and C/EBPδ. We suggest that, besides its canonical anti-TNFα effect, thalidomide plays a role in inhibiting adipogenesis of orbital fibroblasts in GO patients.

Thalidomide attenuates learning and memory deficits induced by intracerebroventricular administration of streptozotocin in rats.

PubMed

Elçioğlu, Hk; Kabasakal, L; Alan, S; Salva, E; Tufan, F; Karan, Ma

2013-05-01

Neuroinflammatory responses caused by amyloid β (Aβ) peptide deposits are involved in the pathogenesis of Alzheimer's disease (AD). Thalidomide has a significant anti-inflammatory effect by inhibiting TNF-α, which plays role in Aβ neurotoxicity. We investigated the effect of thalidomide on AD-like cognitive deficits caused by intracerebroventricular injection of streptozotocin (STZ). Intraperitoneal thalidomide was administered 1 h before the first dose of STZ and continued for 21 days. Learning and memory behavior was evaluated on days 17, 18 and 19, and the rats were sacrificed on day 21 to examine histopathological changes. STZ injection caused a significant decrease in the mean escape latency in passive avoidance and decreased improvement of performance in Morris water maze tests. Histopathological changes were examined using hematoxylin-eosin and Bielschowsky staining. Brain sections of STZ treated rats showed increased neurodegeneration and disturbed linear arrangement of cells in the cortical area compared to controls. Thalidomide treatment attenuated significantly STZ induced cognitive impairment and histopathological changes. Thalidomide appears to provide neuroprotection from the memory deficits and neuronal damage induced by STZ.

A combination of thalidomide and augmentin protects BALB/c mice suffering from Klebsiella pneumoniae B5055-induced sepsis.

PubMed

Kumar, V; Harjai, K; Chhibber, S

2009-04-01

Despite extensive research, the mortality associated with sepsis in hospitals remains very high. We have evaluated the protective immunomodulatory effect of thalidomide alone or with Augmentin in Klebsiella pneumoniae B5055-induced sepsis in BALB/c mice. The mouse model of sepsis was developed by placing K. pneumoniae B5055 entrapped in fibrin and thrombin clots in the peritoneal cavity of mice. The septic mice were treated with thalidomide alone (30 mg/kg/day/po), Augmentin alone (20 microg/ml/ip) and with their combination. the thalidomide-alone treated mice showed 75% survival whereas 60% of the Augmentin-alone treated group survived. Combination treatment provided 100% survival. Treatment with thalidomide alone significantly (p<0.05) decreased interleukin-1 alpha (IL-1alpha), nitric oxide (NO) and malondialdehyde (MDA) levels in the serum without significantly (p<0.05) decreasing the bacterial count in blood. Augmentin alone only decreased the bacterial load in blood significantly (p<0.05). However, a combination of thalidomide with Augmentin significantly (p<0.05) decreased both the bacterial count and inflammatory mediators.

Effect of thalidomide on clinical remission in children and adolescents with refractory Crohn disease: a randomized clinical trial.

PubMed

Lazzerini, Marzia; Martelossi, Stefano; Magazzù, Giuseppe; Pellegrino, Salvatore; Lucanto, Maria Cristina; Barabino, Arrigo; Calvi, Angela; Arrigo, Serena; Lionetti, Paolo; Lorusso, Monica; Mangiantini, Francesca; Fontana, Massimo; Zuin, Giovanna; Palla, Gabriella; Maggiore, Giuseppe; Bramuzzo, Matteo; Pellegrin, Maria Chiara; Maschio, Massimo; Villanacci, Vincenzo; Manenti, Stefania; Decorti, Giuliana; De Iudicibus, Sara; Paparazzo, Rossella; Montico, Marcella; Ventura, Alessandro

2013-11-27

Pediatric-onset Crohn disease is more aggressive than adult-onset disease, has high rates of resistance to existing drugs, and can lead to permanent impairments. Few trials have evaluated new drugs for refractory Crohn disease in children. To determine whether thalidomide is effective in inducing remission in refractory pediatric Crohn disease. Multicenter, double-blind, placebo-controlled, randomized clinical trial of 56 children with active Crohn disease despite immunosuppressive treatment, conducted August 2008-September 2012 in 6 pediatric tertiary care centers in Italy. Thalidomide, 1.5 to 2.5 mg/kg per day, or placebo once daily for 8 weeks. In an open-label extension, nonresponders to placebo received thalidomide for an additional 8 weeks. All responders continued to receive thalidomide for an additional minimum 52 weeks. Primary outcomes were clinical remission at week 8, measured by Pediatric Crohn Disease Activity Index (PCDAI) score and reduction in PCDAI by ≥25% or ≥75% at weeks 4 and 8. Primary outcomes during the open-label follow-up were clinical remission and 75% response. Twenty-eight children were randomized to thalidomide and 26 to placebo. Clinical remission was achieved by significantly more children treated with thalidomide (13/28 [46.4%] vs 3/26 [11.5%]; risk ratio [RR], 4.0 [95% CI, 1.2-12.5]; P = .01; number needed to treat [NNT], 2.86). Responses were not different at 4 weeks, but greater improvement was observed at 8 weeks in the thalidomide group (75% response, 13/28 [46.4%] vs 3/26 [11.5%]; RR, 4.0 [95% CI, 1.2-12.5]; NNT = 2.86; P = .01; and 25% response, 18/28 [64.2%] vs 8/26 [30.8%]; RR, 2.1 [95% CI, 1.1-3.9]; NNT = 2.99; P = .01). Of the nonresponders to placebo who began receiving thalidomide, 11 of 21 (52.4%) subsequently reached remission at week 8 (RR, 4.5 [95% CI, 1.4-14.1]; NNT = 2.45; P = .01). Overall, 31 of 49 children treated with thalidomide (63.3%) achieved clinical remission, and 32 of 49 (65.3%) achieved 75% response. Mean duration of clinical remission in the thalidomide group was 181.1 weeks (95% CI, 144.53-217.76) vs 6.3 weeks (95% CI, 3.51-9.15) in the placebo group (P < .001). Cumulative incidence of severe adverse events was 2.1 per 1000 patient-weeks, with peripheral neuropathy the most frequent severe adverse event. In children and adolescents with refractory Crohn disease, thalidomide compared with placebo resulted in improved clinical remission at 8 weeks of treatment and longer-term maintenance of remission in an open-label follow-up. These findings require replication to definitively determine clinical utility of this treatment. clinicaltrials.gov Identifier: NCT00720538.

Anti-inflammatory effect of thalidomide alone or in combination with augmentin in Klebsiella pneumoniae B5055 induced acute lung infection in BALB/c mice.

PubMed

Kumar, Vijay; Chhibber, Sanjay

2008-09-11

Thalidomide (alpha-naphtylimidoglutarimide), a psychoactive drug that readily crosses blood-brain barrier, has been shown to exhibit anti-inflammatory, anti-angiogenic, immunomodulatory properties through a mechanism that is not fully established. Keeping these properties in mind, we tried to find out the anti-inflammatory properties of thalidomide in mouse model of acute inflammation by introducing K. pneumoniae B5055 in BALB/c mice via intranasal route. The intranasal instillation of bacteria in this mouse model of acute pneumonia induced inflammation accompanied with significant increase in neutrophil infiltration in the lungs and also increased production of mediators of inflammation (i.e. malondialdehyde, myeloperoxidase and nitric oxide) in the lung tissue. The animals, which received thalidomide alone orally or in combination with augmentin, 30 min prior to bacterial instillation into the lungs via intranasal route, showed significant (P<0.05) decrease in neutrophil influx into the lungs and there was significant (P<0.05) decrease in the production of malondialdehyde, nitric oxide and myeloperoxidase activity. But the augmentin treatment alone did not decrease the malondialdehyde, myeloperoxidase and nitric oxide significantly (P>0.05) as compared to the control group. We therefore conclude that thalidomide ameliorates lung inflammation induced by K. pneumoniae B5055 without significantly (P<0.05) decreasing the bacterial load in the lung tissue whereas augmentin takes care of bacterial proliferation. Hence, it can be used as an adjunct therapy along with antibiotics as an anti-inflammatory or an immunomodulatory agent in case of acute lung infection.

A Phase III Study of Conventional Radiation Therapy Plus Thalidomide Versus Conventional Radiation Therapy for Multiple Brain Metastases (RTOG 0118)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Knisely, Jonathan P.S.; Berkey, Brian; Chakravarti, Arnab

2008-05-01

Purpose: To compare whole-brain radiation therapy (WBRT) with WBRT combined with thalidomide for patients with brain metastases not amenable to resection or radiosurgery. Patients and Methods: Patients with Zubrod performance status 0-1, MRI-documented multiple (>3), large (>4 cm), or midbrain brain metastases arising from a histopathologically confirmed extracranial primary tumor, and an anticipated survival of >8 weeks were randomized to receive WBRT to a dose of 37.5 Gy in 15 fractions with or without thalidomide during and after WBRT. Prerandomization stratification used Radiation Therapy Oncology Group (RTOG) Recursive Partitioning Analysis (RPA) Class and whether post-WBRT chemotherapy was planned. Endpoints includedmore » overall survival, progression-free survival, time to neurocognitive progression, the cause of death, toxicities, and quality of life. A protocol-planned interim analysis documented that the trial had an extremely low probability of ever showing a significant difference favoring the thalidomide arm given the results at the time of the analysis, and it was therefore closed on the basis of predefined statistical guidelines. Results: Enrolled in the study were 332 patients. Of 183 accrued patients, 93 were randomized to receive WBRT alone and 90 to WBRT and thalidomide. Median survival was 3.9 months for both arms. No novel toxicities were seen, but thalidomide was not well tolerated in this population. Forty-eight percent of patients discontinued thalidomide because of side effects. Conclusion: Thalidomide provided no survival benefit for patients with multiple, large, or midbrain metastases when combined with WBRT; nearly half the patients discontinued thalidomide due to side effects.« less

Effect of dipyrone and thalidomide alone and in combination on STZ-induced diabetic neuropathic pain.

PubMed

Chauhan, Neha; Taliyan, Rajeev; Sharma, Pyare Lal

2012-05-01

Diabetic neuropathy is recognized as one of the most common complications of chronic diabetes, but its pathophysiological mechanism is complex and yet to be completely explored. Monotherapy with conventional analgesics fails to provide adequate pain relief in peripheral diabetic neuropathy. There are a number of evidence suggesting that tumor necrosis factor (TNF-α) plays an important role in the pathogenesis of peripheral diabetic neuropathy. TNF-α up-regulation activates nuclear factor κB, which further up-regulates cyclooxygenase (COX)-2 leading to altered prostaglandin profile. Inhibition of TNF-α and COX-2 provides beneficial effect on diabetic neuropathy by decreasing the oxidative stress level and by preventing neuronal hypersensitivity due to an increased prostaglandin level. The present study was designed to assess the effect of dipyrone and thalidomide on streptozotocin (STZ)-induced neuropathic pain behavior in rats. STZ 50 mg/kg, i.p. was administered to induce experimental diabetes in the rats. Three weeks following STZ, dipyrone (300 and 600 mg/kg, i.p.) and thalidomide (25 and 50 mg/kg, i.p.) alone and subeffective dose combination of dipyrone and thalidomide (300 and 25 mg/kg(-1), i.p.) administered daily for 2 weeks significantly attenuated thermal hyperalgesia, mechanical allodynia, and formalin-induced phase-2 flinching response. Moreover, the subeffective dose combination of dipyrone and thalidomide and preemptive treatment with thalidomide (50 mg/kg) reduces oxidative stress in diabetic rats. In conclusion, the combination of subeffective dose of dipyrone and thalidomide prevented the development and maintenance of experimental diabetic neuropathy. The combination of thalidomide (TNF-α inhibitor) and dipyrone (COX inhibitor) may be used as a potential therapeutic agent for the treatment of diabetic neuropathy.

Thalidomide plus oral melphalan compared with thalidomide alone for advanced multiple myeloma.

PubMed

Offidani, Massimo; Corvatta, Laura; Marconi, Monica; Olivieri, Attilio; Catarini, Massimo; Mele, Anna; Brunori, Marino; Candela, Marco; Malerba, Lara; Capelli, Debora; Montanari, Mauro; Leoni, Pietro

2004-01-01

Thalidomide, the prototype of a new class of agents active against multiple myeloma (MM), exerts synergistic/additive effects when combined with other drugs. The aim of this study was to compare the toxicity and efficacy of thalidomide alone and in combination with oral melphalan. Patients with advanced MM received 100 mg/day oral thalidomide escalated weekly up to 600 mg/day (n=23; T group), alone or with 0.20 oral mg/kg/die melphalan administered monthly for four consecutive days (n=27; TM group). A>/=50% paraprotein reduction was observed in 59% of TM compared with 26% of T patients (P=0.009); three TM patients were found to have an absence of paraprotein by immunofixation. After a median follow-up of 13 months (range 6-32), progression-free survival (PFS) at 2 years was significantly longer in the TM group (61 versus 45%; P=0.0376), whereas overall survival did not differ significantly. Toxicity was not significantly greater with the combination therapy; although DVT was more frequent (11 versus 4%), as was grade 3 leukopenia (30 versus 13%; P=0.073), there were no cases of severe infection. Thalidomide administered with oral melphalan improved response rates and PFS in patients with advanced MM without significantly increasing severe toxicity.

Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma

PubMed Central

Zhu, Yuan Xiao; Kortuem, K. Martin; Stewart, A. Keith

2014-01-01

Although several mechanisms have been proposed to explain the activity of thalidomide, lenalidomide and pomalidomide in multiple myeloma (MM), including demonstrable anti-angiogenic, anti-proliferative and immunomodulatory effects, the precise cellular targets and molecular mechanisms have only recently become clear. A landmark study recently identified cereblon (CRBN) as a primary target of thalidomide teratogenicity. Subsequently it was demonstrated that CRBN is also required for the anti-myeloma activity of thalidomide and related drugs, the so-called immune-modulatory drugs (IMiDs). Low CRBN expression was found to correlate with drug resistance in MM cell lines and primary MM cells. One of the downstream targets of CRBN identified is interferon regulatory factor 4 (IRF4), which is critical for myeloma cell survival and is down-regulated by IMiD treatment. CRBN is also implicated in several effects of IMiDs, such as down-regulation of tumor necrosis factor-α (TNF-α) and T cell immunomodulatory activity, demonstrating that the pleotropic actions of the IMiDs are initiated by binding to CRBN. Future dissection of CRBN downstream signaling will help to delineate the underlying mechanisms for IMiD action and eventually lead to development of new drugs with more specific anti-myeloma activities. It may also provide a biomarker to predict IMiD response and resistance. PMID:22966948

Effect of thalidomide and pentoxifylline on experimental autoimmune encephalomyelitis (EAE).

PubMed

Corrêa, José Otávio do Amaral; Aarestrup, Beatriz Julião Vieira; Aarestrup, Fernando Monteiro

2010-11-01

Autoimmune encephalomyelitis (EAE) in Lewis rats is a classical experimental model of demyelinating inflammatory disease of the central nervous system. EAE is widely accepted for study of immune-inflammatory mechanisms in the CNS related to multiple sclerosis (MS) due to similar clinical evolution. In the present study we investigated the effects of Thalidomide and pentoxifylline during EAE development in Lewis rats. EAE was induced in Lewis rats and treatment with Thalidomide or pentoxifylline was performed. Clinical evaluation was carried out daily. Histopathological analysis of the brain tissue and spinal cord was performed. Griess method was used for determination of NO serum levels. TNF-alpha and IFN-gamma serum levels were investigated using ELISA method. Thalidomide and pentoxifylline treatment is associated with significant reduction of neuroinflammation in CNS. Serum levels of NO, IFN-gamma and TNF-alpha showed a marked reduction. Such findings were correlated with improvement of clinical symptoms, particularly in thalidomide treated rats. Taken together the data suggested that thalidomide and pentoxifylline may be therapeutic options for the treatment of MS, however further experiments must be performed to investigate this hypothesis. Copyright © 2010 Elsevier Inc. All rights reserved.

Thalidomide–A Notorious Sedative to a Wonder Anticancer Drug

PubMed Central

Zhou, Shuang; Wang, Fengfei; Hsieh, Tze-Chen; Wu, Joseph M.; Wu, Erxi

2014-01-01

In the past 50 years, thalidomide has undergone a remarkable metamorphosis from a notorious drug inducing birth defects into a highly effective therapy for treating leprosy and multiple myeloma. Today, most notably, thalidomide and its analogs have shown efficacy against a wide variety of diseases, including inflammation and cancer. The mechanism underlying its teratogenicity as well as its anticancer activities has been intensively studied. This review summarizes the biological effects and therapeutic uses of thalidomide and its analogs, and the underlying mechanisms of thalidomide’s action with a focus on its suppression of tumor growth. PMID:23931282

Activity of thalidomide and capecitabine in patients with advanced hepatocellular carcinoma.

PubMed

Ang, Soo-Fan; Tan, Sze-Huey; Toh, Han-Chong; Poon, Donald Y H; Ong, Simon Y K; Foo, Kian-Fong; Choo, Su-Pin

2012-06-01

Thalidomide has shown modest activity in advanced hepatocellular carcinomas (HCCs). Single-agent capecitabine has also been used in patients with HCC, with objective responses being reported. In our study, we review the use of thalidomide and capecitabine combination in advanced HCC. From November 2003 and September 2008, 42 patients with advanced HCC who were not eligible for clinical trial or conventional chemotherapy were treated with oral capecitabine (2000 mg/m/d) for 14 days every 3 weeks and oral thalidomide at the doses of 50 to 200 mg/d. Almost 50% of patients had Child-Pugh B or C liver cirrhosis and a history of regional or systemic therapy. Three patients achieved complete responses lasting more than 52 weeks, including 1 patient who achieved pathological complete response and underwent curative resection. There were 3 patients with partial responses and 13 with stable disease. Median overall survival of all 42 patients was 9.9 months. The median progression-free survival was 5.1 months. The presence of ascites, portal vein thrombosis, and poorer Child-Pugh liver cirrhosis status also resulted in significantly poorer survival outcome. Treatment was well tolerated. Fatigue was the most common side effect occurring in 16 (38%) patients, but only 1 patient had grade 3 toxicity and had to stop treatment. Two other patients developed grade 3 palmar-plantar erythrodysesthesia from capecitabine. The combination of thalidomide and capecitabine has activity in advanced HCC and can result in complete pathological response. Treatment is well tolerated even in less-fit patients who have been pretreated and deserve further study.

Melphalan, prednisone, thalidomide and defibrotide in relapsed/refractory multiple myeloma: results of a multicenter phase I/II trial.

PubMed

Palumbo, Antonio; Larocca, Alessandra; Genuardi, Mariella; Kotwica, Katarzyna; Gay, Francesca; Rossi, Davide; Benevolo, Giulia; Magarotto, Valeria; Cavallo, Federica; Bringhen, Sara; Rus, Cecilia; Masini, Luciano; Iacobelli, Massimo; Gaidano, Gianluca; Mitsiades, Constantine; Anderson, Kenneth; Boccadoro, Mario; Richardson, Paul

2010-07-01

Defibrotide is a novel orally bioavailable polydisperse oligonucleotide with anti-thrombotic and anti-adhesive effects. In SCID/NOD mice, defibrotide showed activity in human myeloma xenografts. This phase I/II study was conducted to identify the most appropriate dose of defibrotide in combination with melphalan, prednisone and thalidomide in patients with relapsed and relapsed/refractory multiple myeloma, and to determine its safety and tolerability as part of this regimen. This was a phase I/II, multicenter, dose-escalating, non-comparative, open label study. Oral melphalan was administered at a dose of 0.25 mg/kg on days 1-4, prednisone at a dose of 1.5 mg/kg also on days 1-4 and thalidomide at a dose of 50-100 mg/day continuously. Defibrotide was administered orally at three dose-levels: 2.4, 4.8 or 7.2 g on days 1-4 and 1.6, 3.2, or 4.8 g on days 5-35. Twenty-four patients with relapsed/refractory multiple myeloma were enrolled. No dose-limiting toxicity was observed. In all patients, the complete response plus very good partial response rate was 9%, and the partial response rate was 43%. The 1-year progression-free survival and 1-year overall survival rates were 34% and 90%, respectively. The most frequent grade 3-4 adverse events included neutropenia, thrombocytopenia, anemia and fatigue. Deep vein thrombosis was reported in only one patient. This combination of melphalan, prednisone and thalidomide together with defibrotide showed anti-tumor activity with a favorable tolerability. The maximum tolerated dose of defibrotide was identified as 7.2 g p.o. on days 1-4 followed by 4.8 g p.o. on days 5-35. Further trials are needed to confirm the role of this regimen and to evaluate the combination of defibrotide with new drugs.

Melphalan, prednisone, thalidomide and defibrotide in relapsed/refractory multiple myeloma: results of a multicenter phase I/II trial

PubMed Central

Palumbo, Antonio; Larocca, Alessandra; Genuardi, Mariella; Kotwica, Katarzyna; Gay, Francesca; Rossi, Davide; Benevolo, Giulia; Magarotto, Valeria; Cavallo, Federica; Bringhen, Sara; Rus, Cecilia; Masini, Luciano; Iacobelli, Massimo; Gaidano, Gianluca; Mitsiades, Constantine; Anderson, Kenneth; Boccadoro, Mario; Richardson, Paul

2010-01-01

Background Defibrotide is a novel orally bioavailable polydisperse oligonucleotide with anti-thrombotic and anti-adhesive effects. In SCID/NOD mice, defibrotide showed activity in human myeloma xenografts. This phase I/II study was conducted to identify the most appropriate dose of defibrotide in combination with melphalan, prednisone and thalidomide in patients with relapsed and relapsed/refractory multiple myeloma, and to determine its safety and tolerability as part of this regimen. Design and Methods This was a phase I/II, multicenter, dose-escalating, non-comparative, open label study. Oral melphalan was administered at a dose of 0.25 mg/kg on days 1–4, prednisone at a dose of 1.5 mg/kg also on days 1–4 and thalidomide at a dose of 50–100 mg/day continuously. Defibrotide was administered orally at three dose-levels: 2.4, 4.8 or 7.2 g on days 1–4 and 1.6, 3.2, or 4.8 g on days 5–35. Results Twenty-four patients with relapsed/refractory multiple myeloma were enrolled. No dose-limiting toxicity was observed. In all patients, the complete response plus very good partial response rate was 9%, and the partial response rate was 43%. The 1-year progression-free survival and 1-year overall survival rates were 34% and 90%, respectively. The most frequent grade 3–4 adverse events included neutropenia, thrombocytopenia, anemia and fatigue. Deep vein thrombosis was reported in only one patient. Conclusions This combination of melphalan, prednisone and thalidomide together with defibrotide showed anti-tumor activity with a favorable tolerability. The maximum tolerated dose of defibrotide was identified as 7.2 g p.o. on days 1–4 followed by 4.8 g p.o. on days 5–35. Further trials are needed to confirm the role of this regimen and to evaluate the combination of defibrotide with new drugs (ClinicalTrials.gov Identifier: NCT00406978). PMID:20053869

Effects of thalidomide, cytochrome P-450 and TNF-alpha on angiogenesis in a three-dimensional collagen gel-culture.

PubMed

Fujita, Keiko; Asami, Yoshiko; Murata, Eiko; Akita, Masumi; Kaneko, Katsuji

2002-10-01

The anti-angiogenic effects of thalidomide were examined in mouse aortae grown in a three-dimensional collagen gel-culture. In our in vitro model, (+/-)-thalidomide and (-)-thalidomide exhibited no anti-angiogenic effects. On the other hand, when the culture was treated with thalidomide plus cytochrome P-450, both types of thalidomides significantly inhibited angiogenesis. Co-administration of 100 microg/ml thalidomide plus 200 microg/ml cytochrome P-450 inhibited angiogenesis more strongly than thalidomide plus cytochrome P-450 at other concentrations (10 microg/ml + 200 microg/ml and 100 microg/ml + 20 microg/ml). To study the relation between the anti-angiogenic effect and TNF-alpha, we also evaluated the concentration of TNF-alpha in the culture medium. We found that the concentration of TNF-alpha was correlated to the strength of the anti-angiogenic effect. The inhibition of angiogenesis by thalidomide and cytochrome P-450 takes place through a suppression of TNF-alpha and involves the metabolism of the thalidomide.

Effect of thalidomide on signal transduction pathways and secondary damage in experimental spinal cord trauma.

PubMed

Genovese, Tiziana; Mazzon, Emanuela; Esposito, Emanuela; Di Paola, Rosanna; Caminiti, Rocco; Meli, Rosaria; Bramanti, Placido; Cuzzocrea, Salvatore

2008-09-01

TNF-alpha seems to play a central role in the inflammatory process of spinal cord injury. We tested the neuroprotective effects of thalidomide, an immunomodulatory agent that inhibits TNF-alpha production, which have not been investigated so far. The aim of our study was to evaluate the therapeutic efficacy of thalidomide in an experimental model of spinal cord trauma, which was induced by the application of vascular clips (force of 24 g) to the dura via a 4-level T5 to T8 laminectomy. Spinal cord injury in mice resulted in severe trauma characterized by edema, neutrophil infiltration, and cytokine production that is followed by recruitment of other inflammatory cells, production of a range of inflammation mediators, tissue damage, apoptosis, and disease. Thalidomide treatment significantly reduced the degree of: 1) spinal cord inflammation and tissue injury (histological score); 2) neutrophil infiltration (myeloperoxidase evaluation); 3) iNOS, nitrotyrosine, lipid peroxidation, and cytokine expression (TNF-alpha and IL-1beta); 4) apoptosis (terminal deoxynucleotidyltransferase-mediated UTP end labeling staining, and Bax and Bcl-2 expression); and 5) nuclear factor-kappaB activation. In a separate set of experiments, we have also clearly demonstrated that thalidomide significantly ameliorated the recovery of limb function (evaluated by motor recovery score). Taken together, our results clearly demonstrate that treatment with thalidomide reduces the development of inflammation and tissue injury events associated with spinal cord trauma.

CC-10004 but not thalidomide or lenalidomide inhibits lamina propria mononuclear cell TNF-α and MMP-3 production in patients with inflammatory bowel disease.

PubMed

Gordon, J N; Prothero, J D; Thornton, C A; Pickard, K M; Di Sabatino, A; Goggin, P M; Pender, S L; Macdonald, T T

2009-09-01

Thalidomide, one of whose activities is to inhibit Tumour Necrosis Factor (TNF)-α production, has been reported to be an effective treatment for refractory inflammatory bowel disease (IBD). TNF-α driven production of matrix metalloproteinase (MMP)-3 by gut lamina propria mononuclear cells (LPMCs) is a major pathway of tissue injury in IBD; however the effect of thalidomide and newer more potent immunomodulatory derivatives on this pathway has not been studied. To investigate the effect of thalidomide, CC-4047 (pomalidomide), CC-5013 (lenalidomide), and CC-10004 (apremilast) on gut LPMC TNFα and MMP-3 production in patients with IBD. Gut LPMCs and myofibroblasts were isolated from patients with IBD, and cultured with thalidomide, CC-4047, CC-5013, and CC-10004. MMP-3 and TIMP-1 levels were determined by western blotting and real-time PCR, and TNF-α levels by ELISA. CC-10004 significantly reduced both TNF-α production and MMP-3 production by cultured LPMCs. Thalidomide and CC-4047 and CC-5013 had no significant effect on the production of TNF-α or MMP-3 by LPMCs. These results provides a mechanistic rationale for both the failure of lenalidomide (CC-5013) in a recent randomised controlled trial in Crohn's disease, and for the evaluation of CC-10004 as a novel oral therapy in the treatment of CD and UC.

The Molecular Mechanisms of Thalidomide Teratogenicity and Implications for Modern Medicine.

PubMed

Knobloch, J; Jungck, D; Koch, A

2017-01-01

Thalidomide is a teratogen that affects many organs but primarily induces limb truncations like phocomelia. Rodents are thalidomide resistant. In the 1950s, this has led to misinterpretations of animal tests and to the fatal assumption that the drug was safe for pregnant women to use against morning sickness. The result was one of the biggest scandals in medical history: 10.000 and more infants with birth defects in Europe. Nonetheless, thalidomide still has its place in modern medicine as it has strong therapeutic potential: it has been approved by the FDA for multiple myeloma and erythema nodosum leprosum, and its anti-inflammatory, immunomodulatory and antiangiogenic activities are considered in many other refractory diseases. The aim is to develop derivatives that are not teratogenic but maintain the therapeutic potential. This requires detailed knowledge about the underlying molecular mechanisms. Much progress has been made in deciphering the teratogenic mechanisms in the last decade. Here, we summarize these mechanisms, explain thalidomide resistance of rodents, and discuss possible mechanisms that could explain why the drug primarily targets the developing limb in the embryo. We also summarize the most important therapeutic mechanisms. Finally, we discuss which therapeutic and teratogenic mechanisms do and do not overlap, and if there is a chance for the development of non-teratogenic thalidomide derivatives with therapeutic potential. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Therapeutic potential of thalidomide for gemcitabine-resistant bladder cancer.

PubMed

Huang, Yen Ta; Cheng, Chuan Chu; Chiu, Ted H; Lai, Pei Chun

2015-11-01

Controversial effects of thalidomide for solid malignancies have been reported. In the present study, we evaluate the effects of thalidomide for transitional cell carcinoma (TCC), the most common type of bladder cancer. Thalidomide precipitates were observed when its DMSO solution was added to the culture medium. No precipitation was found when thalidomide was dissolved in 45% γ-cyclodextrin, and this concentration of γ-cyclodextrin elicited slight cytotoxicity on TCC BFTC905 and primary human urothelial cells. Thalidomide-γ-cyclodextrin complex exerted a concentration-dependent cytotoxicity in TCC cells, but was relatively less cytotoxic (with IC50 of 200 µM) in BFTC905 cells than the other 3 TCC cell lines, possibly due to upregulation of Bcl-xL and HIF-1α mediated carbonic anhydrase IX, and promotion of quiescence. Gemcitabine-resistant BFTC905 cells were chosen for additional experiments. Thalidomide induced apoptosis through downregulation of survivin and securin. The secretion of VEGF and TNF-α was ameliorated by thalidomide, but they did not affect cell proliferation. Immune-modulating lenalidomide and pomalidomide did not elicit cytotoxicity. In addition, cereblon did not play a role in the thalidomide effect. Oxidative DNA damage was triggered by thalidomide, and anti-oxidants reversed the effect. Thalidomide also inhibited TNF-α induced invasion through inhibition of NF-κB, and downregulation of effectors, ICAM-1 and MMP-9. Thalidomide inhibited the growth of BFTC905 xenograft tumors in SCID mice via induction of DNA damage and suppression of angiogenesis. Higher average body weight, indicating less chachexia, was observed in thalidomide treated group. Sedative effect was observed within one-week of treatment. These pre-clinical results suggest therapeutic potential of thalidomide for gemcitabine-resistant bladder cancer.

History, heresy and radiology in scientific discovery.

PubMed

McCredie, J

2009-10-01

Nowadays, most drugs reach the market after research has established their pharmacology, safety and efficacy. That was not always the case 50 years ago. Thalidomide was used before its target cell or mode of action were known. Commencing with the thalidomide catastrophe--an epidemic of gross birth defects (1958-1962)--thalidomide's origins are revisited to show how this drug came to be made and sold in the 1950s. Thalidomide intersected with Australian radiology in the 1970s. The site and mode of action of the drug was deduced from X-rays of thalidomide-induced bone defects, which have classical radiological signs of sensory neuropathic osteoarthropathy. The longitudinal reduction deformities follow the distribution of segmental sensory innervation of the limb skeleton, indicating neural crest as the target organ. Injury to one level of neural crest halts normal neurotrophism and deletes the dependent segment--a previously unrecognised embryonic mechanism that explains most non-genetic birth defects. The final common pathway is neural crest injury and failure of normal neurotrophism to result in longitudinal reduction deformities, for example, phocomelia.

Thalidomide induces apoptosis in undifferentiated human induced pluripotent stem cells.

PubMed

Tachikawa, Saoko; Nishimura, Toshinobu; Nakauchi, Hiromitsu; Ohnuma, Kiyoshi

2017-10-01

Thalidomide, which was formerly available commercially to control the symptoms of morning sickness, is a strong teratogen that causes fetal abnormalities. However, the mechanism of thalidomide teratogenicity is not fully understood; thalidomide toxicity is not apparent in rodents, and the use of human embryos is ethically and technically untenable. In this study, we designed an experimental system featuring human-induced pluripotent stem cells (hiPSCs) to investigate the effects of thalidomide. These cells exhibit the same characteristics as those of epiblasts originating from implanted fertilized ova, which give rise to the fetus. Therefore, theoretically, thalidomide exposure during hiPSC differentiation is equivalent to that in the human fetus. We examined the effects of thalidomide on undifferentiated hiPSCs and early-differentiated hiPSCs cultured in media containing bone morphogenetic protein-4, which correspond, respectively, to epiblast (future fetus) and trophoblast (future extra-embryonic tissue). We found that only the number of undifferentiated cells was reduced. In undifferentiated cells, application of thalidomide increased the number of apoptotic and dead cells at day 2 but not day 4. Application of thalidomide did not affect the cell cycle. Furthermore, immunostaining and flow cytometric analysis revealed that thalidomide exposure had no effect on the expression of specific markers of undifferentiated and early trophectodermal differentiated cells. These results suggest that the effect of thalidomide was successfully detected in our experimental system and that thalidomide eliminated a subpopulation of undifferentiated hiPSCs. This study may help to elucidate the mechanisms underlying thalidomide teratogenicity and reveal potential strategies for safely prescribing this drug to pregnant women.

Depressive-like behaviour induced by an intracerebroventricular injection of streptozotocin in mice: the protective effect of fluoxetine, antitumour necrosis factor-α and thalidomide therapies.

PubMed

Souza, Leandro C; Filho, Carlos B; Fabbro, Lucian D; de Gomes, Marcelo G; Goes, André T R; Jesse, Cristiano R

2013-04-01

Information on the effect of an intracerebroventricular (i.c.v.) injection of streptozotocin (STZ) on noncognitive behaviour in rodents such as depression states is scarce. Thus, the aim of this study was to examine the depressive-like effect of STZ injected by the i.c.v. route in mice and the potential protective effect of fluoxetine, antitumour necrosis factor-α (anti-TNF-α) and thalidomide. Our results indicated that a single injection of STZ (0.1 mg/site) promoted depressive-like behaviour in the tail suspension and sucrose preference tests without altering either locomotor activity or plasma glucose levels. We also showed that STZ increased TNF-α levels in the hippocampus of mice. Fluoxetine (32 mg/kg, intraperitoneally. 30 min before STZ injection), and the anti-TNF-α antibody (0.1 pg/site, i.c.v.) and thalidomide (3 mg/kg, subcutaneously), coadministered with STZ, prevented these effects. This is the first study to report depressive-like effects of STZ using the i.c.v. route in mice. We concluded that fluoxetine, anti-TNF-α antibody and thalidomide were effective in preventing depressive-like behaviour and the increase in TNF-α levels in the hippocampus of mice induced by an i.c.v. injection of STZ, reinforcing the involvement of TNF-α in the pathophysiology of depression. This model and the mechanisms studied may contribute towards the development of new antidepressant drugs and enhance the options for studying depression.

In vivo screening and discovery of novel candidate thalidomide analogs in the zebrafish embryo and chicken embryo model systems

PubMed Central

Beedie, Shaunna L.; Rore, Holly M.; Barnett, Shelby; Chau, Cindy H.; Luo, Weiming; Greig, Nigel H.; Figg, William D.; Vargesson, Neil

2016-01-01

Thalidomide, a drug known for its teratogenic side-effects, is used successfully to treat a variety of clinical conditions including leprosy and multiple myeloma. Intense efforts are underway to synthesize and identify safer, clinically relevant analogs. Here, we conduct a preliminary in vivo screen of a library of new thalidomide analogs to determine which agents demonstrate activity, and describe a cohort of compounds with anti-angiogenic properties, anti-inflammatory properties and some compounds which exhibited both. The combination of the in vivo zebrafish and chicken embryo model systems allows for the accelerated discovery of new, potential therapies for cancerous and inflammatory conditions. PMID:27120781

New Findings in eNOS gene and Thalidomide Embryopathy Suggest pre-transcriptional effect variants as susceptibility factors

PubMed Central

Kowalski, Thayne Woycinck; Fraga, Lucas Rosa; Tovo-Rodrigues, Luciana; Sanseverino, Maria Teresa Vieira; Hutz, Mara Helena; Schuler-Faccini, Lavínia; Vianna, Fernanda Sales Luiz

2016-01-01

Antiangiogenic properties of thalidomide have created an interest in the use of the drug in treatment of cancer. However, thalidomide is responsible for thalidomide embryopathy (TE). A lack of knowledge regarding the mechanisms of thalidomide teratogenesis acts as a barrier in the aim to synthesize a safer analogue of thalidomide. Recently, our group detected a higher frequency of alleles that impair the pro-angiogenic mechanisms of endothelial nitric oxide synthase (eNOS), coded by the NOS3 gene. In this study we evaluated variable number tandem repeats (VNTR) functional polymorphism in intron 4 of NOS3 in individuals with TE (38) and Brazilians without congenital anomalies (136). Haplotypes were estimated for this VNTR with previously analyzed polymorphisms, rs2070744 (−786C > T) and rs1799983 (894T > G), in promoter region and exon 7, respectively. Haplotypic distribution was different between the groups (p = 0.007). Alleles −786C (rs2070744) and 4b (VNTR), associated with decreased NOS3 expression, presented in higher frequency in TE individuals (p = 0.018; OR = 2.57; IC = 1.2–5.8). This association was not identified with polymorphism 894T > G (p = 0.079), which influences eNOS enzymatic activity. These results suggest variants in NOS3, with pre-transcriptional effects as susceptibility factors, influencing the risk TE development. This finding generates insight for a new approach to research that pursues a safer analogue. PMID:27004986

Thalidomide in rat liver cirrhosis: blockade of tumor necrosis factor-alpha via inhibition of degradation of an inhibitor of nuclear factor-kappaB.

PubMed

Paul, Shelley Chireyath; Lv, Peng; Xiao, Yan-Jv; An, Ping; Liu, Shi-Quan; Luo, He-Sheng

2006-01-01

Thalidomide inhibited tumor necrosis factor-alpha (TNF-alpha) effectively in many trials. The aim of this study was to investigate the effect of thalidomide on the expression of nuclear factor-kappaB (NF-kappaB), inhibitor of NF-kappaB (IkappaB) and TNF-alpha in a rat model of liver cirrhosis. Liver cirrhosis was achieved by intraperitoneal injection of carbon tetrachloride thrice weekly, and thalidomide (10 or 100 mg/kg/day) was given daily by intragastric route for 8 weeks. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), prealbumin (PA), hyaluronic acid (HA) and laminin (LN), and hydroxyproline (HYP), NF-kappaBp65, alpha-smooth muscle actin (alpha-SMA) protein and TNF-alpha mRNA were studied in the liver, IkappaBalpha and TNF-alpha protein in the cytoplasm and NF-kappaBp65 protein in the nucleus. Compared with nontreated cirrhotic rats, the histopathology of rats given thalidomide (100 mg/kg) was significantly better. Serum ALT, AST, HA and LN and HYP content in the liver were significantly decreased and PA was elevated (p < 0.01) in this group; the expression of TNF-alpha mRNA and protein, NF-kappaBp65 and alpha-SMA were significantly decreased and IkappaBalpha protein was also elevated (p < 0.01). Thalidomide downregulates NF-kappaB-induced TNF-alpha and activates hepatic stellate cells (HSC) via inhibition of IkappaB degradation to prevent liver cirrhosis. Copyright 2006 S. Karger AG, Basel.

Stabilization of a progressive hemangioblastoma under treatment with thalidomide.

PubMed

Piribauer, Maria; Czech, Thomas; Dieckmann, Karin; Birner, Peter; Hainfellner, Johannes A; Prayer, Daniela; Fazeny-Dörner, Barbara; Weinländer, Georg; Marosi, Christine

2004-02-01

After the second recurrence of spinal seeding in hemangioblastoma not associated to von-Hippel-Lindau disease, we treated an adult female patient with thalidomide 200 mg orally/day at night for longer than 1 year. The patient reported subjective relief of symptoms after 1 month. Magnetic resonance imaging (MRI) controls 1,6 and 11 months after begin of thalidomide treatment did not show further tumor progression. She remained wheelchair-bound, but mobility of her arms continuously improved. There was no thalidomide associated side-effect in this patient until her death from pneumonia due to legionnaire's disease. Antiangiogenic treatment with interferon (IFN) alpha-2a and IFN alpha-2b and with SU 5416 has been reported to be effective and well tolerated in several patients with previously progressive angioblastomas and hemangioblastomas. This case adds further evidence of the efficacy of an antiangiogenic treatment concept in a progressive hemangioblastoma.

The role of thalidomide and placebo for the treatment of cancer-related anorexia-cachexia symptoms: results of a double-blind placebo-controlled randomized study.

PubMed

Yennurajalingam, Sriram; Willey, Jie S; Palmer, J Lynn; Allo, Julio; Del Fabbro, Egidio; Cohen, Evan N; Tin, Sanda; Reuben, James M; Bruera, Eduardo

2012-10-01

To determine the effects of thalidomide and placebo on anorexia-cachexia and its related symptoms, body composition, resting metabolic rate, and serum cytokines and their receptors in patients with advanced cancer. Included in the study were patients with advanced cancer with weight loss greater than 5% in 6 months and who reported anorexia, fatigue, and one of the following: anxiety, depression, or sleep disturbances. Patients on chemotherapy within 2 weeks prior or during the study were excluded from the study. Patients were randomly assigned to either 100 mg thalidomide or placebo once a day for 14 days. The Edmonton Symptom Assessment Scale (ESAS), Functional Assessment of Anorexia/Cachexia Therapy (FAACT), Functional Assessment of Cancer Illness Therapy (FACIT-F), Hospital Anxiety Depression Scale (HADS) Pittsburgh Sleep Quality Index (PSQI) were utilized, and in addition body composition, Resting Energy Expenditure (REE), and serum cytokine levels were assessed. Of the 31 patients entered in the study, 15 were assigned to the thalidomide group and 16 to the placebo group. However only 21/31 patients were able to complete the study. Compared with their baseline values, both the thalidomide and the placebo groups showed significant reduction in cytokines. Tumor necrosis factor (TNF)-α (p=0.04) and its receptors TNFR1 (p=0.04), TNFR2 (p=0.04), and interleukin (IL)-8 (p=0.04) were statistically significant in the thalidomide group. In the placebo group, TNF-α (p=0.008), TNFR1 (p=0.005), TNFR2 (p=0.005), IL-RA (p=0.005), IL-6 (p=0.005), and IL-8 (p=0.005) were statistically significant. However, improvement in these symptoms and cytokine levels were not significantly different in the thalidomide group compared with the placebo group. None of the patients withdrew from the study because of toxicity of either thalidomide or placebo. Based on the poor accrual rate and attrition observed in this study, it is important that future research on thalidomide as a treatment for cancer-related anorexia-cachexia symptoms (ACS) in patients with advanced cancer use less stringent entry criteria and less exhaustive outcome measures.

Fetal malformations and early embryonic gene expression response in cynomolgus monkeys maternally exposed to thalidomide

EPA Science Inventory

The present study was performed to determine experimental conditions for thalidomide induction of fetal malformations and to understand the molecular mechanisms underlying thalidomide teratogenicity in cynomolgus monkeys. Cynomolgus monkeys were orally administered (±)-thalidomid...

[Thalidomide teratogenicity and its direct target identification].

PubMed

Ito, Takumi; Ando, Hideki; Handa, Hiroshi

2015-01-01

Half a century ago, thalidomide was developed as a sedative drug and was wildly used over 40 countries. However the drug has serious birth defects such as amelia and phocomelia. Now thalidomide is regarded as a clinically effective drug and used for the treatment of multiple myeloma under strict controls. The direct target of thalidomide had been a long-standing question. We identified cereblon as a primary direct target protein for thalidomide teratogenicity using new affinity bead technology in 2010. In this review, we introduce an overview of thalidomide teratogenicity, a story about how we identified cereblon, and recent advances in cereblon studies.

Does thalidomide prolong survival in dogs with splenic haemangiosarcoma?

PubMed

Bray, J P; Orbell, G; Cave, N; Munday, J S

2018-02-01

To investigate thalidomide as an adjuvant treatment for canine haemangiosarcoma. Fifteen dogs with splenic haemangiosarcoma, initially treated by splenectomy, were included. Following recovery from surgery, all dogs received thalidomide continuously until their death. Tumour stage was established using CT scans of the chest and abdomen immediately before starting thalidomide treatment and again three months later. Cause of death was confirmed by post mortem examination. The median survival time of dogs receiving thalidomide was 172 days (95% confidence interval: 93 to 250 days). Five dogs (33% of the population receiving thalidomide) survived more than 1 year (range 458 to 660 days) after surgery. Dogs with stage 2 disease that received thalidomide also had a longer survival time than dogs with stage 3 disease (median survival time 303 versus 40 days). Of 15 dogs, 13 died from metastatic haemangiosarcoma. Treatment using thalidomide may improve survival of dogs with splenic haemangiosarcoma and should be considered a possible adjuvant therapy. © 2017 British Small Animal Veterinary Association.

The effect of thalidomide on spinal cord ischemia/reperfusion injury in a rabbit model.

PubMed

Lee, C-J; Kim, K-W; Lee, H-M; Nahm, F S; Lim, Y-J; Park, J-H; Kim, C-S

2007-02-01

Randomized study. To evaluate the effects of thalidomide on spinal cord ischemia/reperfusion injury via reduced TNF-alpha production. Animal experimental laboratory, Clinical Research Institute of Seoul National University Hospital, Seoul, Korea. Spinal cord ischemia was induced in rabbits by occluding the infrarenal aorta. Rabbits in group N did not undergo ischemic insult, but rabbits in groups C (the untreated group), THA, and THB underwent ischemic insult for 15 min. The THA and THB groups received thalidomide (20 mg/kg) intraperitoneally (i.p.) before ischemia, but only the THB group received thalidomide (i.p., 20 mg/kg) after 24 and 48 h of reperfusion. After evaluating neurologic functions at 1.5 h, 3, and 5 days of reperfusion, rabbits were killed for histopathologic examination and Western blot analysis of TNF-alpha. The THA and THB groups showed significantly less neurologic dysfunction than the C group at 1.5 h, 3, and 5 days of reperfusion. The number of normal spinal motor neurons in ventral gray matter was higher in THA and THB than in C, but no difference was observed between THA and THB. Western blot analysis showed a significantly higher level of TNF-alpha in C than in THA and THB at 1.5 h of reperfusion, but no difference was observed between C, THA, or THB at 3 or 5 days of reperfusion. Thalidomide treatment before ischemic insult reduces early phase ischemia/reperfusion injury of the spinal cord in rabbits.

Thalidomide attenuates multiple low-dose streptozotocin-induced diabetes in mice by inhibition of proinflammatory cytokines.

PubMed

Amirshahrokhi, K; Ghazi-Khansari, M

2012-11-01

Thalidomide is an immunomodulatory and anti-inflammatory agent and is used in autoimmune disorders. It has been shown that thalidomide inhibits proinflammatory cytokines production. The purpose of this study was to investigate the effect of thalidomide on the prevention of autoimmune diabetes in mice. Diabetes was induced by multiple low-dose of streptozotocin (MLDS) injection. Mice were treated with thalidomide (300 mg/kg/day orally) for 21 days. Plasma levels of glucose, insulin and nitrate/nitrite as well as pancreatic cytokine levels were measured. Pathological examinations of the pancreas revealed that thalidomide reduced the islet inflammation (insulitis) and destruction of beta cells. Thalidomide treatment prevented hyperglycemia and preserved pancreatic insulin secretion in the diabetic mice. Thalidomide treatment also significantly decreased plasma levels of nitric oxide and pancreatic proinflammatory cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-12, IL-17 and interferon (IFN)-γ)] while increased anti-inflammatory cytokine IL-10. In conclusion, these findings indicate that thalidomide may have a protective effect against the autoimmune destruction of the pancreatic beta-cells during the development of MLDS-induced type 1 diabetes in mice. Copyright © 2012 Elsevier Ltd. All rights reserved.

Efficacy of thalidomide on trinitrobenzene sulfonate-induced colitis in young rats and its mechanism.

PubMed

Xu, Jiahua; Zheng, Cuifang; Huang, Ying; Liang, Yingjie

2014-01-01

Thalidomide could relieve clinical symptoms and intestinal mucosal lesions effectively in children with refractory inflammatory bowel disease (IBD) from the pre-clinical study. This study aimed to observe the therapeutic effect of thalidomide by the established animal model of IBD model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in Sprague-Dawley (SD) rats and to investigate the possible mechanism of action. A total of 82 SD rats of about 4-5 weeks were randomly divided into three groups: the control group (25 rats), TNBS-treated group (29 rats), and thalidomide treatment group (28 rats). Daily activities were recorded. At least eight rats from each group were killed on the 4th, 7th, and 14th days. Morphological and histological changes in the colon were individually assessed. Serum was collected and the levels of TNF-α and interleukins (IL-1β and IL-10) were assayed by ELISA method. The expression of colonic mucosal nuclear factor (NF)-κB was assayed with the immunohistochemical method. (1) In the control group, diarrhea and rectal bleeding recovered rapidly and no death was recorded. In the TNBS-treated group, diarrhea and rectal bleeding persisted for a longer time. The mortality rate was 10.34% during the observation period. In the thalidomide treatment group, diarrhea and rectal bleeding persisted for a significantly shorter time than the TNBS-treated group (P < 0.01). The rats of this group also exhibited faster weight gain on day 7 compared with the TNBS-treated group but still lower than that of the control group. The mortality rate of the thalidomide treatment group was 3.57%. (2) Macroscopic and microscopic scores of the thalidomide-treated group were significantly lower than those of the TNBS model group on the 14th day (P < 0.01). These results suggested faster and better colonic recovery in the thalidomide-treated group. (3) NF-κB expression in the colonic mucosa of the control group was lower than in the others, mainly distributed in the cytoplasm. A large amount of intra-nuclear and cytoplasm staining was observed (more prominently intra-nuclear) in the TNBS model group and the thalidomide treatment group. On the 7th and 14th days, intra-nuclear NF-κB-containing cells in the thalidomide treatment group were still significantly lower than those in the TNBS model group (P < 0.01). (4) In the control group, the cellular inflammatory factors (TNF-α, IL-1β, and IL-10) were expressed at a low level while in the other two groups they were already expressed at a significantly higher level on day 4. On day 7 the expressions of TNF-α and IL-1β in the thalidomide treatment group were lower than in the TNBS model group. On day 14, the expressions of TNF-α and IL-1β in the thalidomide treatment group were significantly lower than in the TNBS model group (P < 0.05). On day 4, the IL-10 levels of the thalidomide treatment group became significantly elevated. The levels gradually decreased but still remained at a higher level. In the TNBS model group, the IL-10 expression peaked later than in the thalidomide treatment group. Thalidomide was effective in the management of TNBS-induced colitis in young rats. This may be due to the suppression and down-regulation of NF-κB and the expression of the downstream inflammatory mediators (TNF-α and IL-1β). There is also indication that the expression of the anti-inflammatory cytokine (IL-10) is concomitantly up-regulated as well.

Phase II Study of Concomitant Thalidomide During Radiotherapy for Hepatocellular Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ch'ang, Hui-Ju, E-mail: hjmc@nhri.org.tw; Department of Radiation Oncology, National Cheng Kung University Hospital, Tainan, Taiwan; Hsu, Chiun

2012-02-01

Purpose: Thalidomide has been demonstrated to possess antitumor activity in patients with advanced hepatocellular carcinoma (HCC). The objective of the present study was to determine whether the combined treatment of thalidomide with radiotherapy (RT) is associated with acceptable toxicity and an improved clinical outcome in HCC patients. Methods and Materials: A total of 24 patients were enrolled to receive RT combined with thalidomide. A total dose of 50 Gy was delivered in 2-Gy fractions within 5 weeks. Thalidomide was administered 100 mg twice daily starting 3 days before RT until the development of unacceptable toxicity or disease progression. Blood samplesmore » were collected before, during, and after treatment to measure the levels of angiogenic factors and cytokines. The results of patients receiving the combined therapy were compared with those from 18 HCC patients receiving RT only. Results: No significant difference in the clinical parameters was noted between the two groups, except for the baseline interleukin-6 level, which was greater in the concomitant group (p = .05). The most common toxicities related to thalidomide use were skin rash (54.2%), somnolence (37.5%), and constipation (33.3%). No significant differences were seen in the response rate (55.6% vs. 58.3%, p = .48), median progression-free survival (182 {+-} 48.9 vs. 148 {+-} 6.2 days, p = .15), or median overall survival (258 {+-} 45.6 vs. 241 {+-} 38.6, p = .16) between those who received concomitant therapy and those who received RT alone. Thalidomide suppressed the serum basic fibroblast growth factor level significantly during RT (p = .03) and, to a lesser extent, the interleukin-6 and tumor necrosis factor-{alpha} levels. After adjusting for other potential prognostic factors in the multivariate analysis, only the baseline interleukin-6 level and stem cell-derived factor-1 during RT independently predicted the progression-free survival. A decreased serum stem cell-derived factor-1 level 1 month after RT completion was a significant predictor of the overall survival of HCC patients receiving RT. Conclusions: Despite the acceptable toxicity, thalidomide provided no additional benefit for HCC patients undergoing RT.« less

Thalidomide combined with transcatheter artierial chemoembolzation for primary hepatocellular carcinoma: a systematic review and meta-analysis

PubMed Central

Cao, De-Dong; Xu, Hui-Lin; Liu, Liang; Zheng, Yong-Fa; Gao, Si-Fa; Xu, Xi-Ming; Ge, Wei

2017-01-01

Objective Transcatheter arterial chemoembolization (TACE) and thalidomide have been used for treating primary hepatocellular carcinoma(HCC). This study aims to evaluate the clinical efficacy and safety of thalidomide and TACE in primary HCC. Methods Randomized controlled trials(RCTs) about efficacy and safety of thalidomide combined with TACE for primary HCC were identified from the Cochrane Library, Pubmed, Embase, CNKI, and Wan Fang until August, 2016. The retrieved trials were reviewed and the data were extracted by two reviewers, independently. Combined analyses of survival rates, overall response rate(ORR), disease control rate(DCR), changes of KPS, parameters of cellular immunity and vascular endothelial growth factor(VEGF), and adverse events were performed using RevMan 5.3 software. Results A total of 23 RCTs involving 1836 patients were included. The results showed that thalidomide plus TACE was significantly superior in increasing 6-month survival rate(OR=1.79, 95% CI:1.02-3.15, P=0.04), 1-year survival rate(OR=1.76, 95% CI:1.38-2.24, P<0.0001), 1.5-year survival rate(OR=4.72, 95% CI:2.64-8.43, P<0.001), 2-year survival rate(OR=1.78, 95% CI:1.37-2.30, P<0.001), ORR(OR=1.89, 95% CI:1.48-2.42, P<0.0001), DCR(OR=2.62, 95% CI:1.90-3.63, P<0.001), improvement in cellular immunity(MD=0.63, 95% CI:0.45-0.80, P<0.0001), and reduction of VEGF(MD=-119.71, 95% CI:-135.75—103.68, P<0.0001), when compared with TACE group. The incidences of gastrointestinal reactions, myelosuppression, and liver dysfunction were similar between combination group and TACE group(P>0.05). However, compared to TACE, the combination of thalidomide and TACE had a higher incidence of drug rash(OR=6.35, 95% CI:2.75-14.68, P<0.0001). Conclusion Our findings suggest that thalidomide combined with TACE shows better clinical efficacy and tolerable adverse events in patients with primary HCC when compared with TACE alone. PMID:28402958

Thalidomide prolongs survival after experimental musculoskeletal injury, through an effect on mononuclear apoptosis.

PubMed

Panousis, Konstantinos; Nikolaou, Vassilios S; Tsaganos, Thomas; Lallos, Stergios; Giamarellos-Bourboulis, Evangelos J; Efstathopoulos, Nicolas

2014-05-01

This study was conducted to investigate the effects of intravenous thalidomide administration in an experimental model of musculoskeletal trauma. We hypothesized that because thalidomide inhibits secretion of tumor necrosis factor alpha (TNF-α), survival of animals that received thalidomide would be significantly prolonged. After an open fracture of the right femur, 24 rabbits were randomly assigned to control and thalidomide groups. Intravenous therapy with thalidomide was started 30 min after fracture. Hemodynamic monitoring of all animals was performed for 4 h. Survival was recorded and bacterial growth in blood and organs was measured after animal death or sacrifice. Blood was sampled for TNF-α measurement and for isolation of peripheral blood mononuclear cells (PBMCs). Apoptosis of PBMCs was measured by flow cytometry. Survival was significantly prolonged in the thalidomide group. Apoptosis of PBMCs was increased in the control group compared with the thalidomide group at 24 h. There were no differences in vital signs, blood and tissue cultures, and serum TNF-α concentration between the two groups. Intravenous thalidomide prolonged survival in an experimental model of severe musculoskeletal injury in rabbits. Its mechanism of action did not involve TNF-α suppression but prevention of mononuclear apoptosis. In view of these promising results, further research is needed to clarify the immunomodulatory mechanism of action of thalidomide and its potential use for the management of severe trauma. Copyright © 2014 Elsevier Inc. All rights reserved.

Thalidomide inhibits tumor necrosis factor-alpha production and antigen presentation by Langerhans cells.

PubMed

Deng, Liang; Ding, Wanhong; Granstein, Richard D

2003-11-01

Thalidomide is an effective treatment for several inflammatory and autoimmune disorders including erythema nodosum leprosum, Behcet's syndrome, discoid lupus erythematosus, and Crohn's disease. Thalidomide is believed to exert its anti-inflammatory effects, at least in part, by inhibiting tumor necrosis factor-alpha (TNF-alpha) production by monocytes. We studied the effects of thalidomide on epidermal Langerhans cells (LC). LCs are epidermal antigen-presenting dendritic cells that play important roles in skin immune responses. Using the murine epidermis-derived dendritic cell lines, XS106A from A/J mice and XS52 from BALB/c mice as surrogates for LC, we found that thalidomide inhibited TNF-alpha production in a concentration-dependent manner. Northern blot analysis revealed that thalidomide significantly decreased the peak-induced mRNA level of TNF-alpha in XS106A cells and XS52 cells. We then examined the effect of thalidomide on fresh LC enriched to approximately 98% using positive selection of Ia+ cells with antibodies conjugated to magnetic microspheres. TNF-alpha production was reduced by 67.7% at a thalidomide concentration of 200 microg per mL. Thalidomide also had a profound inhibitory effect on the ability of LC to present antigen to a responsive TH1 clone. Thalidomide inhibits TNF-alpha production and the antigen-presenting ability of epidermal LCs. These mechanisms may contribute to the therapeutic effects observed with this agent.

Two cases of bacterial meningitis accompanied by thalidomide therapy in patients with multiple myeloma: is thalidomide associated with bacterial meningitis?

PubMed

Pasa, Semir; Altintas, Abdullah; Cil, Timucin; Ustun, Cemal; Bayan, Kadim; Danis, Ramazan; Urakci, Zuhat; Tuzun, Yekta; Ayyildiz, Orhan

2009-01-01

Morbidity and mortality in multiple myeloma is often attributed to life-threatening infections. A defect in humoral immunity has been proposed for the predisposition to bacterial infections. Most of the infections are of bacterial origin, and the most serious are septicemia, meningitis, and pneumonia. Thalidomide is a drug with pleiotropic effects. The immunomodulatory effects of thalidomide are at least partially mediated through its ability to down-regulate the pathogenic over-production of tumor necrosis factor-alpha (TNF-alpha). TNF-alpha is a cytokine that plays a central role in the regulation of the host immune and inflammatory response to infection. In the central nervous system, TNF-alpha is involved in induction of a fever response and triggers the release of other cytokines, and may also influence transport of compounds into the brain, leading to cerebrospinal fluid leukocytosis, increased protein influx, and lactate accumulation. Thalidomide has been shown to down-regulate the production of TNF-alpha. On the other hand, knowledge of the effects of thalidomide on granulocyte functions is limited. Thalidomide has been shown to attenuate neutrophil adhesion and chemotaxis. We present herein two cases of Streptococcus pneumoniae bacterial meningitis that developed soon after the initiation of thalidomide treatment, and discuss the effect of thalidomide on the immune system. Although, it is not clear whether thalidomide caused the development of the bacterial infections and meningitis, or what its pathogenetic mechanisms are, physicians should be alert for signs and symptoms of meningitis in patients with multiple myeloma who are treated with thalidomide, especially those in neutropenic states.

Nitric oxide rescues thalidomide mediated teratogenicity

PubMed Central

Siamwala, Jamila H.; Veeriah, Vimal; Priya, M. Krishna; Rajendran, Saranya; Saran, Uttara; Sinha, Swaraj; Nagarajan, Shunmugam; T, Pradeep; Chatterjee, Suvro

2012-01-01

Thalidomide, a sedative drug given to pregnant women, unfortunately caused limb deformities in thousands of babies. Recently the drug was revived because of its therapeutic potential; however the search is still ongoing for an antidote against thalidomide induced limb deformities. In the current study we found that nitric oxide (NO) rescues thalidomide affected chick (Gallus gallus) and zebrafish (Danio rerio) embryos. This study confirms that NO reduced the number of thalidomide mediated limb deformities by 94% and 80% in chick and zebrafish embryos respectively. NO prevents limb deformities by promoting angiogenesis, reducing oxidative stress and inactivating caspase-3 dependent apoptosis. We conclude that NO secures angiogenesis in the thalidomide treated embryos to protect them from deformities. PMID:22997553

The Rise, Fall and Subsequent Triumph of Thalidomide: Lessons Learned in Drug Development

PubMed Central

Rehman, Waqas; Arfons, Lisa M.; Lazarus, Hillard M.

2011-01-01

Perhaps no other drug in modern medicine rivals the dramatic revitalization of thalidomide. Originally marketed as a sedative, thalidomide gained immense popularity worldwide among pregnant women because of its effective anti-emetic properties in morning sickness. Mounting evidence of human teratogenicity marked a dramatic fall from grace and led to widespread social, legal and economic ramifications. Despite its tragic past thalidomide emerged several decades later as a novel and highly effective agent in the treatment of various inflammatory and malignant diseases. In 2006 thalidomide completed its remarkable renaissance becoming the first new agent in over a decade to gain approval for the treatment of plasma cell myeloma. The catastrophic collapse yet subsequent revival of thalidomide provides important lessons in drug development. Never entirely abandoned by the medical community, thalidomide resurfaced as an important drug once the mechanisms of action were further studied and better understood. Ongoing research and development of related drugs such as lenalidomide now represent a class of irreplaceable drugs in hematological malignancies. Further, the tragedies associated with this agent stimulated the legislation which revamped the FDA regulatory process, expanded patient informed consent procedures and mandated more transparency from drug manufacturers. Finally, we review recent clinical trials summarizing selected medical indications for thalidomide with an emphasis on hematologic malignancies. Herein, we provide a historic perspective regarding the up-and-down development of thalidomide. Using PubMed databases we conducted searches using thalidomide and associated keywords highlighting pharmacology, mechanisms of action, and clinical uses. PMID:23556097

Preventive and therapeutic anti-inflammatory effects of systemic and topical thalidomide on endotoxin-induced uveitis in rats.

PubMed

Rodrigues, Gustavo Büchele; Passos, Giselle Fazzioni; Di Giunta, Gabriella; Figueiredo, Cláudia Pinto; Rodrigues, Eduardo Büchele; Grumman, Astor; Medeiros, Rodrigo; Calixto, João B

2007-03-01

The present study examined the outcomes of systemic or topical treatment with thalidomide, a compound that possesses anti-inflammatory, immunomodulatory and anti-angiogenic properties, in rats subjected to endotoxin-induced uveitis (EIU). The effects of thalidomide were evaluated on endotoxin-induced leucocyte and protein infiltration and also on the production of interleukin (IL)-1beta and tumour necrosis factor (TNF)-alpha in rat aqueous humour (AqH). Moreover, the actions of thalidomide were assessed on the cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) protein expression in retinal tissue. EIU was produced by a hindpaw injection of lipopolysaccharide (LPS), in male Wistar rats. Thalidomide (5, 25 and 50 mg/kg) was administered orally 1 h before LPS injection. In another set of experiments, to evaluate the therapeutic efficacy, 5% thalidomide was applied topically to both eyes at 6, 12 and 18 h after LPS administration. The oral pre-treatment with thalidomide decreased, in a dose-dependent manner, the number of inflammatory cells, the protein concentration, and the levels of IL-1beta and TNF-alpha in the AqH. Similar results were found in the AqH of rats that received a topical application of thalidomide. Furthermore, oral (50 mg/kg) and local (5%) thalidomide treatment also reduced expression of the pro-inflammatory proteins COX-2 and iNOS in the posterior segment of the eye. Thalidomide exhibited marked preventive and curative ocular effects in EIU in rats, a property that might be associated with its ability to inhibit the production of inflammatory cytokines and the expression of COX-2 and iNOS. This assembly of data provides additional molecular and functional insights into beneficial effects of thalidomide as an agent for the management of ocular inflammation.

Nitric oxide mediates the anticonvulsant effects of thalidomide on pentylenetetrazole-induced clonic seizures in mice.

PubMed

Payandemehr, Borna; Rahimian, Reza; Gooshe, Maziar; Bahremand, Arash; Gholizadeh, Ramtin; Berijani, Sina; Ahmadi-Dastgerdi, Mohammad; Aminizade, Mehdi; Sarreshte-Dari, Ali; Dianati, Vahid; Amanlou, Massoud; Dehpour, Ahmad Reza

2014-05-01

Thalidomide is an old glutamic acid derivative which was initially used as a sedative medication but withdrawn from the market due to the high incidence of teratogenicity. Recently, it has reemerged because of its potential for counteracting number of diseases, including neurodegenerative disorders. Other than the antiemetic and hypnotic aspects, thalidomide exerts some anticonvulsant properties in experimental settings. However, the underlying mechanisms of thalidomide actions are not fully realized yet. Some investigations revealed that thalidomide could elicit immunomodulatory or neuromodulatory properties by affecting different targets, including cytokines (such as TNF α), neurotransmitters, and nitric oxide (NO). In this regard, we used a model of clonic seizure induced by pentylenetetrazole (PTZ) in male NMRI mice to investigate whether the anticonvulsant effect of thalidomide is affected through modulation of the l-arginine-nitric oxide pathway or not. Injection of a single effective dose of thalidomide (10 mg/kg, i.p. or higher) significantly increased the seizure threshold (P<0.05). On the one hand, pretreatment with low and per se noneffective dose of l-arginine [NO precursor] (10, 30 and 60 mg/kg) prevented the anticonvulsant effect of thalidomide. On the other hand, NOS inhibitors [l-NAME and 7-NI] augmented the anticonvulsant effect of a subeffective dose of thalidomide (1 and 5 mg/kg, i.p.) at relatively low doses. Meanwhile, several doses of aminoguanidine [an inducible NOS inhibitor] (20, 50 and 100 mg/kg) failed to alter the anticonvulsant effect of thalidomide significantly. In summary, our findings demonstrated that the l-arginine-nitric oxide pathway can be involved in the anticonvulsant properties of thalidomide, and the role of constitutive nNOS is prominent in the reported neuroprotective feature. Copyright © 2014 Elsevier Inc. All rights reserved.

Therapeutic and prophylactic thalidomide in TNBS-induced colitis: Synergistic effects on TNF-α, IL-12 and VEGF production

PubMed Central

Carvalho, Ana Teresa; Souza, Heitor; Carneiro, Antonio Jose; Castelo-Branco, Morgana; Madi, Kalil; Schanaider, Alberto; Silva, Flavia; Pereira Jứnior, Fernando Antonio; Pereira, Márcia G; Tortori, Cláudio; Dines, Ilana; Carvalho, Jane; Rocha, Eduardo; Elia, Celeste

2007-01-01

AIM: To evaluated the therapeutic and prophylactic effect of thalidomide on 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. Thalidomide has been reported to downregulate the expression of tumor necrosis factor α (TNF-α), IL-12, and vascular endothelial growth factor (VEGF), hallmarks of intestinal inflammation in Crohn’s disease (CD). METHODS: Male Wistar rats were divided in five groups of ten animals each. Four groups received a rectal infusion of TNBS in ethanol. The first group was sacrificed 7 d after colitis induction. The second and third groups received either thalidomide or placebo by gavage and were sacrificed at 14 d. The fourth group received thalidomide 6 h before TNBS administration, and was sacrificed 7 d after induction. The fifth group acted as the control group and colitis was not induced. Histological inflammatory scores of the colon were performed and lamina propria CD4+ T cells, macrophages, and VEGF+ cells were detected by immunohistochemistry. TNF-α and IL-12 were quantified in the supernatant of organ cultures by ELISA. RESULTS: Significant reduction in the inflammatory score and in the percentage of VEGF+ cells was observed in the group treated with thalidomide compared with animals not treated with thalidomide. Both TNF-α and IL-12 levels were significantly reduced among TNBS induced colitis animals treated with thalidomide compared with animals that did not receive thalidomide. TNF-α levels were also significantly reduced among the animals receiving thalidomide prophylaxis compared with untreated animals with TNBS-induced colitis. Intestinal levels of TNF-α and IL-12 were significantly correlated with the inflammatory score and the number of VEGF+ cells. CONCLUSION: Thalidomide significantly attenuates TNBS-induced colitis by inhibiting the intestinal production of TNF-α, IL-12, and VEGF. This effect may support the use of thalidomide as an alternate approach in selected patients with CD. PMID:17465495

Therapeutic and prophylactic thalidomide in TNBS-induced colitis: synergistic effects on TNF-alpha, IL-12 and VEGF production.

PubMed

Carvalho, Ana Teresa; Souza, Heitor; Carneiro, Antonio Jose; Castelo-Branco, Morgana; Madi, Kalil; Schanaider, Alberto; Silv, Flavia; Pereira Junior, Fernando Antonio; Pereira, Marcia G; Tortori, Claudio; Dines, Ilana; Carvalho, Jane; Rocha, Eduardo; Elia, Celeste

2007-04-21

To evaluated the therapeutic and prophylactic effect of thalidomide on 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. Thalidomide has been reported to downregulate the expression of tumor necrosis factor alpha (TNF-alpha), IL-12, and vascular endothelial growth factor (VEGF), hallmarks of intestinal inflammation in Crohnos disease (CD). Male Wistar rats were divided in five groups of ten animals each. Four groups received a rectal infusion of TNBS in ethanol. The first group was sacrificed 7 d after colitis induction. The second and third groups received either thalidomide or placebo by gavage and were sacrificed at 14 d. The fourth group received thalidomide 6 h before TNBS administration, and was sacrificed 7 d after induction. The fifth group acted as the control group and colitis was not induced. Histological inflammatory scores of the colon were performed and lamina propria CD4+ T cells, macrophages, and VEGF+ cells were detected by immunohistochemistry. TNF-alpha and IL-12 were quantified in the supernatant of organ cultures by ELISA. Significant reduction in the inflammatory score and in the percentage of VEGF+ cells was observed in the group treated with thalidomide compared with animals not treated with thalidomide. Both TNF-alpha and IL-12 levels were significantly reduced among TNBS induced colitis animals treated with thalidomide compared with animals that did not receive thalidomide. TNF-alpha levels were also significantly reduced among the animals receiving thalidomide prophylaxis compared with untreated animals with TNBS-induced colitis. Intestinal levels of TNF-alpha and IL-12 were significantly correlated with the inflammatory score and the number of VEGF+ cells. Thalidomide significantly attenuates TNBS-induced colitis by inhibiting the intestinal production of TNF-alpha, IL-12, and VEGF. This effect may support the use of thalidomide as an alternate approach in selected patients with CD.

Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide

PubMed Central

Fischer, Eric S.; Böhm, Kerstin; Lydeard, John R.; Yang, Haidi; Stadler, Michael B.; Cavadini, Simone; Nagel, Jane; Serluca, Fabrizio; Acker, Vincent; Lingaraju, Gondichatnahalli M.; Tichkule, Ritesh B.; Schebesta, Michael; Forrester, William C.; Schirle, Markus; Hassiepen, Ulrich; Ottl, Johannes; Hild, Marc; Beckwith, Rohan E. J.; Harper, J. Wade; Jenkins, Jeremy L.; Thomä, Nicolas H.

2015-01-01

In the 1950s the drug thalidomide administered as a sedative to pregnant women led to the birth of thousands of children with multiple defects. Despite its teratogenicity, thalidomide and its derivatives lenalidomide and pomalidomide (together known as Immunomodulatory Drugs: IMiDs) recently emerged as effective treatments for multiple myeloma and 5q-dysplasia. IMiDs target the CUL4-RBX1-DDB1-CRBN (CRL4CRBN) E3 ubiquitin ligase and promote the ubiquitination of Ikaros/Aiolos transcription factors by CRL4CRBN. Here we present the crystal structure of the DDB1-CRBN complex bound to thalidomide, lenalidomide and pomalidomide. The structure establishes CRBN as a CRL4CRBN substrate receptor, which enantioselectively binds IMiDs. Through an unbiased screen we identify the homeobox transcription factor MEIS2 as an endogenous substrate of CRL4CRBN. Our studies suggest that IMiDs block endogenous substrates (MEIS2) from binding to CRL4CRBN when recruiting Ikaros/Aiolos for degradation. This dual activity implies that small molecules can principally modulate a ligase to up- or down-regulate the ubiquitination of proteins. PMID:25043012

Mucosal healing with thalidomide in refractory Crohn's disease patients intolerant of anti-TNF-α drugs: report of 3 cases and literature review.

PubMed

Scribano, Maria Lia; Cantoro, Laura; Marrollo, Marzia; Cosintino, Rocco; Kohn, Anna

2014-07-01

Thalidomide is an oral immunomodulatory and anti-inflammatory drug with antitumor necrosis factor-α (TNF-α) activity. Several case reports and some clinical trials have demonstrated its efficacy in the treatment of refractory Crohn's disease (CD). We report the effect and tolerability of thalidomide in 3 patients with moderate-to-severe CD who were not responsive to anti-TNF-α therapies, and review the relevant literature. The first case is of a 28-year-old female affected by Crohn's colitis complicated by a severe fistulizing perianal disease; she was treated with infliximab, adalimumab, and certolizumab pegol, which were stopped because of intolerance. The second case is of a 39-year-old female with fistulizing ileocolitis complicated by severe arthralgias and perianal disease with loss of response to infliximab and intolerance of certolizumab pegol. The third case is of a 39-year-old male with gastric and ileocolonic CD refractory to immunosuppressors and intolerant of infliximab. All the 3 cases achieved complete clinical remission and endoscopic healing of mucosal lesions at a low dose of thalidomide (50 to 150 mg/d). In our CD patients who experienced loss of response or were unable to tolerate anti-TNF-α drugs, thalidomide was an effective and well-tolerated therapy for inducing and maintaining long-term remission.

Thalidomide in Dermatology: Revisited

PubMed Central

Hassan, Iffat; Dorjay, Konchok; Anwar, Parvaiz

2015-01-01

The use of thalidomide in relation to dermatology is well- known and enough data is available in the literature about various aspects of thalidomide. Despite being an interesting and useful drug for many dermatoses, it is associated with many health hazards including the birth defects, phocomelia. We hereby present a comprehensive review about thalidomide and its application in dermatology. PMID:25814738

Which one is more effective for the treatment of rat sepsis model: thalidomide or etanercept?

PubMed

Ilhan, N; Susam, S; Gul, H F; Bardas, R; Ilhan, N

2017-01-01

We aimed to investigate the protective effect of selected treatment agents on liver injury in lipopolysaccharide (LPS)-induced rat sepsis model. The sepsis includes complex inflammatory responses between a microbial pathogen and the host immune system, and leads to organ failure and also death. This study was performed with 29 male Wistar Albino rats. Rats were divided randomly into five groups: Sham group, LPS-treated sepsis group, LPS+thalidomide treated group, LPS+etanercept treated group and LPS+thalidomide+etanercept treated group, respectively. Liver tissue tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and interleukin 6 (IL-6) levels were determined by enzyme-linked immuno-sorbent assay (ELISA) method. The expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) was performed using western blot analysis. The levels of tissue TNF-α, IL-1β and IL-6 were found statistically significantly higher in sepsis group than in the sham group. TNF-α levels were found statistically significantly decreased in LPS+etanercept and LPS+thalidomide+etanercept treated groups when compared with LPS group (p < 0.05). For IL-1β and IL-6 levels a statistically significant decline was observed in the LPS+thalidomide and LPS+etanercept treated groups compared to the LPS group (p < 0.05). Expression of NF-κB protein in liver tissue was significantly elevated in the LPS group compared to sham group (p < 0.001). In treatment groups, a marked decrease was observed in NF-κB protein expression. The results of this investigation suggested that etanercept and thalidomide administration may have a beneficial effect on LPS-induced sepsis. So, the present study may have significant clinical relevance, but clinical trials are needed to confirm these results (Tab. 1, Fig. 1, Ref. 36).

Novel Use of Thalidomide in Recurrent Gastrointestinal Tract Bleeding in Patients with Left Ventricular Assist Devices: A Case Series.

PubMed

Chan, Laura Lihua; Lim, Choon Pin; Lim, Chong Hee; Tan, Teing Ee; Sim, David; Sivathasan, Cumaraswamy

2017-10-01

Bleeding is an important and common complication of left ventricular assist devices (LVADs). One of the common causes of gastrointestinal bleeding is arteriovenous malformations. However, the source of bleeding is often hard to identify. Thalidomide is efficacious in treatment of gastrointestinal (GI) bleeding in non-LVAD patients. We report our experience of the use of thalidomide in the treatment of GI bleeding in four patients with LVAD. Four patients who had recurrent GI bleeding from May 2009 to December 2014 were started on thalidomide. All of them responded to treatment and had no further gastrointestinal bleeding while on thalidomide. One patient developed constipation, requiring thalidomide to be stopped. Another patient developed symptomatic neuropathy, that resolved with reduction of dosage. Thalidomide appears safe and efficacious in LVAD patients with recurrent gastrointestinal bleeding. Copyright © 2016 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

Expression of CD64 on Circulating Neutrophils Favoring Systemic Inflammatory Status in Erythema Nodosum Leprosum

PubMed Central

Prata, Rhana Berto da Silva; Barbosa, Mayara Garcia de Mattos; Mendes, Mayara Abud; Brandão, Sheila Santos; Amadeu, Thaís Porto; Rodrigues, Luciana Silva; Ferreira, Helen; Costa, Fabrício da Mota Ramalho; dos Santos, Jessica Brandão; Pacheco, Fabiana dos Santos; Machado, Alice de Miranda; Nery, José Augusto da Costa; Hacker, Mariana de Andrea; Sales, Anna Maria; Pinheiro, Roberta Olmo; Sarno, Euzenir Nunes

2016-01-01

Erythema Nodosum Leprosum (ENL) is an immune reaction in leprosy that aggravates the patient´s clinical condition. ENL presents systemic symptoms of an acute infectious syndrome with high leukocytosis and intense malaise clinically similar to sepsis. The treatment of ENL patients requires immunosuppression and thus needs to be early and efficient to prevent both disabilities and permanent nerve damage. Some patients experience multiple episodes of ENL and prolonged use of immunosuppressive drugs may lead to serious adverse effects. Thalidomide treatment is extremely effective at ameliorating ENL symptoms. Several mechanisms have been proposed to explain the efficacy of thalidomide in ENL, including the inhibition of TNF production. Given its teratogenicity, thalidomide is prohibitive for women of childbearing age. A rational search for molecular targets during ENL episodes is essential to better understand the disease mechanisms involved, which may also lead to the discovery of new drugs and diagnostic tests. Previous studies have demonstrated that IFN-γ and GM-CSF, involved in the induction of CD64 expression, increase during ENL. The aim of the present study was to investigate CD64 expression during ENL and whether thalidomide treatment modulated its expression. Leprosy patients were allocated to one of five groups: (1) Lepromatous leprosy, (2) Borderline leprosy, (3) Reversal reaction, (4) ENL, and (5) ENL 7 days after thalidomide treatment. The present study demonstrated that CD64 mRNA and protein were expressed in ENL lesions and that thalidomide treatment reduced CD64 expression and neutrophil infiltrates—a hallmark of ENL. We also showed that ENL blood neutrophils exclusively expressed CD64 on the cell surface and that thalidomide diminished overall expression. Patient classification based on clinical symptoms found that severe ENL presented high levels of neutrophil CD64. Collectively, these data revealed that ENL neutrophils express CD64, presumably contributing to the immunopathogenesis of the disease. PMID:27556927

Expression of CD64 on Circulating Neutrophils Favoring Systemic Inflammatory Status in Erythema Nodosum Leprosum.

PubMed

Schmitz, Veronica; Prata, Rhana Berto da Silva; Barbosa, Mayara Garcia de Mattos; Mendes, Mayara Abud; Brandão, Sheila Santos; Amadeu, Thaís Porto; Rodrigues, Luciana Silva; Ferreira, Helen; Costa, Fabrício da Mota Ramalho; Dos Santos, Jessica Brandão; Pacheco, Fabiana Dos Santos; Machado, Alice de Miranda; Nery, José Augusto da Costa; Hacker, Mariana de Andrea; Sales, Anna Maria; Pinheiro, Roberta Olmo; Sarno, Euzenir Nunes

2016-08-01

Erythema Nodosum Leprosum (ENL) is an immune reaction in leprosy that aggravates the patient´s clinical condition. ENL presents systemic symptoms of an acute infectious syndrome with high leukocytosis and intense malaise clinically similar to sepsis. The treatment of ENL patients requires immunosuppression and thus needs to be early and efficient to prevent both disabilities and permanent nerve damage. Some patients experience multiple episodes of ENL and prolonged use of immunosuppressive drugs may lead to serious adverse effects. Thalidomide treatment is extremely effective at ameliorating ENL symptoms. Several mechanisms have been proposed to explain the efficacy of thalidomide in ENL, including the inhibition of TNF production. Given its teratogenicity, thalidomide is prohibitive for women of childbearing age. A rational search for molecular targets during ENL episodes is essential to better understand the disease mechanisms involved, which may also lead to the discovery of new drugs and diagnostic tests. Previous studies have demonstrated that IFN-γ and GM-CSF, involved in the induction of CD64 expression, increase during ENL. The aim of the present study was to investigate CD64 expression during ENL and whether thalidomide treatment modulated its expression. Leprosy patients were allocated to one of five groups: (1) Lepromatous leprosy, (2) Borderline leprosy, (3) Reversal reaction, (4) ENL, and (5) ENL 7 days after thalidomide treatment. The present study demonstrated that CD64 mRNA and protein were expressed in ENL lesions and that thalidomide treatment reduced CD64 expression and neutrophil infiltrates-a hallmark of ENL. We also showed that ENL blood neutrophils exclusively expressed CD64 on the cell surface and that thalidomide diminished overall expression. Patient classification based on clinical symptoms found that severe ENL presented high levels of neutrophil CD64. Collectively, these data revealed that ENL neutrophils express CD64, presumably contributing to the immunopathogenesis of the disease.

Thalidomide induces mucosal healing in postoperative Crohn disease endoscopic recurrence

PubMed Central

Hu, Huiqin; Wang, Xinying; Liu, Side

2016-01-01

Abstract Background: Thalidomide has been successful use in patients with refractory Crohn disease (CD) in recent years. Methods: We collected the data of a postoperative CD patient who was prescribed thalidomide to induce remission and reviewed the relevant literatures. Results: A 51-year-old female was diagnosed as CD after an urgent terminal intestinal resection and presented endoscopic recurrence despite the prophylactic treatment with azathioprine (AZA). Fortunately, she achieved mucosal healing (MH) at a low dose of thalidomide for 15 months. Conclusion: Thalidomide is effective to induce MH in the postoperative CD endoscopic recurrence. PMID:27603389

Thalidomide and Pregnancy

MedlinePlus

... taking thalidomide have an effect on my baby’s behavior and development? The only long-term studies of thalidomide exposure during pregnancy have been done on children born with birth defects. Some of these children ...

Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure.

PubMed

Spencer, Andrew; Prince, H Miles; Roberts, Andrew W; Prosser, Ian W; Bradstock, Kenneth F; Coyle, Luke; Gill, Devinder S; Horvath, Noemi; Reynolds, John; Kennedy, Nola

2009-04-10

Thalidomide is effective in the treatment of newly diagnosed and relapsed/refractory multiple myeloma (MM). However, the role of thalidomide in the post-autologous stem cell transplantation (ASCT) context remains unclear. This study assessed whether the addition of thalidomide consolidation following ASCT would improve the durability of responses achieved and overall survival. Between January 2002 and March 2005, 269 patients with newly diagnosed MM who achieved disease stabilization or better with conventional induction chemotherapy received a single high-dose melphalan conditioned ASCT. Post-ASCT, 129 patients were randomly assigned to receive indefinite prednisolone maintenance therapy (control group) and 114 to receive the same in addition to 12 months of thalidomide consolidation (thalidomide group). The primary study end points were progression-free survival (PFS) and overall survival (OS). The secondary end point was tolerability. After a median follow-up of 3 years, the postrandomization 3-year PFS rates were 42% and 23% (P < .001; hazard ratio [HR], 0.5; 95% CI, 0.35 to 0.71) and the OS rates were 86% and 75% (P = .004; HR, 0.41; 95% CI, 0.22 to 0.76) in the thalidomide and control groups, respectively. There was no difference in survival between groups 12 months after disease progression (79% v 77%; P = .237). Neurological toxicities were more common in the thalidomide arm but there were no differences between arms for thromboembolic events. Consolidation therapy with 12 months of thalidomide combined with prednisolone prolongs survival when used after a single high-dose therapy supported ASCT in patients with newly diagnosed MM. Furthermore, thalidomide consolidation therapy did not adversely impact on survival in the subsequent salvage setting.

[Comparison of dissolution profile and plasma concentration-time profile of the thalidomide formulations made by Japanese, Mexican and British companies].

PubMed

Fujita, Yukiyoshi; Yamamoto, Koujirou; Aomori, Tohru; Murakami, Hirokazu; Horiuchi, Ryuya

2008-10-01

Thalidomide is an important advance in the treatment of multiple myeloma. In Japan thalidomide is now on the approval step for the treatment of multiple myeloma. The drug has some bothersome side effects such as defect of organogenesis, neuropathy, constipation and fatigue, but is likely more effective than standard chemotherapy and is changing multiple myeloma treatment. At this moment, Japanese patients must import the thalidomide preparations from Mexico, Britain and elsewhere, but after approval, they patients will be able to get the new Japanese thalidomide capsules. In order to determine appropriate amounts of Japanese thalidomide capsules in the treatment of multiple myeloma, we compared the dissolution profile and plasma thalidomide concentrations of Japanese and British capsules and Mexican tablets. The dissolution test was performed according to the Japanese and the United States Pharmacopoeia. The pharmacokinetic data for Japanese capsules were obtained from the clinical trial in Japanese subjects and compared with those data published for other formulations. The dissolution rate of the Japanese capsule was the fastest, followed by British and Mexican formulations. The pharmacokinetic profiles of Japanese and British capsules were similar, while the 100 mg Japanese thalidomide capsule demonstrated a 1.6-fold higher maximum plasma concentration than the 200 mg Mexican thalidomide tablet (1.7 vs. 1.1 microg/ml), greatly shortened t(max) (4.5 vs. 6.2 h), and the apparent half life was only one-third of the Mexican tablet (4.8 vs. 13.5 h). A comparison of the dissolution and the pharmacokinetic absorption profiles demonstrated a rank-order correlation. Physicians and pharmacists should be aware of the probable alteration in plasma thalidomide concentration when switching to the Japanese capsule, especially from the Mexican tablet, and should monitor clinical response carefully.

[Protective effect of thalidomide on ALI induced by paraquat poisoning in rats and its mechanism].

PubMed

Liu, Tao; Xie, Yuan; Xu, Mengtong; Zheng, Fenshuang

2017-11-01

To investigate the protective effect of thalidomide on acute lung injury (ALI) induced by paraquat (PQ) poisoning in rats and its possible mechanism. Sixty SPF Wistar rats were randomly divided into six groups with 10 rats in each group. The rat model of PQ poisoning was reproduced by intraperitoneal injection of PQ solution 20 mg/kg (PQ model group), and the rats were treated by intraperitoneal injection of gradient thalidomide (50, 100, 200 mg/kg treatment groups) 30 minutes later continuously for 3 days. The normal saline (NS) control group and thalidomide control group (thalidomide 200 mg/kg) were established. After 3 days, the abdominal aorta blood was collected, and the superoxide dismutase (SOD) activity was determined by hydroxylamine method, serum malondialdehyde (MDA) content was determined by thiobarbituric acid method. The rats were sacrificed for lung tissue, the levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were determined by enzyme-linked immunosorbent assay (ELISA). The phosphorylation levels of p65 and inhibitor-α of nuclear factor-κB (NF-κB) (IκB-α), which were the NF-κB signaling pathway proteins, were determined by Western Blot. The pathological changes in lung tissue were observed under light microscope by hematoxylin-eosin (HE) staining. Under microscope, obvious congestion of pulmonary interstitial and alveolar septum, a large number of inflammatory cells infiltration and thickened alveolar wall were observed after 3 days of PQ poisoning, and the congestion of pulmonary interstitial and alveolar septum, edema and inflammatory cells infiltration in the lung tissue were significantly reduced after treatment of 50, 100, 200 mg/kg thalidomide, but compared with NS control group, there was still a small amount of edema fluid, inflammatory cells and erythrocytes in the lungs tissue. Compared with the NS control group, serum MDA content and the levels of TNF-α and IL-6, and the phosphorylation of p65 and IκB-α in lung tissue were significantly increased after PQ exposure, and the activity of serum SOD was significantly decreased. Treatment with 50, 100, 200 mg/kg thalidomide could significantly reduce the levels of MDA, TNF-α, IL-6, and phosphorylation of IκB-α and p65, and increase SOD activity, in a dose-dependent manner, and the levels were significantly different from PQ model group [MDA (mmol/L): 8.26±1.20, 6.72±1.18, 5.51±1.44 vs. 9.02±1.03, TNF-α (ng/mg): 3.00±0.14, 1.84±0.18, 1.58±0.11 vs. 3.30±0.14, IL-6 (ng/mg): 1.26±0.04, 1.06±0.04, 0.97±0.08 vs. 1.97±0.07, p-p65/p65: 6.01±0.35, 3.64±0.15, 2.89±0.18 vs. 6.34±0.23, p-IκB-α/IκB-α: 2.27±0.13, 2.14±0.22, 1.52±0.14 vs. 2.96±0.20, SOD (kU/L): 195.7±19.3, 207.1±25.6, 225.8±23.1 vs. 188.2±26.6, all P < 0.05]. There was no significant effect on lung by 200 mg/kg thalidomide alone. Thalidomide has a protective effect on ALI induced by PQ poisoning in rats in a dose-dependent manner, the mechanism may be achieved by reducing the level of oxygen free radicals, reducing the inflammatory factor and inhibiting the IκB-α/NF-κB signal pathway activation.

Thalidomide prevents formation of multinucleated giant cells (Langhans-type cells) from cultured monocytes: possible pharmaceutical applications for granulomatous disorders.

PubMed

Yasui, K; Yashiro, M; Nagaoka, Y; Manki, A; Wada, T; Tsuge, M; Kondo, Y; Morishima, T

2009-01-01

Thalidomide is an effective drug for chronic inflammatory diseases, but the mechanism underlying its immunomodulatory action remains uncertain. Thalidomide has been reported to clinically improve chronic inflammatory granulomatous disorders. In such disorders, the granulomas consist of epithelioid cells, scattered lymphocytes and multinucleated giant cells (MNGC; Langhans-type cells). The present experimental approach permitted the reproduction of MNGC formation from peripheral blood monocytes and examination of thalidomides effect on it. MNGC can be effectively generated from monocytes cultured in the presence of interleukin-4 (IL-4) and macrophage colony-stimulating factor(M-CSF) for 14 days. Thalidomide can inhibit the formation of MNGC in a dose-dependent manner. MNGC formation was partly inhibited by the presence of neutralizing TNF-alpha antibody in the responses induced by IL-4 and M-CSF. Autocrinal TNF-alpha production and modulation of cadhelin expression to regulate cell adhesion might be involved in this inhibitory action of thalidomide. Our results support thalidomides clinical efficacy in the treatment of chronic granulomatous disorders (granulomatosis).

The thalidomide analgesic effect is associated with differential TNF-α receptor expression in the dorsal horn of the spinal cord as studied in a rat model of neuropathic pain.

PubMed

Andrade, Pablo; Visser-Vandewalle, Veerle; Del Rosario, John S; Daemen, Marc A; Buurman, Wim A; Steinbusch, Harry W; Hoogland, Govert

2012-04-23

The proinflammatory cytokine tumor necrosis factor-α (TNF-α) is well recognized as a key player in nociceptive signaling. Yet, therapeutic capitalization of this knowledge requires a better understanding of how TNF receptors (TNFR) contribute to pain. To address this question, we studied TNFR expression in the chronic sciatic nerve constriction (CCI) model of neuropathic pain. CCI and sham operated rats received two subcutaneous injections (one immediately after surgery, the other on postoperative day 5) containing either saline, GABA-reuptake inhibitor (NO-711), insulin-like growth factor-1 (IGF-1), ZVAD or thalidomide. Mechanical (using von Frey filaments) and thermal hypersensitivity (Hargreaves test) were assessed preoperatively and weekly during the first four postoperative weeks. Spinal cord dorsal horn samples were collected from animals that were sacrificed at 2 weeks and 4 weeks after surgery, and analyzed for TNFR1 and TNFR2 mRNA levels by qPCR and protein levels by Western blot. Compared to saline, all applied drug treatments resulted in a faster recovery from mechanical and thermal hypersensitivity, yet in a potency order of thalidomide>ZVAD=IGF-1>NO-711. CCI resulted in increased TNFR1 and TNFR2 mRNA and protein levels in the ipsilateral dorsal horn. Thalidomide was the only treatment that attenuated these increases. Finally, animals that showed a poor behavioral recovery were characterized by a significantly higher TNFR1/TNFR2 mRNA ratio. These data show that differential expression of TNFR in the dorsal horn is associated with recovery from pain in this model and suggest that the analgesic effects of thalidomide may act via this mechanism. Copyright © 2012 Elsevier B.V. All rights reserved.

The Clinical Development of Thalidomide as an Angiogenesis Inhibitor Therapy for Prostate Cancer

DTIC Science & Technology

2006-10-01

LFA-1 and ICAM-1 after in vitro treatment with the anti- TNF - alpha agent thalidomide . Cell Mol Biol (Noisy-le-grand) 2001 Nov;47(7):1105-14. 5...trial has been completed. Data regarding the biologic effects of thalidomide have been generated and analysed. BODY AIM 1. Assessment of...Tumor Necrosis Factor ( TNF )-α prior to and following thalidomide treatment have been assessed in 16 patients. Serum Levels of Interleukin (IL)-6 and

Assessing the ability of the antiangiogenic and anticytokine agent thalidomide to modulate radiation-induced lung injury

DOE Office of Scientific and Technical Information (OSTI.GOV)

Anscher, Mitchell S.; Garst, Jennifer; Marks, Lawrence B.

2006-10-01

Purpose: Thalidomide has broad anticytokine properties, which might protect normal tissues in patients undergoing chemoradiotherapy. The purpose of this study was to determine the maximal tolerated dose of thalidomide when used in combination with vinorelbine plus thoracic radiotherapy. Methods and Materials: Eligible patients had inoperable Stage III non-small-cell lung cancer, a Karnofsky Performance Status {>=}70, and life expectancy {>=}6 months. Patients underwent pretreatment evaluation of lung function. Radiotherapy consisted of 66 Gy in 6.5 weeks. Vinorelbine was administered i.v. (5 mg/m{sup 2}) 3 times per week just before radiotherapy. Thalidomide was begun at 50 mg, p.o., on day 1 ofmore » chemoradiotherapy and continued once daily for 6 months. Side effects were scored using National Cancer Institute Common Toxicity Criteria. Results: Ten patients were enrolled. Of the first 6 patients, 2 developed major thrombotic events that were believed to be possibly related to thalidomide. The study was suspended and modified to require prophylactic anticoagulation. Of the last 4 patients, 2 developed dose-limiting toxicity attributable to thalidomide; both patients required a dose reduction of thalidomide to <50 mg/day. Because the drug is not available in an oral product providing <50 mg/day, the study was closed. Conclusions: The combination of thalidomide concurrently with thoracic radiotherapy and vinorelbine resulted in excessive toxicity.« less

Thalidomide suppressed interleukin-6 but not tumor necrosis factor-alpha in volunteers with experimental endotoxemia.

PubMed

Shannon, Edward; Noveck, Robert; Sandoval, Felipe; Kamath, Burde; Kearney, Michael

2007-11-01

An early rationale for using thalidomide to treat erythema nodosum leprosum had been based on some reports that it suppresses tumor necrosis factor-alpha (TNF-alpha). However, in vivo and in vitro studies have yielded variable results, having shown that thalidomide can either enhance or suppress TNF-alpha. Since the course of circulating cytokines like TNF-alpha after infusion of endotoxin into volunteers is reproducible and characteristic, we investigated the effect of thalidomide on endotoxin-induced synthesis of TNF-alpha, interleukin (IL)-6, and IL-8. The cytokine response from 18 placebo-treated subjects who had undergone the endotoxin challenge were pooled with a placebo-treated subject from the current study and were compared with 4 subjects who received thalidomide (100 mg) every 6 h for 5 doses before endotoxin challenge. Thirty minutes after the last dose of thalidomide or placebo, volunteers were infused with 4-ng/kg endotoxin. Plasma was collected and assayed for cytokines by enzyme-linked immunosorbent assay. Endotoxin evoked the synthesis of the cytokines in all volunteers. The peak response for TNF-alpha was 1.5 h, 2.5 h for IL-8, and 3.0 h for IL-6. Thalidomide did not significantly delay the release of cytokines into the circulating blood. At the peak response, thalidomide reduced the concentration of the cytokines in the plasma. Using the area under the dose response curve (AUC(0 to 24) h), thalidomide reduced the AUC for IL-6 by 56%, for IL-8 by 30%, and TNF-alpha by 32%. In this model, thalidomide did not suppress TNF-alpha or IL-8, but it did suppress IL-6 at 4-h postinfusion with lipopolysaccharide (P=0.004), at 6 h (P=0.014), at 12 h (P=0.001), and at 16 h (P=0.012).

Thalidomide and the Titanic: reconstructing the technology tragedies of the twentieth century.

PubMed

Annas, G J; Elias, S

1999-01-01

The Titanic has become a metaphor for the disastrous consequences of an unqualified belief in the safety and invincibility of new technology. Similarly, the thalidomide tragedy stands for all of the "monsters" that can be inadvertently or negligently created by modern medicine. Thalidomide, once banned, has returned to the center of controversy with the Food and Drug Administration's (FDA's) announcement that thalidomide will be placed on the market for the treatment of erythema nodosum leprosum, a severe dermatological complication of Hansen's disease. Although this indication is very restricted, thalidomide will be available for off-label uses once it is on the market. New laws regarding abortion and a new technology, ultrasound, make reasonable the approval of thalidomide for patients who suffer from serious conditions it can alleviate. In addition, the FDA and the manufacturer have proposed the most stringent postmarketing monitoring ever used for a prescription drug, including counseling, contraception, and ultrasonography in the event of pregnancy. The Titanic/thalidomide lesson for the FDA and public health is that rules and guidelines alone are not sufficient to guarantee safety. Continuous vigilance will be required to ensure that all reasonable postmarketing monitoring steps are actually taken to avoid predictable and preventable teratogenic disasters.

A PHASE II TRIAL OF THALIDOMIDE IN PATIENTS WITH REFRACTORY ENDOMETRIAL CANCER AND CORRELATION WITH ANGIOGENESIS BIOMARKERS: A GYNECOLOGIC ONCOLOGY GROUP STUDY

PubMed Central

McMeekin, D. Scott; Sill, Michael W.; Benbrook, Doris; Darcy, Kathleen M.; Stearns-Kurosawa, Deborah J.; Eaton, Lynne; Yamada, S. Diane

2007-01-01

Objectives A phase II trial was conducted to evaluate the anti-tumor activity and adverse effects of thalidomide in persistent or recurrent endometrial cancer refractory to cytotoxic chemotherapy, and to correlate angiogenesis biomarker expression with clinical outcome. Methods Consenting patients were treated until progression or intolerable toxicity with an oral starting dose of 200 mg thalidomide/day that was to increase by 200 mg every 2 weeks to a target dose of 1000 mg/day. Vascular endothelial growth factor (VEGF), basic fibroblastic growth factor (bFGF), and soluble endothelial protein C receptor (sEPCR) were analyzed by ELISA in pre and post-treatment specimens. Results Twenty-four of 27 patients enrolled in the study were eligible, of whom 2 reached the target dose, 8 progressed before achieving the target dose and 14 refused or had toxicity that prohibited escalation. Two patients (8.3%) remained progression-free ≥ 6 months. There were 3 (12.5%) with partial responses, 2 (8.3%) with stable disease, 15 (62.5%) with increasing disease, and 4 (16.7%) who were inevaluable for response. Median progression-free survival and overall survival were 1.7 months and 6.3 months, respectively. No grade 4 toxicities were observed. Common grade 3 toxicities included hematologic (n=3), cardiovascular (n=3), constitutional (n=3), and neurologic (n=4). Thalidomide did not decrease VEGF or bFGF levels but reduced sEPCR levels in serum. Elevated plasma vascular endothelial growth factor levels were associated with increased risk of progression and death. Conclusions Thalidomide demonstrated limited ability to delay progression (as measured by PFS at 6 months), produce objective responses or reduce angiogenic marker levels in chemotherapy refractory endometrial cancer. VEGF level appears to be prognostically significant in such patients, independent of thalidomide treatment. PMID:17306350

Effect of thalidomide and arsenic trioxide on the release of tumor necrosis factor-α and vascular endothelial growth factor from the KG-1a human acute myelogenous leukemia cell line.

PubMed

Girgis, Erian H; Mahoney, John P; Khalil, Rafaat H; Soliman, Magdi R

2010-07-01

Studies conducted in our lab have indicated that thalidomide cytotoxicity in the KG-1a human acute myelogenous leukemia (AML) cell line was enhanced by combining it with arsenic trioxide. The current investigation was conducted in order to evaluate the effect of thalidomide either alone or in combination with arsenic trioxide on the release of tumor necrosis factor-α (TNF-α) and vascular endothelial growth factor (VEGF) from this cell line in an attempt to clarify its possible cytotoxic mechanism(s). Human AML cell line KG-1a was used in this study. The cells were cultured for 48 h in the presence or absence of thalidomide (5 mg/l), and or arsenic trioxide (4 μM). The levels of TNF-α and VEGF in the supernatant were determined by ELISA. Results obtained indicate that the levels of TNF-α in the supernatant of KG-1a cell cultures incubated with thalidomide, arsenic trioxide, or combination were statistically lower than those observed in the supernatant of control cells (2.89, 5.07, 4.15 and 16.88 pg/ml, respectively). However, the levels of VEGF in the supernatant of thalidomide-treated cells were statistically higher than those in the supernatant of control cells (69.61 vs. 11.48 pg/l). Arsenic trioxide, whether alone or in combination with thalidomide, did not produce any statistically significant difference in the levels of VEGF as compared to the control or thalidomide-treated cell supernatant. These findings indicate that thalidomide and the arsenic trioxide inhibition of TNF-α production by KG-1a cells may play an important role in their cytotoxic effect.

A Tale of Two Citizens: A State Attorney General and a Hematologist Facilitate Translation of Research Into US Food and Drug Administration Actions—A SONAR Report

PubMed Central

Chen, Brian; Restaino, John; Norris, LeAnn; Xirasagar, Sudha; Qureshi, Zaina P.; McKoy, June M.; Lopez, Isaac S.; Trenery, Alyssa; Murday, Alanna; Kahn, Adam; Mattison, Donald R.; Ray, Paul; Sartor, Oliver; Bennett, Charles L.

2012-01-01

Purpose: Pharmaceutical safety is a public health issue. In 2005, the Connecticut Attorney General (AG) raised concerns over adverse drug reactions in off-label settings, noting that thalidomide was approved to treat a rare illness, but more than 90% of its use was off label. A hematologist had reported thalidomide with doxorubicin or dexamethasone was associated with venous thromboembolism (VTE) rates of 25%. We review US Food and Drug Administration (FDA) and manufacturer responses to a citizen petition filed to address these thalidomide safety issues. Methods: Case study. Results: The AG petitioned the FDA requesting thalidomide-related safety actions. Coincidentally, the manufacturer submitted a supplemental New Drug Approval (sNDA), requesting approval to treat multiple myeloma with thalidomide-dexamethasone. FDA safety officers reviewed the petition and the literature and noted that VTE risks with thalidomide were not appropriately addressed in the existing package insert. In the sNDA application, the manufacturer reported thalidomide-associated toxicities for multiple myeloma were primarily somnolence and neurotoxicity, and a proposed package insert did not focus on VTE risks. In October, the FDA informed the Oncology Drug Division that VTE risks with thalidomide were poorly addressed in the existing label. After reviewing this memorandum, an Oncology Drug Division reviewer informed the manufacturer that approval of the sNDA would be delayed until several thalidomide-associated VTE safety actions, including revisions of the package insert, were implemented. The manufacturer and FDA agreed on these actions, and the sNDA was approved. Conclusion: New approaches addressing off-label safety are needed. The conditions that facilitated the successful response to this citizen petition are uncommon. PMID:23598851

A tale of two citizens: a State Attorney General and a hematologist facilitate translation of research into US Food and Drug Administration actions--a SONAR report.

PubMed

Chen, Brian; Restaino, John; Norris, LeAnn; Xirasagar, Sudha; Qureshi, Zaina P; McKoy, June M; Lopez, Isaac S; Trenery, Alyssa; Murday, Alanna; Kahn, Adam; Mattison, Donald R; Ray, Paul; Sartor, Oliver; Bennett, Charles L

2012-11-01

Pharmaceutical safety is a public health issue. In 2005, the Connecticut Attorney General (AG) raised concerns over adverse drug reactions in off-label settings, noting that thalidomide was approved to treat a rare illness, but more than 90% of its use was off label. A hematologist had reported thalidomide with doxorubicin or dexamethasone was associated with venous thromboembolism (VTE) rates of 25%. We review US Food and Drug Administration (FDA) and manufacturer responses to a citizen petition filed to address these thalidomide safety issues. Case study. The AG petitioned the FDA requesting thalidomide-related safety actions. Coincidentally, the manufacturer submitted a supplemental New Drug Approval (sNDA), requesting approval to treat multiple myeloma with thalidomide-dexamethasone. FDA safety officers reviewed the petition and the literature and noted that VTE risks with thalidomide were not appropriately addressed in the existing package insert. In the sNDA application, the manufacturer reported thalidomide-associated toxicities for multiple myeloma were primarily somnolence and neurotoxicity, and a proposed package insert did not focus on VTE risks. In October, the FDA informed the Oncology Drug Division that VTE risks with thalidomide were poorly addressed in the existing label. After reviewing this memorandum, an Oncology Drug Division reviewer informed the manufacturer that approval of the sNDA would be delayed until several thalidomide-associated VTE safety actions, including revisions of the package insert, were implemented. The manufacturer and FDA agreed on these actions, and the sNDA was approved. New approaches addressing off-label safety are needed. The conditions that facilitated the successful response to this citizen petition are uncommon.

Effects of 5HPP-33,an antiangiogenic thalidomide analog, in mouse whole embryo culture

EPA Science Inventory

Thalidomide is a well-known example of a teratogen which has been shown to have an inhibitory effect on angiogenesis. As a result of its targeted effect on immature blood vessels, anti-angiogenic specific chemical analogs were developed to maximize this mechanism of thalidomide e...

Hypercoagulable states in patients with multiple myeloma can affect the thalidomide-associated venous thromboembolism.

PubMed

Talamo, Giampaolo P; Ibrahim, Sulfi; Claxton, David; Tricot, Guido J; Fink, Louis M; Zangari, Maurizio

2009-07-01

The therapeutic use of thalidomide in patients with multiple myeloma is often complicated by the development of venous thromboembolism. The objective of the present study was to identify hypercoagulable states associated with development of venous thromboembolism in thalidomide-treated multiple myeloma patients. We screened 49 consecutive multiple myeloma patients treated with thalidomide at baseline for hypercoagulability. With a median follow-up of 11 months, 10 of 49 multiple myeloma patients developed a thrombotic episode. Laboratory assays revealed an underlying abnormality in nine of the 10 patients; hypercoagulable screenings were normal in 36 of the 39 patients who did not develop venous thromboembolism (P < 0.0001). Our retrospective study results suggest that the multiple myeloma patients with thromboembolic complications during treatment with thalidomide have a frequent concomitant underlying thrombophilic state.

Effect of thalidomide on the expression of TNF-alpha m-RNA and synthesis of TNF-alpha in cells from leprosy patients with reversal reaction.

PubMed

Tadesse, Azeb; Abebe, Markos; Bizuneh, Elizabeth; Mulugeta, Wondwossen; Aseffa, Abraham; Shannon, E J

2006-01-01

Hypersensitivity reactions called reversal reaction (RR) and erythema nodosum leprosum (ENL) occur in leprosy. They are characterized by an increase in tumor necrosis factor-alpha (TNF-alpha). Thalidomide is an effective treatment for ENL but not RR. Its effectiveness in ENL is attributed to inhibition of TNF-alpha, and this does not explain its failure to treat RR. We assessed thalidomide's effect on TNF-alpha in RR. Mononuclear cells from RR and non-RR patients and healthy individuals were treated with thalidomide and M.leprae (AFB), a cytosol fraction of M. leprae or Dharmendra lepromin. Thalidomide suppressed TNF-alpha, but when some RR patients' cells were stimulated with AFB, it enhanced TNF-alpha.

Thalidomide Ameliorates Inflammation and Vascular Injury but Aggravates Tubular Damage in the Irradiated Mouse Kidney

DOE Office of Scientific and Technical Information (OSTI.GOV)

Scharpfenecker, Marion, E-mail: m.scharpfenecker@nki.nl; Floot, Ben; Russell, Nicola S.

Purpose: The late side effects of kidney irradiation include vascular damage and fibrosis, which are promoted by an irradiation-induced inflammatory response. We therefore treated kidney-irradiated mice with the anti-inflammatory and angiogenesis-modulating drug thalidomide in an attempt to prevent the development of late normal tissue damage and radiation nephropathy in the mouse kidney. Methods and Materials: Kidneys of C57Bl/6 mice were irradiated with a single dose of 14 Gy. Starting from week 16 after irradiation, the mice were fed with thalidomide-containing chow (100 mg/kg body weight/day). Gene expression and kidney histology were analyzed at 40 weeks and blood samples at 10, 20, 30, andmore » 40 weeks after irradiation. Results: Thalidomide improved the vascular structure and vessel perfusion after irradiation, associated with a normalization of pericyte coverage. The drug also reduced infiltration of inflammatory cells but could not suppress the development of fibrosis. Irradiation-induced changes in hematocrit and blood urea nitrogen levels were not rescued by thalidomide. Moreover, thalidomide worsened tubular damage after irradiation and also negatively affected basal tubular function. Conclusions: Thalidomide improved the inflammatory and vascular side effects of kidney irradiation but could not reverse tubular toxicity, which probably prevented preservation of kidney function.« less

Thalidomide and the Titanic: reconstructing the technology tragedies of the twentieth century.

PubMed Central

Annas, G J; Elias, S

1999-01-01

The Titanic has become a metaphor for the disastrous consequences of an unqualified belief in the safety and invincibility of new technology. Similarly, the thalidomide tragedy stands for all of the "monsters" that can be inadvertently or negligently created by modern medicine. Thalidomide, once banned, has returned to the center of controversy with the Food and Drug Administration's (FDA's) announcement that thalidomide will be placed on the market for the treatment of erythema nodosum leprosum, a severe dermatological complication of Hansen's disease. Although this indication is very restricted, thalidomide will be available for off-label uses once it is on the market. New laws regarding abortion and a new technology, ultrasound, make reasonable the approval of thalidomide for patients who suffer from serious conditions it can alleviate. In addition, the FDA and the manufacturer have proposed the most stringent postmarketing monitoring ever used for a prescription drug, including counseling, contraception, and ultrasonography in the event of pregnancy. The Titanic/thalidomide lesson for the FDA and public health is that rules and guidelines alone are not sufficient to guarantee safety. Continuous vigilance will be required to ensure that all reasonable postmarketing monitoring steps are actually taken to avoid predictable and preventable teratogenic disasters. PMID:9987477

Anti-inflammatory thalidomide improves islet grafts survival and functions in a xenogenic environment.

PubMed

Chen, Chunguang; Kuehn, Carina; Bretzel, Reinhard G; Linn, Thomas

2009-07-20

Thalidomide possesses both anti-inflammatory and anti-angiogenic properties. This study investigates its potential application in islet transplantation with a xenogenic transplantation model. Transplantation was performed using C57Bl/6 mice and NMRI nu/nu mice as recipients of porcine islets. Moreover, islet graft vasculature and inflammation were investigated to identify the mechanisms of thalidomide action. In the immunocompetent environment of C57Bl/6 mice, a fast graft rejection was observed. The group treated with thalidomide 200 mg/kg BW per day achieved and maintained euglycemia in the complete observation period for 42 days. The treated mice had more functional islet graft mass with less leukocyte infiltration. The pro-inflammatory TNF-alpha and VEGF content in islet grafted kidneys was significantly lowered by the treatment. By comparison, thalidomide was not effective in improving graft survival in immunocompromised nude mice. It strongly inhibited the VEGF and TNF-alpha-induced endothelial proliferation of isolated pig islets in a dose dependent manner. The magnitude of thalidomide's inhibitory effect was nearly identical to the effect of VEGF- receptor 2 inhibitor SU416 and anti-TNF-receptor 1 neutralizing antibody, and was reversed by sphingosine-1-phosphate. In conclusion, the anti-inflammatory effect of thalidomide improved islet graft survival and function in a transplantation model with a maximum immune barrier.

Chronic thalidomide administration enhances vascular responsiveness to vasopressin in portal-systemic collaterals of bile duct-ligated rats.

PubMed

Chang, Ching-Chih; Wang, Sun-Sang; Huang, Hui-Chun; Lee, Fa-Yauh; Lin, Han-Chieh; Lee, Jing-Yi; Chen, Yi-Chou; Lee, Shou-Dong

2009-05-01

Arginine vasopressin (AVP) controls gastroesophageal variceal bleeding, partly due to its vasoconstrictive effect on portal-systemic collaterals. It has been shown that chronic thalidomide treatment decreases portal pressure, attenuates hyperdynamic circulation and inhibits vascular endothelial growth factor (VEGF) and tumor necrosis factor (TNF)-alpha in partially portal vein-ligated rats. This study investigated the effects of chronic thalidomide treatment on portal-systemic collateral vascular responsiveness to AVP in common bile duct-ligated (CBDL) cirrhotic rats. In the first series, CBDL-induced cirrhotic rats received thalidomide (50 mg/kg/day orally) or distilled water (control) from the 35th to 42nd day after ligation. On the 43rd day after ligation, the body weight, mean arterial pressure, portal pressure, and heart rate were measured. An in situ collateral vascular perfusion model was used to obtain the cumulative concentration-response curves of collateral vessels to AVP (10(-10) to 3 x 10(-7) M). Plasma levels of VEGF and TNF-alpha were measured, and expressions of VEGF and TNF-alpha mRNA in the left adrenal veins were also determined. In the second series, the cumulative concentration-response curves of collateral vessels to AVP in CBDL rats with or without thalidomide (10(-5) M) preincubation in the perfusate were obtained. The thalidomide and control groups were not significantly different in terms of heart rate, mean arterial pressure and portal pressure (p > 0.05). The collateral vascular perfusion pressure change to AVP was significantly enhanced at 10(-8) M after thalidomide treatment (p = 0.041). Compared with the control group, thalidomide-treated rats had significantly lower plasma VEGF levels (p < 0.001), accompanied by an insignificant reduction in plasma TNF-alpha levels (p > 0.05). The expressions of VEGF and TNF-alpha mRNA in the left adrenal veins of thalidomide-treated CBDL rats were not significantly changed compared with those of the control group. In addition, thalidomide did not significantly elicit changes in vascular responsiveness to AVP in collateral vessels of CBDL rats when it was added into the perfusate. In cirrhotic rats, chronic thalidomide treatment improves the portal-systemic collateral vascular responsiveness to AVP, which was partly related to VEGF inhibition.

Resolving a double standard for risk management of thalidomide: an evaluation of two different risk management programmes in Japan.

PubMed

Ooba, Nobuhiro; Sato, Tsugumichi; Watanabe, Hikaru; Kubota, Kiyoshi

2010-01-01

Thalidomide, once withdrawn because of its teratogenicity, has now been re-launched worldwide. In Japan, thalidomide has been imported by individual doctors since around the year 2000. In October 2008, it was approved for the treatment of multiple myeloma (MM) by the Ministry of Health, Labour and Welfare (MHLW) on the condition that the manufacturer implemented a risk management programme termed the Thalidomide Education and Risk Management System (TERMS). It is likely that the imports of thalidomide will be used off-label to treat diseases other than MM. Thus, the MHLW is also planning to introduce a web-based registration system, referred to as the Safety Management System for Unapproved Drugs (SMUD), for thalidomide imported by individual doctors. To evaluate the difference between TERMS and SMUD and establish a way to resolve the 'double standard' for risk management of thalidomide treatment in Japan. The fraction of patients with disorders other than MM was estimated by the volume of annual imports obtained from the MHLW and records of the imports for patients with MM, other oncological diseases (ODs) and non-ODs in 2007 through a major supplier covering 63% of the total imported thalidomide. The information for TERMS was obtained from web pages of the manufacturer and the MHLW. The components of TERMS were compared with those in SMUD. Provided that the distribution of the indication for thalidomide (MM) in 2007, estimated from the records of imports through the major supplier, is representative of the entire nation, it is estimated that on average 866 patients, including 851 (98.3%) with MM, are using thalidomide on any one day. However, if the major supplier's imports, which account for 63% of the total imports, are not representative of the nation as a whole, possibly only half of the patients treated with thalidomide in Japan have MM. This would be the case in a scenario where the remaining 37% of imports are exclusively used to treat disorders other than MM. TERMS consists of tools for education and registration of patients, and has the potential for real-time intervention. SMUD is a system for registration of patients and exchange of safety information between health professionals, but has some mandatory components that encourage patient registration. TERMS and SMUD are different in nature, and they impose different criteria that doctors and patients should satisfy in order to use thalidomide. To eliminate this double standard, implementation of a single system would be desirable. However, improvement of SMUD may be the second best option by developing tools for patient education, enhancing the potential for real-time intervention and monitoring thalidomide usage by each patient. On average, a total of about 1000 patients are estimated to be using thalidomide on any one day in Japan. It is likely that those patients are placed under one of two different risk management programmes. SMUD should be improved so that all patients are monitored in a way that results in a similar level of risk management.

Thalidomide ameliorates portal hypertension via nitric oxide synthase independent reduced systolic blood pressure

PubMed Central

Theodorakis, Nicholas G; Wang, Yining N; Korshunov, Vyacheslav A; Maluccio, Mary A; Skill, Nicholas J

2015-01-01

AIM: Portal hypertension is a common complication of liver cirrhosis and significantly increases mortality and morbidity. Previous reports have suggested that the compound thalidomide attenuates portal hypertension (PHT). However, the mechanism for this action is not fully elucidated. One hypothesis is that thalidomide destabilizes tumor necrosis factor α (TNFα) mRNA and therefore diminishes TNFα induction of nitric oxide synthase (NOS) and the production of nitric oxide (NO). To examine this hypothesis, we utilized the murine partial portal vein ligation (PVL) PHT model in combination with endothelial or inducible NOS isoform gene knockout mice. METHODS: Wild type, inducible nitric oxide synthase (iNOS)-/- and endothelial nitric oxide synthase (eNOS)-/- mice received either PVL or sham surgery and were given either thalidomide or vehicle. Serum nitrate (total nitrate, NOx) was measured daily for 7 d as a surrogate of NO synthesis. Serum TNFα level was quantified by enzyme-linked immunosorbent assay. TNFα mRNA was quantified in liver and aorta tissue by reverse transcription-polymerase chain reaction. PHT was determined by recording splenic pulp pressure (SPP) and abdominal aortic flow after 0-7 d. Response to thalidomide was determined by measurement of SPP and mean arterial pressure (MAP). RESULTS: SPP, abdominal aortic flow (Qao) and plasma NOx were increased in wild type and iNOS-/- PVL mice when compared to sham operated control mice. In contrast, SPP, Qao and plasma NOx were not increased in eNOS-/- PVL mice when compared to sham controls. Serum TNFα level in both sham and PVL mice was below the detection limit of the commercial ELISA used. Therefore, the effect of thalidomide on serum TNFα levels was undetermined in wild type, eNOS-/- or iNOS-/- mice. Thalidomide acutely increased plasma NOx in wild type and eNOS-/- mice but not iNOS-/- mice. Moreover, thalidomide temporarily (0-90 min) decreased mean arterial pressure, SPP and Qao in wild type, eNOS-/- and iNOS-/- PVL mice, after which time levels returned to the respective baseline. CONCLUSION: Thalidomide does not reduce portal pressure in the murine PVL model by modulation of NO biosynthesis. Rather, thalidomide reduces PHT by decreasing MAP by an undetermined mechanism. PMID:25892862

Thalidomide ameliorates portal hypertension via nitric oxide synthase independent reduced systolic blood pressure.

PubMed

Theodorakis, Nicholas G; Wang, Yining N; Korshunov, Vyacheslav A; Maluccio, Mary A; Skill, Nicholas J

2015-04-14

Portal hypertension is a common complication of liver cirrhosis and significantly increases mortality and morbidity. Previous reports have suggested that the compound thalidomide attenuates portal hypertension (PHT). However, the mechanism for this action is not fully elucidated. One hypothesis is that thalidomide destabilizes tumor necrosis factor α (TNFα) mRNA and therefore diminishes TNFα induction of nitric oxide synthase (NOS) and the production of nitric oxide (NO). To examine this hypothesis, we utilized the murine partial portal vein ligation (PVL) PHT model in combination with endothelial or inducible NOS isoform gene knockout mice. Wild type, inducible nitric oxide synthase (iNOS)(-/-) and endothelial nitric oxide synthase (eNOS)(-/-) mice received either PVL or sham surgery and were given either thalidomide or vehicle. Serum nitrate (total nitrate, NOx) was measured daily for 7 d as a surrogate of NO synthesis. Serum TNFα level was quantified by enzyme-linked immunosorbent assay. TNFα mRNA was quantified in liver and aorta tissue by reverse transcription-polymerase chain reaction. PHT was determined by recording splenic pulp pressure (SPP) and abdominal aortic flow after 0-7 d. Response to thalidomide was determined by measurement of SPP and mean arterial pressure (MAP). SPP, abdominal aortic flow (Qao) and plasma NOx were increased in wild type and iNOS(-/-) PVL mice when compared to sham operated control mice. In contrast, SPP, Qao and plasma NOx were not increased in eNOS(-/-) PVL mice when compared to sham controls. Serum TNFα level in both sham and PVL mice was below the detection limit of the commercial ELISA used. Therefore, the effect of thalidomide on serum TNFα levels was undetermined in wild type, eNOS(-/-) or iNOS(-/-) mice. Thalidomide acutely increased plasma NOx in wild type and eNOS(-/-) mice but not iNOS(-/-) mice. Moreover, thalidomide temporarily (0-90 min) decreased mean arterial pressure, SPP and Qao in wild type, eNOS(-/-) and iNOS(-/-) PVL mice, after which time levels returned to the respective baseline. Thalidomide does not reduce portal pressure in the murine PVL model by modulation of NO biosynthesis. Rather, thalidomide reduces PHT by decreasing MAP by an undetermined mechanism.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gao, Xiugong, E-mail: xiugong.gao@fda.hhs.gov; Sprando, Robert L.; Yourick, Jeffrey J.

Developmental toxicity testing has traditionally relied on animal models which are costly, time consuming, and require the sacrifice of large numbers of animals. In addition, there are significant disparities between human beings and animals in their responses to chemicals. Thalidomide is a species-specific developmental toxicant that causes severe limb malformations in humans but not in mice. Here, we used microarrays to study transcriptomic changes induced by thalidomide in an in vitro model based on differentiation of mouse embryonic stem cells (mESCs). C57BL/6 mESCs were allowed to differentiate spontaneously and RNA was collected at 24, 48, and 72 h after exposuremore » to 0.25 mM thalidomide. Global gene expression analysis using microarrays revealed hundreds of differentially expressed genes upon thalidomide exposure that were enriched in gene ontology (GO) terms and canonical pathways associated with embryonic development and differentiation. In addition, many genes were found to be involved in small GTPases-mediated signal transduction, heart development, and inflammatory responses, which coincide with clinical evidences and may represent critical embryotoxicities of thalidomide. These results demonstrate that transcriptomics in combination with mouse embryonic stem cell differentiation is a promising alternative model for developmental toxicity assessment. - Highlights: • Studied genomic changes in mouse embryonic stem cells upon thalidomide exposure • Identified gene expression changes that may represent thalidomide embryotoxicity • The toxicogenomic changes coincide well with known thalidomide clinical outcomes. • The mouse embryonic stem cell model is suitable for developmental toxicity testing. • The model has the potential for high-throughput screening of a multitude of compounds.« less

Thalidomide suppressed IL-1beta while enhancing TNF-alpha and IL-10, when cells in whole blood were stimulated with lipopolysaccharide.

PubMed

Shannon, Edward; Noveck, Robert; Sandoval, Felipe; Kamath, Burde

2008-01-01

Thalidomide is used to treat erythema nodosum leprosum (ENL). The events that precipitate this inflammatory reaction, which may occur in multibacillary leprosy patients, and the mechanism by which thalidomide arrest ENL, are not known. Thalidomide's ability to inhibit tumor necrosis factor alpha (TNF-alpha) in vitro has been proposed as a partial explanation of its effective treatment of ENL. In in vitro assays, thalidomide can enhance or suppress TNF-alpha. This is dependent on the stimulant used to evoke TNF-alpha; the procedure used to isolate the mononuclear cells from blood, and the predominant mononuclear cell type in the culture. To avoid artifacts that may occur during isolation of mononuclear cells from blood, we stimulated normal human blood with LPS and evaluated the effect of thalidomide and dexamethasone on TNF-alpha, and other inflammatory cytokines and biomarkers. Thalidomide suppressed interleukin 1 beta (IL-1beta) (p = 0.007), and it enhanced TNF-alpha (p = 0.007) and interleukin 10 (IL-10) (p = 0.031). Dexamethasone enhanced IL-10 (p = 0.013) and suppressed IL-1beta, TNF-alpha, interleukin 6 (IL-6), and interleukin 8 (IL-8) (p = 0.013). The two drugs did not suppress: C-reactive protein (CRP), Ig-superfamily cell-adhesion molecule 1 (ICAM 1), tumor necrosis factor receptor 1 (TNFR1), tumor necrosis factor receptor 2 (TNFR2), or amyloid A. In vitro and in vivo evidence is accumulating that TNF-alpha is not the primary cytokine targeted by thalidomide in ENL and other inflammatory conditions.

Stability of an extemporaneously prepared thalidomide suspension.

PubMed

Kraft, Shawna; Johnson, Cary E; Tyler, Ryan P

2012-01-01

The short-term physical and chemical stability of an oral suspension of thalidomide 20 mg/mL was studied. An oral suspension of thalidomide 20 mg/mL was prepared by emptying the contents of 12 100-mg thalidomide capsules into a glass mortar; 30 mL of Ora-Plus and 30 mL of Ora-Sweet were mixed and added to the thalidomide powder to make a final volume of 60 mL. Three identical samples of the formulation were prepared and placed in 2-oz amber plastic bottles with child-resistant caps and stored under refrigeration (3-5 °C). A 1-mL sample was withdrawn from each of the three samples with a micropipette immediately after preparation and at 7, 14, 21, 28, and 35 days. After further dilution to an expected concentration of 20 μg/mL with acetonitrile-methanol and then dilution with mobile phase, the samples were assayed in duplicate using stability-indicating high-performance liquid chromatography. Stability was determined by evaluating the percentage of the initial concentration remaining at each time point; stability was defined as the retention of at least 90% of the initial concentration of thalidomide. At least 92% of the initial thalidomide concentration remained throughout the 35-day study period. There were no detectable changes in color, odor, or pH and no visible microbial growth in any sample. An extemporaneously prepared suspension of thalidomide 20 mg/mL in a 1:1 mixture of Ora-Plus and Ora-Sweet was stable for at least 35 days when stored in 2-oz amber plastic bottles under refrigeration.

The effect of thalidomide on the pharmacokinetics of irinotecan and metabolites in advanced solid tumor patients

PubMed Central

Ramírez, Jacqueline; Wu, Kehua; Janisch, Linda; Karrison, Theodore; House, Larry K.; Innocenti, Federico; Cohen, Ezra E. W.; Ratain, Mark J.

2011-01-01

Purpose Irinotecan and thalidomide are commonly administered antineoplastic drugs. Combination treatment may potentiate their antitumor effect and protect against irinotecan's intestinal toxicity. We investigated whether thalidomide can modulate the pharmacokinetics of irinotecan and metabolites. Methods The study employed a crossover design in which advanced solid tumor patients were randomized to two arms and treated with irinotecan 350 mg/m2 intravenously (IV) every 3 weeks and thalidomide orally (p.o.) 400 mg daily. Pharmacokinetic data when irinotecan was administered as a single agent in each arm were compared to data when the two study agents were co-administered using paired t tests. Eighty percent and 90% confidence intervals for the true difference were also calculated. Results The differences in pharmacokinetic parameters and metabolic markers after thalidomide administration were small and unlikely to be clinically significant. With the exception of APC T1/2, none of the upper confidence limits exceeds a 50% increase. Conclusions This study did not find any clinically meaningful effects of thalidomide on the pharmacokinetics of irinotecan or its metabolites. PMID:21861128

Thalidomide induces haematologic responses in patients with β-thalassaemia.

PubMed

Chen, Jiangming; Zhu, Weijian; Cai, Ning; Bu, Shengdi; Li, Jinyan; Huang, Lan

2017-11-01

This study aimed to evaluate the clinical and laboratory outcomes of a group of patients with β-thalassaemia major or intermedia treated with thalidomide. Clinical and laboratory data were obtained by analysing medical records of β-thalassaemia patients. Using the self-control method, the levels of haemoglobin (Hb), foetal haemoglobin (HbF), white blood cells (WBC) and platelets were detected before and after the treatment, and adverse reactions were recorded. Data from the medical records of 9 patients were analysed. The median haemoglobin levels of these patients increased from 5.13 ± 2.15 g/dL before treatment to 10.38 ± 1.19 g/dL after treatment. The average spleen size decreased from a pretreatment length of 8.19 ± 3.10 to 5.49 ± 1.80 cm below the costal margin after treatment. The mean HbF levels increased from a pretreatment value of 35.67% ± 26.82% to 75.67% ± 14.64% after treatment in the 9 patients for whom these measurements were available. All patients no longer needed transfusions by 1 month after treatment. No serious adverse reactions were observed in any of the thalidomide-treated patients. In this study, thalidomide showed an outstanding effect on β-thalassaemia patients who required frequent red-cell transfusions. Thalidomide increased haemoglobin levels without causing serious adverse reactions, but the long-term curative outcomes and other side effects should be observed continuously. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Effects of thalidomide on the expression of adhesion molecules in rat liver cirrhosis.

PubMed

Lv, Peng; Paul, Shelley Chireyath; Xiao, Yanjv; Liu, Shiquan; Luo, Hesheng

2006-01-01

This study was to evaluate the effects of thalidomide on expression of adhesion molecules in liver cirrhosis. The cirrhosis was induced in Wistar rats by intraperitoneal injection of CCl(4), and thalidomide (10 mg/kg/day or 100 mg/kg/day) was given by intragastric administration for 8 weeks. Liver histopathology and immunohistochemistry were significantly improved and the expressions of ICAM-1, VCAM-1, E-selectin, and TNF-alpha mRNA and protein were decreased significantly in rats treated with a high dose of thalidomide. Close positive correlation was observed in the expression of the TNF-alpha mRNA and that of ICAM-1, VCAM-1, and E-selectin mRNA, respectively. These results indicate that thalidomide exerts its effect on the downregulation of adhesion molecules via TNF-alpha signaling pathway to inhibit liver fibrosis.

Effects of Thalidomide on the Expression of Adhesion Molecules in Rat Liver Cirrhosis

PubMed Central

Lv, Peng; Paul, Shelley Chireyath; Xiao, Yanjv; Liu, Shiquan; Luo, Hesheng

2006-01-01

This study was to evaluate the effects of thalidomide on expression of adhesion molecules in liver cirrhosis. The cirrhosis was induced in Wistar rats by intraperitoneal injection of CCl4, and thalidomide (10 mg/kg/day or 100 mg/kg/day) was given by intragastric administration for 8 weeks. Liver histopathology and immunohistochemistry were significantly improved and the expressions of ICAM-1, VCAM-1, E-selectin, and TNF-α mRNA and protein were decreased significantly in rats treated with a high dose of thalidomide. Close positive correlation was observed in the expression of the TNF-α mRNA and that of ICAM-1, VCAM-1, and E-selectin mRNA, respectively. These results indicate that thalidomide exerts its effect on the downregulation of adhesion molecules via TNF-α signaling pathway to inhibit liver fibrosis. PMID:17047296

Novel thalidomide analogues from diamines inhibit pro-inflammatory cytokine production and CD80 expression while enhancing IL-10.

PubMed

Mazzoccoli, Luciano; Cadoso, Silvia H; Amarante, Giovanni W; de Souza, Marcus V N; Domingues, Robert; Machado, Marco A; de Almeida, Mauro V; Teixeira, Henrique C

2012-07-01

Thalidomide is used to treat a variety of diseases including erythema nodosum leprosum, an inflammatory complication of leprosy. However, this drug has severe teratogenic activity and novel thalidomide analogues might be used to treat diseases without this severe side effect. A series of diamine compounds containing two hydrolyzed phthalimide units were chosen as analogues of thalidomide and evaluated regarding their capacity to regulate the production of molecules involved in inflammatory responses. TNF-α, IL-12 and IL-10 production, and the expression of CD80 and CD86 were investigated in LPS plus IFN-γ-stimulated J774A.1 cells by ELISA and flow cytometry, respectively. The expression of TNF-α and IL-10 mRNA was analyzed by real time RT-PCR. TNF-α, IL-6, IFN-γ, CXCL9 and CXCL10 production by human peripheral blood mononuclear cells (PBMC) were evaluated by flow cytometry. Compounds 3, 6 and 9 greatly inhibited TNF-α and IL-12 production while enhancing IL-10. In addition, CD80 expression was inhibited, but not CD86. The compounds inhibited TNF-α production by PBMC more than thalidomide and also had an inhibitory effect on the production of IL-6, IFN-γ, CXCL9 and CXCL10. Levels of mRNA for TNF-α were reduced after treatment with the compounds, suggesting post- transcriptional effects. The compounds had no effect on cell viability. Our results indicate that the novel diamine compounds 3, 6 and 9 inhibit critical pro-inflammatory cytokines and stimulate IL-10, which make them attractive candidate drugs for the treatment of certain inflammatory conditions and cancer. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Thalidomide Reduces Hemorrhage of Brain Arteriovenous Malformations in a Mouse Model.

PubMed

Zhu, Wan; Chen, Wanqiu; Zou, Dingquan; Wang, Liang; Bao, Chen; Zhan, Lei; Saw, Daniel; Wang, Sen; Winkler, Ethan; Li, Zhengxi; Zhang, Meng; Shen, Fanxia; Shaligram, Sonali; Lawton, Michael; Su, Hua

2018-05-01

Brain arteriovenous malformation (bAVM) is an important risk factor for intracranial hemorrhage. Current treatments for bAVM are all associated with considerable risks. There is no safe method to prevent bAVM hemorrhage. Thalidomide reduces nose bleeding in patients with hereditary hemorrhagic telangiectasia, an inherited disorder characterized by vascular malformations. In this study, we tested whether thalidomide and its less toxic analog, lenalidomide, reduce bAVM hemorrhage using a mouse model. bAVMs were induced through induction of brain focal activin-like kinase 1 ( Alk1 , an AVM causative gene) gene deletion and angiogenesis in adult Alk1 -floxed mice. Thalidomide was injected intraperitoneally twice per week for 6 weeks, starting either 2 or 8 weeks after AVM induction. Lenalidomide was injected intraperitoneally daily starting 8 weeks after AVM induction for 6 weeks. Brain samples were collected at the end of the treatments for morphology, mRNA, and protein analyses. The influence of Alk1 downregulation on PDGFB (platelet-derived growth factor B) expression was also studied on cultured human brain microvascular endothelial cells. The effect of PDGFB in mural cell recruitment in bAVM was explored by injection of a PDGFB overexpressing lentiviral vector to the mouse brain. Thalidomide or lenalidomide treatment reduced the number of dysplastic vessels and hemorrhage and increased mural cell (vascular smooth muscle cells and pericytes) coverage in the bAVM lesion. Thalidomide reduced the burden of CD68 + cells and the expression of inflammatory cytokines in the bAVM lesions. PDGFB expression was reduced in ALK1-knockdown human brain microvascular endothelial cells and in mouse bAVM lesion. Thalidomide increased Pdgfb expression in bAVM lesion. Overexpression of PDGFB mimicked the effect of thalidomide. Thalidomide and lenalidomide improve mural cell coverage of bAVM vessels and reduce bAVM hemorrhage, which is likely through upregulation of Pdgfb expression. © 2018 American Heart Association, Inc.

Anti-inflammatory effect of thalidomide on H1N1 influenza virus-induced pulmonary injury in mice.

PubMed

Zhu, Haiyan; Shi, Xunlong; Ju, Dianwen; Huang, Hai; Wei, Wei; Dong, Xiaoying

2014-12-01

The purpose of this study is to investigate the anti-inflammatory effect of thalidomide (Thd) on H1N1-induced acute lung injury in mice. BALB/C mice were infected intranasally with influenza A virus (H1N1) and then treated with Thd at a dose of 100 or 200 mg/kg/day for 7 days. Weight loss and survival of mice were monitored for 14 days after virus challenge, and the serum and lung tissues were collected at 4 days for histological and biochemical analysis. The results showed that Thd significantly improved the survival rate, reduced the infiltration of inflammatory cells and cytokine (e.g., IL-6, TNF-α) and chemokine (e.g., RANTES, IP-10) levels, and inhibited activated p-NFκB p65 in infected mice. These findings suggested that Thd may attenuate H1N1-induced pulmonary injury and thus may find use in the treatment of viral diseases.

Anti-Inflammatory Thalidomide Improves Islet Grafts Survival and Functions in a Xenogenic Environment

PubMed Central

Chen, Chunguang; Kuehn, Carina; Bretzel, Reinhard G.; Linn, Thomas

2009-01-01

Thalidomide possesses both anti-inflammatory and anti-angiogenic properties. This study investigates its potential application in islet transplantation with a xenogenic transplantation model. Transplantation was performed using C57Bl/6 mice and NMRI nu/nu mice as recipients of porcine islets. Moreover, islet graft vasculature and inflammation were investigated to identify the mechanisms of thalidomide action. In the immunocompetent environment of C57Bl/6 mice, a fast graft rejection was observed. The group treated with thalidomide 200 mg/kg BW per day achieved and maintained euglycemia in the complete observation period for 42 days. The treated mice had more functional islet graft mass with less leukocyte infiltration. The pro-inflammatory TNF-α and VEGF content in islet grafted kidneys was significantly lowered by the treatment. By comparison, thalidomide was not effective in improving graft survival in immunocompromised nude mice. It strongly inhibited the VEGF and TNF-α-induced endothelial proliferation of isolated pig islets in a dose dependent manner. The magnitude of thalidomide's inhibitory effect was nearly identical to the effect of VEGF- receptor 2 inhibitor SU416 and anti-TNF-receptor 1 neutralizing antibody, and was reversed by sphingosine-1-phosphate. In conclusion, the anti-inflammatory effect of thalidomide improved islet graft survival and function in a transplantation model with a maximum immune barrier. PMID:19617916

Thalidomide, clarithromycin, lenalidomide and dexamethasone therapy in newly diagnosed, symptomatic multiple myeloma.

PubMed

Mark, Tomer M; Bowman, Isaac A; Rossi, Adriana C; Shah, Manan; Rodriguez, Melissa; Quinn, Ryann; Pearse, Roger N; Zafar, Faiza; Pekle, Karen; Jayabalan, David; Ely, Scott; Coleman, Morton; Chen-Kiang, Selina; Niesvizky, Ruben

2014-12-01

We studied T-BiRD (thalidomide [Thalomid(®)], clarithromycin [Biaxin(®)], lenalidomide [Revlimid(®)] and dexamethasone) in symptomatic, newly diagnosed multiple myeloma. In 28-day cycles, patients received dexamethasone 40 mg/day on days 1, 8, 15, 22, clarithromycin 500 mg twice daily on days 1-28; lenalidomide 25 mg/day on days 1-21; and thalidomide 100 mg/day (50 mg/day on days 1-7 of cycle 1 only) on days 1-28. Twenty-six patients received a median of 6 cycles (range 0-41). Overall response rate (ORR) was 80% for the group and 100% in 11 patients who underwent autologous stem cell transplantation as part of first-line therapy. The 4-year overall survival rate was 74.9%, and the median progression-free survival was 35.6 months. Eight patients discontinued due to regimen toxicity. Grade 3 non hematologic toxicity affected 12 patients (46.2%). T-BiRD is a highly active regimen with potential toxicity limitations. ClinicalTrials.gov identifier: NCT00538733.

Comparative effectiveness and safety of thalidomide and lenalidomide in patients with multiple myeloma in the United States of America: A population-based cohort study.

PubMed

Luo, Jing; Gagne, Joshua J; Landon, Joan; Avorn, Jerry; Kesselheim, Aaron S

2017-01-01

The comparative effectiveness of thalidomide and lenalidomide in the treatment of multiple myeloma has not been established. We conducted an observational cohort study of multiple myeloma patients receiving either thalidomide or lenalidomide in routine care in the United States of America to assess their comparative survival and rates of peripheral neuropathy. Myeloma patients were identified and followed using administrative claims data from a large national health insurance provider (UnitedHealth). Patients were eligible if they initiated treatment with either lenalidomide or thalidomide between 2004 and 2013. Propensity score stratified Cox proportional hazards regression was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for death and new-onset peripheral neuropathy (defined by International Classification of Disease, Ninth Revision codes or a new prescription intended to treat neuropathic pain). Our cohort included 1264 myeloma patients who initiated either thalidomide or lenalidomide. Among 406 new users of thalidomide, 142 (35%) developed peripheral neuropathy during a mean 499 person-days of follow-up. Among 858 new users of lenalidomide, 244 (29%) developed neuropathy during 587 person-days. Compared with thalidomide initiators, lenalidomide initiators had a reduced risk of peripheral neuropathy (HR 0.71, 95% CI: 0.56-0.92). We found no difference in rates of death (HR 1.00, 95% CI: 0.71-1.41). Our results agree with the findings of recently published trials suggesting that thalidomide and lenalidomide are equivalent with respect to survival outcomes but different with respect to neurotoxicity in clinical practice settings. Copyright © 2016 Elsevier Ltd. All rights reserved.

Thalidomide and prednisolone versus prednisolone alone as consolidation therapy after autologous stem-cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the ALLG MM6 multicentre, open-label, randomised phase 3 study.

PubMed

Kalff, Anna; Kennedy, Nola; Smiley, Angela; Prince, H Miles; Roberts, Andrew W; Bradstock, Kenneth; De Abreu Lourenço, Richard; Frampton, Chris; Spencer, Andrew

2014-12-01

We previously showed that consolidation therapy with thalidomide and prednisolone improved progression-free and overall survival in patients with multiple myeloma who had undergone autologous stem-cell transplantation. We aimed to assess whether these survival advantages were durable at 5 years. The ALLG MM6 trial was a multicentre, open-label, randomised phase 3 trial done between Jan 13, 2002, and March 15, 2005, at 29 sites in Australia and New Zealand. Patients with newly diagnosed multiple myeloma were randomly assigned (1:1), via computer-generated randomisation charts, to receive indefinite prednisolone maintenance alone (control group) or in combination with 12 months of thalidomide consolidation (thalidomide group) after autologous stem-cell transplantation. Randomisation was stratified by treating centre and pre-transplantation concentrations of β2 microglobulin. Patients and treating physicians were not masked to treatment allocation. Primary endpoints were progression-free survival and overall survival. Analysis was by intention to treat. Secondary endpoints were overall response to salvage therapy, incidence of second primary malignancy incidence, and cost-effectiveness. This trial is registered with the Australian and New Zealand Clinical Trials Registry, number ACTRN12607000382471. We randomly assigned 269 patients to the thalidomide (n=114) or control group (n=129). After a median follow-up of 5·4 years (IQR 3·1-7·2), estimated 5-year progression-free survival was 27% (95% CI 23-32) in the thalidomide group and 15% (11-18) in the control group (hazard ratio [HR] 0·16, 95% CI 0·044-0·58; p=0·0054) and 5-year overall survival was 66% (95% CI 61-70) and 47% (42-51), respectively (HR 0·12, 95% CI 0·028-0·56; p=0·0072). There was no difference in overall response to salvage therapy, survival post-progression, or incidence of secondary malignancies between the two groups. Incremental cost-effectiveness ratio was AUS$26 996 per mean life-year gained. Consolidation therapy with thalidomide and prednisolone after autologous stem-cell transplantaion is an acceptable therapeutic approach when alternative drugs are not available. Pharmion Corporation, Novartis Pharmaceuticals, Amgen Australia, The Merrin Foundation, and Alfred Health. Copyright © 2014 Elsevier Ltd. All rights reserved.

Clinical studies on teenage Brazilian victims of thalidomide.

PubMed

Schmidt, M; Salzano, F M

1983-07-01

Ninety-three Brazilian teenagers with thalidomide embryopathy were studied. The pattern of distribution of their most significant defect was: upper limbs, 66; lower limbs, 8; all four limbs, 12; head, 7. Only 10 individuals presented the major defect unilaterally. In 30 of 83 with bilateral defects there were differences in severity between the two sides. Of the 31 patients whose spines had been X-rayed, 16 showed defects, the most common being spina bifida occulta at S1. Gynecomasty was found in three of the patients having major upper limb defects.

Use of thalidomide for severe recurrent aphthous stomatitis: a multicenter cohort analysis.

PubMed

Hello, Muriel; Barbarot, Sébastien; Bastuji-Garin, Sylvie; Revuz, Jean; Chosidow, Olivier

2010-05-01

Severe recurrent aphthous stomatitis (SRAS) is a rare, disabling disorder of unknown etiology. Thalidomide is an effective second-line therapy for SRAS, but is suppressive rather than curative, and adverse events limit its use. Few reports describe the efficacy, tolerance, and safety of thalidomide, and how it is actually used as long-term (maintenance) therapy for SRAS. Therefore, we conducted this study to describe thalidomide use in the real-life management of a cohort of patients with SRAS. This multicenter retrospective cohort study covered a period of 5 years and 5 months (January 2003-May 2008). Patients who had started thalidomide monotherapy for SRAS during the 2003-2006 period were eligible. Data were collected from patients' medical charts and supplemented by patients' responses during a targeted telephone interview. Ninety-two patients followed at 14 centers were included: 76 had oral or bipolar aphthosis, and 16 had Behçet disease. Thalidomide was rapidly effective: 85% (78/92) entered complete remission (CR) within a median of 14 days. Response time was independent of the initial thalidomide dose (r = 0.04). Thalidomide was continued for > or =3 months (maintenance therapy) by 77/92 (84%) of the patients on 1 of 2 maintenance regimens: continuous therapy with regular intake (60/77) or intermittent therapy in response to attacks (17/77). Although intermittent therapy was less restrictive than continuous therapy, medical supervision under the former was less rigorous. The median maintenance dose was 100 mg/week, and did not reflect the initial dose (r = 0.18). The intermittent-treatment group's median dose was significantly lower and its median duration of thalidomide intake significantly longer than for patients on continuous therapy (19 vs. 150 mg/wk; p < 0.0001, and 32 vs. 19 mo; p = 0.002, respectively). Adverse events were reported by 84% (77/92) of patients. They were mostly mild (78% of patients), but sometimes severe (21%). Nevertheless, after 40 months of follow-up, 60% of patients were still receiving continuous or intermittent maintenance therapy with favorable efficacy/tolerance ratios. Despite its retrospective nature, this detailed study provides novel information on the different ways thalidomide is used as SRAS maintenance therapy in a large and unselected cohort of patients. Low-dose maintenance regimens appear to be widely used, effective, and relatively well tolerated. These observations suggest the value of undertaking a randomized trial to assess various maintenance regimens.

Thalidomide enhances both primary and secondary host resistances to Listeria monocytogenes infection by a neutrophil-related mechanism in female B6C3F1 mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guo, Tai L.; Chi, Rui P.; Karrow, Niel A.

2005-12-15

Previously, we have reported that thalidomide can modulate the immune responses in female B6C3F1 mice. Furthermore, thalidomide immunomodulation increased primary host resistance to intravenously infected Listeria monocytogenes. The present study was intended to evaluate the mechanisms underlying the enhanced host resistance to L. monocytogenes by focusing on the neutrophils. Female B6C3F1 mice were treated intraperitoneally with thalidomide (100 mg/kg) for 15 days. Exposure to thalidomide increased the numbers of neutrophils in the spleens and livers of L. monocytogenes-infected mice when compared to the L. monocytogenes-infected control mice. Additionally, the percentage of neutrophils was also significantly increased after Thd treatment inmore » L. monocytogenes-infected mice. Further studies using antibodies to deplete corresponding cells indicated that thalidomide-mediated increase in primary host resistance (both the moribundity and colony counts in the liver and spleen) to L. monocytogenes infection was due to its effect on neutrophils but not CD8{sup +} T cells or NK cells. Finally, Thd exposure also increased host resistance to secondary host resistance to L. monocytogenes infection, and depletion of neutrophils abolished the protective effect. In conclusion, thalidomide enhanced host resistance to both primary and secondary L. monocytogenes infections by a neutrophil-related mechanism in female B6C3F1 mice.« less

[Study the effect and mechanism of thalidomide in model of inflammatory bowed disease].

PubMed

Wang, Xuan; Ouyang, Qin

2005-07-01

To assess the effect of thalidomide on Trinitrobenzensulphonic acid (TNBS)-induced or oxazolone-induced colitis and discuss the possible mechanism of its action. Transmural colitis was induced by TNBS in three groups of rats (n=6 each), and distal colitis was induced by oxazolone in three groups of rats (n=6 each). Then the rats of the groups were treated with thalidomide [200 mg/(kg x d)], prednisone [5 mg/(kg x d)] or vehicle (olive oil) respectively by oral gavage. The colitis was allowed to run its course for 7 d after gavage and at that time the following endpoints were assessed. Colitis was evaluated by macroscopic and microscopic score; the expression of NF-kappaB P65 was examined by immunohistchemical (IHC); the expression of TNF-alpha mRNA was assayed by hybridization in situ (ISH); the cytokine TNF-alpha, IL-4, IFN-gamma were estimated by enzyme-linked immunoadsordent assay (ELISA). With respect to TNBS model, in the control, prednisone-treatment and thalidomide-treatment groups, the macroscopic and microscopic scores were 6.33 +/- 1.03, 1.67 +/- 0.82, 2.00 +/- 0.89 and 7.33 +/- 1.03, 2.67s +/- 0.82, 3.17 +/- 0.75 respectively; the expression levels of NF-kappaB P65 and TNF-alpha mRNA in the three groups were 62.45 +/- 12.38, 23.62 +/- 8.54, 34.18 +/- 9.65 and 12.42 +/- 4.63, 9.86 +/- 3.29, 4.35 +/- 1.74 respectively; the levels of TNF-alpha, IL-4, IFN-gamma were 540.32 +/- 80.76, 94.58 +/- 14.45, 486.18 +/- 68.47; 396.53 +/- 92.42, 78.45 +/- 12.69, 347.56 +/- 82.94; and 385.68 +/- 88.57, 123.68 +/- 38.15, 378.27 +/- 90.65 respectively. The results indicated that thalidomide treatment significantly reduced colonic inflammation, suppressed NF-kappaB activation,enhanced TNF-alpha mRNA degradation, inhibited the synthesis of the TNF-alpha, IEN-gamma and increased the production of IL-4. However, with respect to oxazolone model, the macroscopic score and microscopic score were 2.00 +/- 0.89, 0.33 +/- 0.52, 1.83 +/- 0.75 and 7.83 +/- 1.47, 3.33 +/- 0.82, 6.50 +/- 1.22 respectively. Thalidomide appeared not to be effective in reducing the oxazolone-induced chronic colitis. Thalidomide may be proposed as a useful drug for Crohn's disease, but further work is needed to clarify whether it is an efficacious agent for ulcerative colitis.

Does thalidomide have an analgesic effect? Current status and future directions.

PubMed

Goli, Veeraindar

2007-04-01

Dramatic relief of pain and life-altering changes in quality of life in some patients treated with immunomodulators such as thalidomide compel us to look more closely at unconventional mechanisms that may be involved in propagation of persistent pain. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and IL-10 are the cytokines with the most evidence in pain modulation. TNF-alpha and IL-1beta seem to initiate neuropathic pain, IL-6 maintains such pain, and IL-10 inhibits this persistent pain. Thalidomide was found to be effective in animal models by inhibiting TNF-alpha production. Several case reports and case series in humans have demonstrated mixed results, with some patients having dramatic responses, especially in chronic intractable conditions such as complex regional pain syndrome. Thalidomide may be an alternative for some patients with intractable pain. However, use of thalidomide is limited by its neurotoxic and teratogenic effects. Newer analogues may significantly improve the risk/benefit of using such immunomodulators.

Prophylactic low-dose aspirin is effective antithrombotic therapy for combination treatments of thalidomide or lenalidomide in myeloma.

PubMed

Niesvizky, Ruben; Martínez-Baños, Déborah; Jalbrzikowski, Jessica; Christos, Paul; Furst, Jessica; De Sancho, Maria; Mark, Tomer; Pearse, Roger; Mazumdar, Madhu; Zafar, Faiza; Pekle, Karen; Leonard, John; Jayabalan, David; Coleman, Morton

2007-12-01

Multiple myeloma (MM) patients have a propensity for thromboembolic events (TE), and treatment with thalidomide/dexamethasone or lenalidomide/dexamethasone increases this risk. This report describes the use of low-dose aspirin (81 mg) as primary thromboprophylaxis in three series of MM patients receiving thalidomide or lenalidomide with other drugs. In the first regimen (clarithromycin, thalidomide, dexamethasone), initiation of low-dose aspirin negated the occurrence of any further TE. In a second study, prophylactic aspirin given with thalidomide/dexamethasone resulted in a rate of TE similar to that seen with dexamethasone alone (without aspirin). A third study (n = 72) evaluated thrombosis rates with aspirin and a lenalidomide-containing regimen (clarithromycin, lenalidomide, dexamethasone). Of nine occurrences of thromboembolism, five were associated with aspirin interruption or poor compliance. Low-dose aspirin appears to reduce the incidence of thrombosis with these regimens. Routine use of aspirin as antithrombotic prophylaxis in MM patients receiving immunomodulatory drugs with corticosteroids is warranted.

Thalidomide Makes a Comeback: A Case Discussion Exercise That Integrates Biochemistry and Organic Chemistry

NASA Astrophysics Data System (ADS)

Bennett, Nicole; Cornely, Kathleen

2001-06-01

The case discussion method, which involves teaching scientific theory in a framework that students can relate to their own world, is an interdisciplinary pedagogical tool. Therefore, case study exercises can be used to integrate biochemistry with other advanced chemistry courses. The case presented here can be used at the end of a second-semester organic chemistry course or in an introductory biochemistry course. The case is a fact-based, fictional story in which an FDA official must decide whether to carry out the agency's threat to shut down several buyers clubs that import thalidomide from overseas and dispense it to their members for the treatment of AIDS. Students are required to read the body of the case, analyze data, and search for information using limited leads. Using well-considered arguments based on their research, they are asked to come to conclusions about how the element of risk involved in thalidomide distribution is assessed. They apply their knowledge of biochemistry to assess how thalidomide acts at the cellular level and they apply their knowledge of organic chemistry in writing mechanisms of thalidomide hydrolysis and in the design of thalidomide analogs. Students are assessed on their ability to work in groups, to critically analyze scientific data, and to develop public policies based on risk-benefit analysis.

Effects of thalidomide in experimental models of post-endoscopic retrograde cholangiopancreatography pancreatitis.

PubMed

Xiong, Guang-Su; Wu, Shu-Ming; Wang, Zhen-Hua; Mo, Jian-Zhong; Xiao, Shu-Dong

2007-03-01

Tumor necrosis factor-alpha (TNF-alpha) plays a central role in the pathogenesis of acute pancreatitis and related systemic complications. The authors hypothesized that it may also play an important role in the development of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). The aim of the study was to evaluate the effectiveness of thalidomide, an immunomodulator that exerts an inhibitory action on TNF-alpha by enhancing mRNA degradation, in reducing post-ERCP pancreatitis in a rat model. A total of 200 mg/kg thalidomide was given intragastric once a day (total 8 days) before the experimental models of post-ERCP pancreatitis were established. After 24 h, histology and edema of pancreas, serum amylase, and TNF-alpha mRNA in the pancreatic tissue were evaluated. Intraductal contrast infusion caused increases in serum amylase, edema, histological grade, and TNF-alpha mRNA of pancreas. The prophylactic use of thalidomide significantly reduced serum amylase, pancreatic edema and the histologic grade of pancreatitis accompanied by a decrease in mRNA expression of TNF-alpha in the pancreatic tissue. Prophylactic intragastric administration of thalidomide provides a protective effect in post-ERCP pancreatitis. The mechanism of the protective effects of thalidomide seems to be the reduction of expression of TNF-alpha mRNA in pancreatic tissue.

Efficacy of thalidomide for the treatment of amyotrophic lateral sclerosis: A phase II open label clinical trial

PubMed Central

STOMMEL, ELIJAH W.; COHEN, JEFFREY A.; FADUL, CAMILO E.; COGBILL, CHRISTOPHER H.; GRABER, DAVID J.; KINGMAN, LINDA; MACKENZIE, TODD; SMITH, JACQUELINE Y. CHANNON; HARRIS, BRENT T.

2013-01-01

Neuroinflammation through the cytokine, tumor necrosis factor-alpha (TNF-α) is thought to play an important role in the pathogenesis of amyotrophic lateral sclerosis (ALS). We conducted a preliminary phase II trial of thalidomide, which reduces levels of TNF-α pre-transcriptionally and post-transcriptionally in vivo and has been shown to prolong disease duration and extend the lifespan of transgenic animal models of ALS. Patients who met diagnostic criteria for ALS received thalidomide at escalating doses to a target dose of 400 mg/day. The primary endpoints in the trial were the ALS Functional Rating Scale (ALSFRS) and pulmonary function testing (PFT) curves after nine months of thalidomide treatment that were compared to historical controls. Secondary endpoints were: survival stratified for newly diagnosed and progressive disease, toxicity, quality of life, and serum cytokine measurements. Twenty-three patients were enrolled, but only 18 were evaluable for the primary outcome. There was no improvement in the ALSFRS or PFT compared to historical controls. Thalidomide had several side-effects in our ALS patients. There was no significant shift in cytokine profile after treatment compared to baseline. In conclusion, treatment of ALS with the TNF-α inhibitor, thalidomide, does not appear to effectively modulate disease progression and can cause adverse effects. PMID:19922130

Effects of thalidomide on DMBA-induced oral carcinogenesis in hamster with respect to angiogenesis.

PubMed

Yang, Y; Ge, J-P; Zhou, Z-T

2009-05-01

Thalidomide has been shown to have anti-angiogenic effects in pre-clinical models as well as a significant antitumor effect in hematologic tumors. However, the effects of thalidomide on oral pre-malignant lesions and oral carcinogenesis remain unexplored. The authors aimed to investigate the chemopreventive effect of thalidomide on 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral carcinogenesis in hamsters with respect to angiogenesis. Seventy male Syrian golden hamsters were randomly divided into five groups, with two of 20 and three of 10. DMBA solution (0.5% in acetone) was applied topically to the left cheek pouch of male Syrian golden hamsters in group A and B, while animals in group C were painted with acetone, three times a week for 6 weeks. For the next 18 weeks, animals in group B and D received thalidomide daily (40 mg/kg body weight/day) by gavage, animals in group A and C received same volume of saline. Animals in group E received no treatment and served as blank control. At the end of the experiment, animals were killed and tissue samples were collected for examinations. Thalidomide significantly decreased the squamous cell carcinoma (SCC) incidence from 57.9 to 11.8%; angiogenesis was inhibited in dysplasia and SCC. The gene expression of vascular endothelium growth factor and tumor necrosis factor (TNF)-alpha was downregulated. Thalidomide has inhibitory effect against the malignant transformation of oral pre-cancerous lesion and angiogenesis during oral carcinogenesis. Such inhibition is related to its modulation of TNF-alpha.

[Effectiveness of thalidomide for erythema nodosum leprosum (ENL): retrospective study of 20 Japanese cases in National Sanatrium Oku-Komyoen].

PubMed

Matsuki, Takanobu; Okano, Yoshiko; Aoki, Yoshinori; Ishida, Yutaka; Hatano, Kentaro; Kumano, Kimiko

2014-12-01

Thalidomide is a TNF-alpha inhibitor and has been administrated for erythema nodosum leprosum (ENL, Type II leprosy reaction) which is one of leprosy reactions and can cause serious illness to patients oflepromatous pole among the immune spectrum. Twenty live cases (at May, 2011) were identified to whom thalidomide had been administrated since 1978 for their ENL reactions. Data were collected from their clinical records in order to evaluate the usage and effectiveness of thalidomide in National Sanatorium Oku-Komyoen, Okayama, Setouchi-city, Japan. Individual data includes bacillary index (BI), total dose, average daily dose, maximum daily dose, minimum daily dose, methods of thalidomide administration and change of symptoms of ENL. Results: No adverse effect was found among 20 cases. Average daily dose of 20 cases was 19 mg. Regarding to the maximum daily dose, in 3 cases (15%) more than 100 mg, in 3 cases (15%) 50 mg, and in 14 cases (70%) less than 40 mg was administrated. Dose was gradually tapered in most cases. From clinical records, thalidomide was found effective for ENL in 19 cases and clinicians concerned were trying to adjust the proper dose of the drug carefully depending on the current symptoms, because there was no guideline of thalidomide administration for ENL. This data suggests that even less than 50-100 mg as the initial daily dose was still effective, though 50-100 mg daily dose is recommended in the current guideline of Japan (2011) and more dose had been administrated in USA and India.

Elotuzumab in combination with thalidomide and low-dose dexamethasone: a phase 2 single-arm safety study in patients with relapsed/refractory multiple myeloma.

PubMed

Mateos, María-Victoria; Granell, Miguel; Oriol, Albert; Martinez-Lopez, Joaquin; Blade, Joan; Hernandez, Miguel T; Martín, Jesus; Gironella, Mercedes; Lynch, Mark; Bleickardt, Eric; Paliwal, Prashni; Singhal, Anil; San-Miguel, Jesus

2016-11-01

Elotuzumab is an immunostimulatory, humanized immunoglobulin G1 monoclonal antibody that selectively targets and kills signalling lymphocytic activation molecule family member 7-expressing myeloma cells. We evaluated the safety and tolerability of elotuzumab 10 mg/kg combined with thalidomide 50-200 mg and dexamethasone 40 mg (with/without cyclophosphamide 50 mg) in patients with relapsed/refractory multiple myeloma (RRMM). The primary endpoint was the proportion of grade ≥3 non-haematological adverse events (AEs); other endpoints included the number of dose reductions/discontinuations and efficacy. Forty patients were treated, who had a median of three previous therapies, including bortezomib (98%) and lenalidomide (73%). Grade ≥3 non-haematological AEs were reported in 63% of patients, most commonly asthenia (35%) and peripheral oedema (25%). Six (15%) patients had an infusion reaction. Twenty-six (65%) patients had ≥1 dose reduction/discontinuation due to an AE, none related to elotuzumab. Overall response rate was 38%; median progression-free survival was 3·9 months. Median overall survival was 16·3 months and the 1-year survival rate was 63%. Minimal incremental toxicity was observed with addition of elotuzumab to thalidomide/dexamethasone with or without cyclophosphamide, and efficacy data suggest clinical benefit in a highly pre-treated population. Elotuzumab combined with thalidomide may provide an additional treatment option for patients with RRMM. © 2016 John Wiley & Sons Ltd.

Cytokines, Neovascularization and Breast Cancer

DTIC Science & Technology

1997-10-01

Specimens: Immunohistochemical Analysis 17 Study rVD: The effect of Thalidomide on IL-8 Expression by Human Breast Cells in vitro 18 Study rVE: IL-8...The effect of Thalidomide on IL-8 Expression bv Human Breast Cells in vitro Our overall plan for this investigation is to utilize angiogenesis...Rationale Page 18 DAMD17-94-J-4317 Scott H. Kurtzman, MD The mechanism of the anti-angiogenic effects of thalidomide are not known. One possibility

Thalidomide Improves the Intestinal Mucosal Injury and Suppresses Mesenteric Angiogenesis and Vasodilatation by Down-Regulating Inflammasomes-Related Cascades in Cirrhotic Rats

PubMed Central

Li, Tzu-Hao; Huang, Chia-Chang; Yang, Ying-Ying; Lee, Kuei-Chuan; Hsieh, Shie-Liang; Hsieh, Yun-Cheng; Alan, Lin; Lin, Han-Chieh; Lee, Shou-Dong; Tsai, Chang-Youh

2016-01-01

Background and Aims By blocking TNFα-related effects, thalidomide not only inhibits hepatic fibrogenesis but improves peripheral vasodilatation and portal hypertension in cirrhotic rats. Nonetheless, the investigation of thalidomide's effects on splanchnic and collateral microcirculation has been limited. Our study explored the roles of intestinal and mesenteric TNFα along with inflammasome-related pathway in relation to cirrhosis and the splanchnic/collateral microcirculation. Methods Using in vivo and in vitro approaches, mechanisms of the effects of thalidomide on intestinal and mesenteric inflammatory, vasodilatory and angiogenic cascades-related abnormalities were explored in cirrhotic rats that had received 1-month thalidomide (C-T) treatment. Results In cirrhotic rats, high tumor necrosis factor (TNF)α, vascular endothelial growth factor (VEGF) and nitric oxide (NO)x levels were associated with the NOD-like receptors protein 3 (NLRP3), IL-1β and caspase-1 inflammasome over-expression in splenorenal shunt and mesenteric tissues. The thalidomide-related inhibition of mesenteric and splenorenal shunt inflammasome expression was accompanied by a significantly decreased intestinal mucosal injury and inflammasome immunohistochemical staining expression. Suppression of various angiogenic cascades, namely VEGF-NOS-NO, was paralleled by a decrease in mesenteric angiogenesis as detected by CD31 immunofluorescence staining and by reduced portosystemic shunting (PSS) in C-T rats. The down-regulation of the mesenteric and collateral vasodilatory VEGF-NOS-NO cascades resulted in a correction of vasoconstrictive hypo-responsiveness and in an attenuation of vasodilatory hyper-responsiveness when analyzed by in situ perfusion of the superior mesenteric arterial (SMA) and portosystemic collaterals. There was also a decrease in SMA blood flow and an increase in SMA resistance in the C-T rats. Additionally, acute incubation with thalidomide abolished TNFα-augmented VEGF-mediated migration of and tube formation of human umbilical vein endothelial cells, which was accompanied by corresponding changes in inflammatory and angiogenic substances release. Conclusions The suppression of inflammasome over-expression by chronic thalidomide treatment ameliorates inflammatory, angiogenic and vasodilatory cascades-related pathogenic changes in the splanchnic and collateral microcirculation of cirrhotic rats. Thalidomide seems to be a promising agent that might bring about beneficial changes to the disarrangements of peripheral, hepatic, splanchnic and collateral systems in cirrhosis. PMID:26820153

Effects of thalidomide treatment in heart failure patients.

PubMed

Orea-Tejeda, Arturo; Arrieta-Rodríguez, Oscar; Castillo-Martínez, Lilia; Rodríguez-Reyna, Tatiana; Asensio-Lafuente, Enrique; Granados-Arriola, Julio; Dorantes-García, Joel

2007-01-01

Several studies have reported a direct association between elevated plasma levels of inflammatory cytokines and worse functional class (New York Heart Association [NYHA]) and cardiac function, measured as left ventricular ejection fraction (LVEF). Thalidomide has recently shown to improve LVEF in chronic heart failure patients, accompanied by a marked decrease in plasma levels of tumor necrosis factor alpha (TNF-alpha). In a randomized prospective open label study of men and women with heart failure (HF) due to ischemic and non-ischemic cardiomyopathy who had systolic dysfunction (LVEF <40%) and NHYA classification, functional classes II and III were assigned to control (without thalidomide, 60 patients) or thalidomide group (20 patients). The initial dose of thalidomide was 100 mg once a day, and it was increased to 100 mg twice a day after a period of 10 days, if the prior dosage was well-tolerated. Demographic characteristics, etiology of HF, prior myocardial infarction, co-morbidities associated were registered and laboratory routine test, TNF-alpha serum levels, and echocardiogram were obtained at the beginning and after 6 months of follow-up. Clinical status (NYHA) at the end of the follow-up period, improved moderately in both groups. TNF-alpha levels were initially of 5.88 +/- 0.9 and 6.49 +/- 1.82 vs. 6.32 +/- 1.6 and 7.94 +/- 3.8 pg/ml during follow-up, for thalidomide and control groups, respectively. There were non-significant differences in echocardiography variables. In conclusion, although there is a large amount of information supporting a direct relationship between TNF-alpha and worsening of symptoms and prognosis in patients with HF and recently, the beneficial effect on thalidomide treatment has been suggested, these preliminary observations should be confirmed in a larger prospective study, specially trying to clarify the action mechanisms. (c) 2007 S. Karger AG, Basel.

Epidemiological Surveillance of Birth Defects Compatible with Thalidomide Embryopathy in Brazil

PubMed Central

Vianna, Fernanda Sales Luiz; Lopez-Camelo, Jorge S.; Leite, Júlio César Louguercio; Sanseverino, Maria Teresa Vieira; Dutra, Maria da Graça; Castilla, Eduardo E.; Schüler-Faccini, Lavínia

2011-01-01

The thalidomide tragedy of the 1960s resulted in thousands of children being born with severe limb reduction defects (LRD), among other malformations. In Brazil, there are still babies born with thalidomide embryopathy (TE) because of leprosy prevalence, availability of thalidomide, and deficiencies in the control of drug dispensation. Our objective was to implement a system of proactive surveillance to identify birth defects compatible with TE. Along one year, newborns with LRD were assessed in the Brazilian hospitals participating in the Latin-American Collaborative Study of Congenital Malformations (ECLAMC). A phenotype of LRD called thalidomide embryopathy phenotype (TEP) was established for surveillance. Children with TEP born between the years 2000–2008 were monitored, and during the 2007–2008 period we clinically investigated in greater detail all cases with TEP (proactive period). The period from 1982 to 1999 was defined as the baseline period for the cumulative sum statistics. The frequency of TEP during the surveillance period, at 3.10/10,000 births (CI 95%: 2.50–3.70), was significantly higher than that observed in the baseline period (1.92/10,000 births; CI 95%: 1.60–2.20), and not uniformly distributed across different Brazilian regions. During the proactive surveillance (2007–2008), two cases of suspected TE were identified, although the two mothers had denied the use of the drug during pregnancy. Our results suggest that TEP has probably increased in recent years, which coincides with the period of greater thalidomide availability. Our proactive surveillance identified two newborns with suspected TE, proving to be a sensitive tool to detect TE. The high frequency of leprosy and the large use of thalidomide reinforce the need for a continuous monitoring of TEP across Brazil. PMID:21754997

In vitro anticancer property of a novel thalidomide analogue through inhibition of NF-kappaB activation in HL-60 cells.

PubMed

Li, Min; Sun, Wan; Yang, Ya-ping; Xu, Bo; Yi, Wen-yuan; Ma, Yan-xia; Li, Zhong-jun; Cui, Jing-rong

2009-01-01

To investigate the anticancer property and possible mechanism of action of a novel sugar-substituted thalidomide derivative (STA-35) on HL-60 cells in vitro. TNF-alpha-induced NF-kappaB activation was determined using a reporter gene assay. The MTT assay was used to measure cytotoxicity of the compound. The appearance of apoptotic Sub-G1 cells was detected by flow cytometry analysis. PARP cleavage and protein expression of NF-kappaB p65 and its inhibitor IkappaB were viewed by Western blotting. TA-35 (1-20 micromol/L) suppressed TNF-alpha-induced NF-kappaB activation in transfected cells (HEK293/pNiFty-SEAP) in a dose- (1-20 micromol/L) and time-dependent (0-48 h) manner. It was also shown that STA-35 exerted a dose-dependent inhibitory effect on HL-60 cell proliferation with an IC(50) value of 9.05 micromol/L. In addition, STA-35 induced apoptosis in HL-60 cells, as indicated by the appearance of a Sub-G1 peak in the cell cycle distribution, as well as poly ADP-ribose polymerase (PARP) cleavage. Subsequently, both NF-kappaB p65 and its inhibitor IkappaB gradually accumulated in cytoplasmic extracts in a dose- and time-dependent manner, indicating the blockage of NF-kappaB translocation induced by TNF-alpha from the cytoplasm to the nucleus. A novel sugar-substituted thalidomide derivative, STA-35, is potent toward HL-60 cells in vitro and induces apoptosis by the suppression of NF-kappaB activation.

The Clinical Development of Thalildomide as an Angiogenesis Inhibitor Therapy for Prostate Cancer

DTIC Science & Technology

2005-10-01

regulation of cell adhesion molecules LFA-1 and ICAM-1 after in vitro treatment with the anti- TNF - alpha agent thalidomide . Settles B, Stevenson A...Plasma levels of circulating TNF -α and VEGF measured in 16 thalidomide treated patients seemed to increase after treatment (Table 2). Serum levels of...Logothetis, Christopher J. Page 6 Table 2. Levels of circulating VEGF, bFGF, TNF -α and IL-6 before and after thalidomide treatment. Comparison of

Discovery of the target for immunomodulatory drugs (IMiDs).

PubMed

Ito, Takumi; Ando, Hideki; Handa, Hiroshi

2016-05-01

Half a century ago, the sedative thalidomide caused a serious drug disaster because of its teratogenicity and was withdrawn from the market. However, thalidomide, which has returned to the market, is now used for the treatment of leprosy and multiple myeloma (MM) under strict control. The mechanism of thalidomide action had been a long-standing question. We developed a new affinity bead technology and identified cereblon (CRBN) as a thalidomide-binding protein. We found that CRBN functions as a substrate receptor of an E3 cullin-Ring ligase complex 4 (CRL4) and is a primary target of thalidomide teratogenicity. Recently, new thalidomide derivatives, called immunomodulatory drugs (IMiDs), have been developed by Celgene. Among them, lenalidomide (Len) and pomalidomide (Pom) were shown to exert strong therapeutic effects against MM. It was found that Len and Pom both bind CRBN-CRL4 and recruit neomorphic substrates (Ikaros and Aiolos). More recently it was reported that casein kinase 1a (Ck1a) was identified as a substrate for CRBN-CRL4 in the presence of Len, but not Pom. Ck1a breakdown explains why Len is specifically effective for myelodysplastic syndrome with 5q deletion. It is now proposed that binding of IMiDs to CRBN appears to alter the substrate specificity of CRBN-CRL4. In this review, we introduce recent findings on IMiDs.

Efficacy of single-agent bortezomib vs. single-agent thalidomide in patients with relapsed or refractory multiple myeloma: a systematic comparison

PubMed Central

Prince, H Miles; Adena, Michael; Smith, Dell Kingsford; Hertel, Judy

2007-01-01

Objective: To conduct a systematic review of the efficacy of single-agent bortezomib vs. single-agent thalidomide in patients with relapsed/refractory multiple. Methods: Publications in English from 1966 to June 2005 (MEDLINE, EMBASE, Cochrane library), publication reference lists, Janssen-Cilag data-on-file and abstracts from recent multiple myeloma conferences were reviewed. Prospective studies containing at least a single arm of either treatment group with n ≥ 30 were included. Studies adding dexamethasone for non-responders were excluded. Statistical pooling was performed for response rate and overall survival. Results: One bortezomib study (n = 333, NEJM 2005, 352; 2487–98) and 15 thalidomide (n = 1007) studies met these criteria and were included. Patient baseline characteristics including age, gender, IgG:IgA, disease duration and beta-2 microglobulin were well matched except that 48% of bortezomib patients had received prior thalidomide. Response rate, defined as serum M-protein reduction ≥ 50%, was 53% for patients receiving bortezomib vs. 32% for thalidomide (P < 0.001, n = 10 studies). Response rate determined by European Group for Blood and Marrow Transplantation (EBMT) criteria was 41% for patients receiving bortezomib vs. 22% for thalidomide (P < 0.001, n = 4 studies). Conclusion: Bortezomib was associated with a significantly higher response rate and complete remission rate using both M-protein and EBMT criteria. PMID:17608711

Thalidomide

MedlinePlus

... myeloma by strengthening the immune system to fight cancer cells. It treats ENL by blocking the action ... infections, and Kaposi's sarcoma (a type of skin cancer). Thalidomide has also been used to treat some ...

Thalidomide induces mucosal healing in Crohn's disease: case report.

PubMed

Leite, Márcio Rios; Santos, Sandra Sousa; Lyra, André Castro; Mota, Jaciane; Santana, Genoile Oliveira

2011-12-07

Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract that is defined by relapsing and remitting episodes. Tumor necrosis factor alpha (TNF-α) appears to play a central role in the pathophysiology of the disease. Standard therapies for inflammatory bowel disease fail to induce remission in about 30% of patients. Biological therapies have been associated with an increased incidence of infections, especially infection by Mycobacterium tuberculosis (Mtb). Thalidomide is an oral immunomodulatory agent with anti-TNF-α properties. Recent studies have suggested that thalidomide is effective in refractory luminal and fistulizing Crohn's disease. Thalidomide costimulates T lymphocytes, with greater effect on CD8+ than on CD4+ T cells, which contributes to the protective immune response to Mtb infection. We present a case of Crohn's disease with gastric, ileal, colon and rectum involvement as well as steroid dependency, which progressed with loss of response to infliximab after three years of therapy. The thorax computed tomography scan demonstrated a pulmonary nodule suspected to be Mtb infection. The patient was started on thalidomide therapy and exhibited an excellent response.

Thalidomide and lenalidomide extend survival in a transgenic mouse model of amyotrophic lateral sclerosis.

PubMed

Kiaei, Mahmoud; Petri, Susanne; Kipiani, Khatuna; Gardian, Gabrielle; Choi, Dong-Kug; Chen, Junyu; Calingasan, Noel Y; Schafer, Peter; Muller, George W; Stewart, Charles; Hensley, Kenneth; Beal, M Flint

2006-03-01

Accumulating evidence suggests that inflammation plays a major role in the pathogenesis of motor neuron death in amyotrophic lateral sclerosis (ALS). Important mediators of inflammation such as the cytokine tumor necrosis factor-alpha (TNF-alpha) and its superfamily member fibroblast-associated cell-surface ligand (FasL) have been implicated in apoptosis. We found increased TNF-alpha and FasL immunoreactivity in lumbar spinal cord sections of ALS patients and G93A transgenic mice. Both increased TNF-alpha and FasL immunostaining in the lumbar spinal cord of the G93A SOD1 transgenic mice occurred at 40-60 d, well before the onset of symptoms and loss of motor neurons. We tested the neuroprotective effect of thalidomide and its analog lenalidomide, pharmacological agents that inhibit the expression of TNF-alpha and other cytokines by destabilizing their mRNA. Treatment with either thalidomide or lenalidomide attenuated weight loss, enhanced motor performance, decreased motor neuron cell death, and significantly increased the life span in G93A transgenic mice. Treated G93A mice showed a reduction in TNF-alpha and FasL immunoreactivity as well as their mRNA in the lumbar spinal cord. Both compounds also reduced interleukin (IL)-12p40, IL-1alpha, and IL-1beta and increased IL-RA and TGF-beta1 mRNA. Therefore, both thalidomide and lenalidomide bear promise as therapeutic interventions for the treatment of ALS.

Efficacy and toxicity of the combination chemotherapy of thalidomide, alkylating agent, and steroid for relapsed/refractory myeloma patients: a report from the Korean Multiple Myeloma Working Party (KMMWP) retrospective study.

PubMed

Kwon, Jihyun; Min, Chang-Ki; Kim, Kihyun; Han, Jae-Joon; Moon, Joon Ho; Kang, Hye Jin; Eom, Hyeon-Seok; Kim, Min Kyoung; Kim, Hyo Jung; Yoon, Dok Hyun; Lee, Jeong-Ok; Lee, Won Sik; Lee, Jae Hoon; Lee, Je-Jung; Choi, Yoon-Seok; Kim, Sung Hyun; Yoon, Sung-Soo

2017-01-01

We analyzed the treatment responses, toxicities, and survival outcomes of patients with relapsed or refractory multiple myeloma who received daily thalidomide, cyclophosphamide, and dexamethasone (CTD) or daily thalidomide, melphalan, and prednisolone (MTP) at 17 medical centers in Korea. Three-hundred and seventy-six patients were enrolled. The combined chemotherapy of thalidomide, corticosteroid, and an alkylating agent (TAS) was second-line chemotherapy in 142 (37.8%) patients, and third-line chemotherapy in 135 (35.9%) patients. The response rate overall was 69.4%. Patients who were not treated with bortezomib and lenalidomide before TAS showed a higher response rate compared to those who were exposed to these agents. The estimated median progression-free survival and overall survival times were 10.4 months and 28.0 months, respectively. The adverse events during TAS were generally tolerable, but 39 (10.4%) patients experienced severe infectious complications. There were no differences in terms of efficacy between CTD and MTP, but infectious complications were more common in CTD group. TAS is an effective treatment regimen which induces a high response rate in relapsed or refractory multiple myeloma patients. Due to the high incidence of grade 3 or 4 infection, proper management of infection is necessary during the TAS treatment, especially the CTD. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Activation of coagulation by a thalidomide-based regimen.

PubMed

Hoshi, Asuka; Matsumoto, Aya; Chung, Jihwa; Isozumi, Yu; Koyama, Takatoshi

2011-09-01

Combining thalidomide (Thal) with chemotherapeutic agents or steroid preparations led to improved response rates in the treatment of multiple myeloma. However, deep vein thrombosis (DVT) is one of the most serious side-effects noted with this regimen, and how a Thal-based regimen causes DVT is unclear. We investigated the procoagulant effects of Thal when combined with chemotherapeutic agents in vitro, focusing on tissue factor (TF) and phosphatidylserine. We examined the effects of the chemotherapeutic doxorubicin hydrochloride (Dox) and the steroid dexamethasone (Dex), with or without Thal. Our study used the human vascular endothelial, monocytic, and myeloma cell lines, EAhy926, THP-1, and RPMI8226, respectively. In EAhy926 and THP-1, Dex treatment increased expression of TF, which may induce procoagulant activity (PCA). Upregulation of TF mRNA correlated with activation of the Egr-1 pathway. In Thal and Dex treatments, the increase of PCA induction from phosphatidylserine exposure was modest. In contrast, Dox and Thal-Dox increased phosphatidylserine exposure in both cell types. In THP-1 cells, cell surface phosphatidylserine exposure correlated with increased PCA by Dox. Thal alone showed a modest increase in phosphatidylserine exposure in endothelial cells and monocytes. When Thal is given in combination with chemotherapies or Dex, endothelial cell and monocyte PCA may be induced through phosphatidylserine exposure, or TF expression. Induction may be protracted by Thal, which has an antiangiogenic activity. Therefore, prophylactic anticoagulant strategies should be considered in Thal-based combination regimens.

Single-dose oral pharmacokinetics of three formulations of thalidomide in healthy male volunteers.

PubMed

Teo, S K; Colburn, W A; Thomas, S D

1999-11-01

Thalidomide was recently approved in the United States for the treatment of erythema nodosum leprosum, a complication of leprosy. The present study determined the bioequivalence and pharmacokinetics of Celgene's commercial and clinical trial thalidomide formulations and the Brazilian Tortuga formulation in an open-label, single-dose, three-way crossover design. Seventeen healthy subjects were given 200 mg of thalidomide on three occasions, and blood samples were collected over 48 hours. Pharmacokinetic parameters were determined using compartmental methods for the two Celgene formulations and using noncompartmental methods for all three formulations. All subjects reported adverse events, none of which was serious or unexpected. Celgene formulations were bioequivalent when comparing Cmax, tmax, and AUC. There was significant variability in plasma levels from the Tortuga formulation, giving a mean profile that was distinctly different from the two Celgene formulations with a lower Cmax value and a longer terminal phase. The lower Cmax was probably due to slower absorption. The terminal rate constant for the Tortuga formulation was significantly less, giving rise to a terminal half-life of 15 hours compared to about 5 to 6 hours for the Celgene formulations. Confidence intervals for Cmax between the Tortuga and the Celgene formulations were outside the 80% to 125% range, indicating a lack of bioequivalence. Extent of absorption, as measured by AUC0-infinity, was approximately equal for all three formulations. Terminal half-life for Tortuga was two to three times longer compared to the Celgene formulations and is clear evidence for absorption rate limitations. The two Celgene formulations showed similar pharmacokinetic parameters with profiles that were best described by a one-compartment model with first-order absorption and elimination. The authors conclude that Celgene's clinical trial and commercial thalidomide formulations are similar to each other and distinctly different from the Tortuga formulation and that all three formulations exhibited absorption rate-limited elimination.

Indeterminate cell histiocytosis in a pediatric patient: successful treatment with thalidomide.

PubMed

Tóth, Béla; Katona, Mária; Hársing, Judit; Szepesi, Agota; Kárpáti, Sarolta

2012-04-01

The 15-year-old male patient presented several 2-6 mm large livid reddish-yellowish, shiny, compact papules on the head, trunk and extremities, which had developed within the last 4 months. Histology showed normal epidermis with dense dermal infiltrate of histiocytes accompanied by few eosinophils, Touton or foamy giant cells. The histiocytes were S100 positive, CD1a negative and did not contain Birbeck granules ultrastructurally. Chest X ray, EEG, skull MRI did not show pathology. Opthalmology, neurology, oto-rhino-laryngology did not reveal alterations. Based upon the clinical symptoms and the histopathology, the diagnosis of indeterminate cell histiocytosis was confirmed. Cryotherapy and cauterization did not stop the progression of the disease, however, under thalidomide treatment no new symptoms developed and the lesions healed with pigmentation.

Intraperitoneal injection of thalidomide attenuates bone cancer pain and decreases spinal tumor necrosis factor-α expression in a mouse model.

PubMed

Gu, Xiaoping; Zheng, Yaguo; Ren, Bingxu; Zhang, Rui; Mei, Fengmei; Zhang, Juan; Ma, Zhengliang

2010-10-05

Tumor necrosis factor α (TNF-α) may have a pivotal role in the genesis of mechanical allodynia and thermal hyperalgesia during inflammatory and neuropathic pain. Thalidomide has been shown to selectively inhibit TNF-α production. Previous studies have suggested that thalidomide exerts anti-nociceptive effects in various pain models, but its effects on bone cancer pain have not previously been studied. Therefore, in the present study, we investigated the effect of thalidomide on bone cancer-induced hyperalgesia and up-regulated expression of spinal TNF-α in a mouse model. Osteosarcoma NCTC 2472 cells were implanted into the intramedullary space of the right femurs of C3H/HeJ mice to induce ongoing bone cancer related pain behaviors. At day 5, 7, 10 and 14 after operation, the expression of TNF-α in the spinal cord was higher in tumor-bearing mice compared to the sham mice. Intraperitoneal injection of thalidomide (50 mg/kg), started at day 1 after surgery and once daily thereafter until day 7, attenuated bone cancer-evoked mechanical allodynia and thermal hyperalgesia as well as the up-regulation of TNF-α in the spinal cord. These results suggest that thalidomide can efficiently alleviate bone cancer pain and it may be a useful alternative or adjunct therapy for bone cancer pain. Our data also suggest a role of spinal TNF-α in the development of bone cancer pain.

Intraperitoneal injection of thalidomide attenuates bone cancer pain and decreases spinal tumor necrosis factor-α expression in a mouse model

PubMed Central

2010-01-01

Background Tumor necrosis factor α (TNF-α) may have a pivotal role in the genesis of mechanical allodynia and thermal hyperalgesia during inflammatory and neuropathic pain. Thalidomide has been shown to selectively inhibit TNF-α production. Previous studies have suggested that thalidomide exerts anti-nociceptive effects in various pain models, but its effects on bone cancer pain have not previously been studied. Therefore, in the present study, we investigated the effect of thalidomide on bone cancer-induced hyperalgesia and up-regulated expression of spinal TNF-α in a mouse model. Results Osteosarcoma NCTC 2472 cells were implanted into the intramedullary space of the right femurs of C3H/HeJ mice to induce ongoing bone cancer related pain behaviors. At day 5, 7, 10 and 14 after operation, the expression of TNF-α in the spinal cord was higher in tumor-bearing mice compared to the sham mice. Intraperitoneal injection of thalidomide (50 mg/kg), started at day 1 after surgery and once daily thereafter until day 7, attenuated bone cancer-evoked mechanical allodynia and thermal hyperalgesia as well as the up-regulation of TNF-α in the spinal cord. Conclusions These results suggest that thalidomide can efficiently alleviate bone cancer pain and it may be a useful alternative or adjunct therapy for bone cancer pain. Our data also suggest a role of spinal TNF-α in the development of bone cancer pain. PMID:20923560

Protective Effect of Thalidomide on Liver Injury in Rats with Acute Pancreatitis via Inhibition of Oxidative Stress.

PubMed

Lv, Peng; Fan, Li-Juan; Li, Hong-Yun; Meng, Qing-Shun; Liu, Jie

2015-01-01

This study was designed to investigate the preventive effect of thalidomide on acute pancreatitis-associated liver injury in the rat and analyze its relationship with oxidative stress. The acute pancreatitis of rats was induced by the retrograde injection of 5% sodium taurocholate into the biliopancreatic duct. Thalidomide (100 mg/kg) was given daily via the intragastric route for 8 days before this injection. The levels of oxidative stress parameters including superoxide dismutase (SOD), glutathione peroxidase (GSHpx), and malondialdehyde (MDA) in the liver were detected by biochemical assay. Nuclear factor-κB p65 (NF-κBp65), tumor necrosis factor α (TNF-α), and intercellular adhesion molecule-1 (ICAM-1) protein and mRNA levels in the liver were detected using western blots and reverse transcriptase polymerase chain reaction, respectively. Compared with the untreated model group, liver histopathology, SOD, GSHpx, MDA levels, NF-κBp65, TNF-α, ICAM-1 protein, and mRNA levels in the liver of rats given thalidomide were improved significantly. Results demonstrate that thalidomide may exert its effects on oxidative stress to attenuate the progression of acute pancreatitis-associated liver injury in rats. © 2015 by the Association of Clinical Scientists, Inc.

Thalidomide alleviates acute pancreatitis-associated lung injury via down-regulation of NFκB induced TNF-α.

PubMed

Lv, Peng; Li, Hong-Yun; Ji, Shu-Sheng; Li, Wen; Fan, Li-Juan

2014-09-01

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 (100mg/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, the 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. Copyright © 2014 Elsevier GmbH. All rights reserved.

Additive Renoprotection by Pioglitazone and Fenofibrate against Inflammatory, Oxidative and Apoptotic Manifestations of Cisplatin Nephrotoxicity: Modulation by PPARs

PubMed Central

Helmy, Mai M.; Helmy, Maged W.; El-Mas, Mahmoud M.

2015-01-01

Nephrotoxicity is a major side effect for the antineoplastic drug cisplatin. Here, we employed pharmacological, biochemical, and molecular studies to investigate the role of peroxisome proliferator-activated receptors (PPARs) in cisplatin nephrotoxicity. Rats were treated with a single i.p. dose of cisplatin (5 mg/kg) alone or combined with pioglitazone (PPARγ agonist), fenofibrate (PPARα agonist), pioglitazone plus fenofibrate, or thalidomide (Tumor necrosis factor-α inhibitor; TNF-α). Cisplatin nephrotoxicity was evidenced by rises in renal indices of functional (blood urea nitrogen, BUN, and creatinine), inflammatory (TNF-α, interleukin 6, IL-6), oxidative (increased malondialdehyde, MDA, and decreased superoxide dismutase, SOD and nitric oxide metabolites, NOx), apoptotic (caspase 3), and histological (glomerular atrophy, acute tubular necrosis and vacuolation) profiles. Cisplatin effects were partly abolished upon concurrent exposure to pioglitazone, fenofibrate, or thalidomide; more renoprotection was observed in rats treated with pioglitazaone plus fenofibrate. Immunostaining showed that renal expressions of PPARα and PPARγ were reduced by cisplatin and restored to vehicle-treated values after simultaneous treatment with pioglitazone or fenofibrate. Fenofibrate or pioglitazone renoprotection remained unaltered after concurrent blockade of PPARα (GW6471) and PPARγ (GW9662), respectively. To complement the rat studies, we also report that in human embryonic kidney cells (HEK293 cells), increases caused by cisplatin in inflammatory, apoptotic, and oxidative biomarkers were (i) partly improved after exposure to pioglitazone, fenofibrate, or thalidomide, and (ii) completely disappeared in cells treated with a combination of all three drugs. These data establish that the combined use of pioglitazone and fenofibrate additively improved manifestations of cisplatin nephrotoxicity through perhaps GW6471/GW9662-insensitive mechanisms. PMID:26536032

Central neurotoxicity of immunomodulatory drugs in multiple myeloma.

PubMed

Patel, Urmeel H; Mir, Muhammad A; Sivik, Jeffrey K; Raheja, Divisha; Pandey, Manoj K; Talamo, Giampaolo

2015-02-24

Immunomodulatory drugs (IMiDs) currently used in the treatment of multiple myeloma, are thalidomide, lenalidomide and pomalidomide. One of the most common side effects of thalidomide is neurotoxicity, predominantly in the form of peripheral neuropathy. We report 6 cases of significant central neurotoxicity associated with IMiD therapy. Treatment with thalidomide (1 patient), lenalidomide (4 patients), and pomalidomide (1 patient) was associated with various clinical manifestations of central neurotoxicity, including reversible coma, amnesia, expressive aphasia, and dysarthria. Central neurotoxicity should be recognized as an important side effect of IMiD therapy.

Central Neurotoxicity of Immunomodulatory Drugs in Multiple Myeloma

PubMed Central

Patel, Urmeel H.; Mir, Muhammad A.; Sivik, Jeffrey K.; Raheja, Divisha; Pandey, Manoj K.; Talamo, Giampaolo

2015-01-01

Immunomodulatory drugs (IMiDs) currently used in the treatment of multiple myeloma, are thalidomide, lenalidomide and pomalidomide. One of the most common side effects of thalidomide is neurotoxicity, predominantly in the form of peripheral neuropathy. We report 6 cases of significant central neurotoxicity associated with IMiD therapy. Treatment with thalidomide (1 patient), lenalidomide (4 patients), and pomalidomide (1 patient) was associated with various clinical manifestations of central neurotoxicity, including reversible coma, amnesia, expressive aphasia, and dysarthria. Central neurotoxicity should be recognized as an important side effect of IMiD therapy. PMID:25852850

TNF-alpha antagonists and thalidomide for the management of gastrointestinal Behçet's syndrome refractory to the conventional treatment modalities: a case series and review of the literature.

PubMed

Hatemi, Ibrahim; Hatemi, Gulen; Pamuk, Omer Nuri; Erzin, Yusuf; Celik, Aykut Ferhat

2015-01-01

Gastrointestinal involvement of Behçet's syndrome is usually treated with glucocorticoids, 5-aminosalicylic acid compounds and azathioprine. However, some patients are refractory to these conventional therapy modalities. In this paper we report our experience on 13 patients with gastrointestinal involvement of Behçet's syndrome who were refractory to the conventional therapy and who were treated with TNF-alpha antagonists and/or thalidomide. We reviewed the charts of our Behçet's syndrome patients with gastrointestinal involvement and identified those who were treated with TNF-alpha antagonists and/or thalidomide. Demographic features, previous and concomitant drugs, previous surgery, time to remission and duration of remission were tabulated. We also performed a systematic review of publications on gastrointestinal involvement of Behçet's syndrome patients treated with TNF-alpha antagonists and/or thalidomide. Among our 64 patients with gastrointestinal involvement of Behçet's syndrome, we identified 13 (20%) (7 women, 6 men, mean age 27.4±9.4) who had been treated with TNF-alpha antagonists and/or thalidomide. Their previous medications were glucocorticoids (13/13), azathioprine (13/13), 5-aminosalicylic acid derivatives (3/13) and budesonide (1/13). Clinical and endoscopic remission was obtained in 10 patients. One patient died with sepsis. The systematic literature search revealed 91 cases who had used TNF-alpha antagonists and 15 who had used thalidomide. Among the patients who had received TNF-alpha antagonists, clinical remission was obtained in 47/91 patients (51%), while endoscopic remission was observed in 21/46 (45%) who had a control colonoscopy. One fifth of our Behçet's syndrome patients with gastrointestinal involvement were refractory to conventional treatment modalities. Remission was obtained with TNF-alpha antagonists and/or thalidomide in about 75% of the cases.

Thalidomide has a significant effect in patients with thalassemia intermedia.

PubMed

Li, YunShuan; Ren, Quan; Zhou, Yali; Li, Pingping; Lin, Wanhua; Yin, Xiaolin

2018-01-01

To investigate the effect of thalidomide in patients with thalassemia intermedia. We observed the effect of thalidomide in seven patients with thalassemia intermedia requiring blood transfusion. Four of the patients were transfusion-independent, and three patients were transfusion-dependent. For the four transfusion-independent patients, hemoglobin concentration increased significantly (≥2 g/dl) in three and moderately (1-2 g/dl) in one. After 3 months of treatment, hemoglobin concentration increased 3.2 ± 1.2 g/dl compared to pretreatment. Among the three transfusion-dependent patients, transfusion was terminated after one month of treatment in one patient and decreased >50% in the other two patients, accompanied by an increase in the average hemoglobin concentration. Thalidomide had a significant effect in patients with thalassemia intermedia. Further studies of a larger scale and more rigorous design are warranted.

Living with thalidomide: health status and quality of life at 40 years.

PubMed

Bent, N; Tennant, A; Neumann, V; Chamberlain, M A

2007-06-01

Thalidomide was first synthesized in 1953 and was subsequently marketed as a mild hypnotic and sedative in more than 20 countries. By 2001 it was estimated that there were 5,000 survivors from the 10,000 - 12,000 babies who were, as a result, born with severe abnormalities. For these survivors, recent concerns have emerged about their physical state, in particular their levels of pain and their ability to maintain independence. It was therefore wished to ascertain health status and current concerns amongst a sample of survivors living in the UK. A combination of qualitative and quantitative methodologies was employed. Qualitative interviews were undertaken with a sample drawn from the population affected by thalidomide known to the Thalidomide Trust. Selection of participants was based upon a theoretical sample frame. Postal questionnaires to examine health status and various psychosocial aspects concerned with living with the consequences of thalidomide were sent subsequently to these same participants and to a random sample of those not originally drawn for the qualitative interviews. For the qualitative interviews, 28 agreed to take part; two refused and the remainder did not respond. Those agreeing to interview were representative of the original compensation bands (Chi-Square = 3.929; p = 0.416). Several themes emerged from these interviews, including the effects on work and career; coping in terms of attitude to life, self-image, confidence, self-esteem, stress and emotion; relationships, independent living issues and emergent problems such as pain, quality of life, and anxiety about the future. A postal questionnaire was then sent to those who had agreed to interview (28), plus a random sample of the remaining group who were not initially chosen for the qualitative interviews. In total 82 people were sent the questionnaire, of whom 41 (50%) responded. Two-thirds of responders were female. Seven out of ten lived with a partner, and over half (56%) had children. Almost half (46%) were in work, but 32% reported they were permanently unable to work because of disability. Current levels of impairment were found to be similar across groups defined by the original compensation band. In contrast, the activity limitation measures showed a steep gradient across bands but only 37% considered themselves disabled. Nevertheless, despite the restriction in activities for some, levels of participation were similar across bands; likewise simple summary items on health status and quality of life were similar and 70% reported their quality of life (QoL) was good or better than good. Yet nine in ten believed that their body was less flexible than in the past. Almost as many reported they were less able to carry things. It turns out that when compensation bands were grouped (1 - 3, 4 - 5) to highlight those most severely affected according to the original assessment, then those in the higher band grouping reported significantly more musculoskeletal problems, high levels of fatigue and increasing dependency and feelings of vulnerability. It is clear that the original ranking of disability severity, as expressed through the compensation, bands (allocated in early childhood in most cases), is consistent with current ranking of limitations in activity and participation. Nevertheless, despite high levels of disability amongst some survivors, lifelong adjustments to the original impairments have resulted in more than two thirds reporting at least a good quality of life. However, survivors expressed increasing concern about emerging musculoskeletal and other problems which may compromise hard-won independence.

Thalidomide results in diminished ovarian reserve in reproductive age female IBD patients

PubMed Central

Peng, Xiang; Zhi, Min; Wei, Ming; Li, Ting-Ting; Zhang, Min; Zhang, Yuan-Qi; He, Huan; Su, Mingli; Wang, Wei; Chen, Jun-rong; Tang, Jian; Gao, Xiang; Hu, Pin-Jin; Liang, Xiao-Yan

2017-01-01

Abstract The effectiveness of thalidomide in treating inflammatory bowel disease (IBD) has been widely recognized. Meanwhile, many serious adverse drug reactions have been observed, but no know reports on ovarian reserve function. Female patients, ranging in age between 18 and 40, were referred to our institution to undergo sex hormone detection and ultrasonic scanning for ovarian function assessment, between February 1, 2016 and September 31, 2016. Thirty-three patients treated with thalidomide (group A), 73 patients without thalidomide (group B), and 78 healthy women as control were studied. Menstrual disorder was higher in group A than group B (78.8% vs 57.2%, P < 0.05), and both groups were higher than control group 33.3%, P < 0.05. Anti-Mullerian hormone (AMH) levels and antral follicle count (AFC) in group A were lower than group B, P < 0.05, while estradiol (E2) and follicle-stimulating hormone (FSH) levels were no different between 2 groups. Crohn Disease Endoscopic Index of Severity (CDEIS) and thalidomide were the independent risk factors in diminished ovarian reserve (DOR), and when dose reached 75 mg/day, 5 g total, or when treatment time reached 10 months respectively. These influence may increasing (P < 0.05), but they may recover after stopping (P < 0.05). Thalidomide was an independent risk factor leading to DOR in female IBD patients, the influence may increasing when daily dose and accumulated dose reached 75 mg/day and 5 g total dose, but may be reversed by stopping. PMID:28538364

Differentiation of antiinflammatory and antitumorigenic properties of stabilized enantiomers of thalidomide analogs

PubMed Central

Jacques, Vincent; Czarnik, Anthony W.; Judge, Thomas M.; Van der Ploeg, Lex H. T.; DeWitt, Sheila H.

2015-01-01

Therapeutics developed and sold as racemates can exhibit a limited therapeutic index because of side effects resulting from the undesired enantiomer (distomer) and/or its metabolites, which at times, forces researchers to abandon valuable scaffolds. Therefore, most chiral drugs are developed as single enantiomers. Unfortunately, the development of some chirally pure drug molecules is hampered by rapid in vivo racemization. The class of compounds known as immunomodulatory drugs derived from thalidomide is developed and sold as racemates because of racemization at the chiral center of the 3-aminoglutarimide moiety. Herein, we show that replacement of the exchangeable hydrogen at the chiral center with deuterium allows the stabilization and testing of individual enantiomers for two thalidomide analogs, including CC-122, a compound currently in human clinical trials for hematological cancers and solid tumors. Using “deuterium-enabled chiral switching” (DECS), in vitro antiinflammatory differences of up to 20-fold are observed between the deuterium-stabilized enantiomers. In vivo, the exposure is dramatically increased for each enantiomer while they retain similar pharmacokinetics. Furthermore, the single deuterated enantiomers related to CC-122 exhibit profoundly different in vivo responses in an NCI-H929 myeloma xenograft model. The (−)-deuterated enantiomer is antitumorigenic, whereas the (+)-deuterated enantiomer has little to no effect on tumor growth. The ability to stabilize and differentiate enantiomers by DECS opens up a vast window of opportunity to characterize the class effects of thalidomide analogs and improve on the therapeutic promise of other racemic compounds, including the development of safer therapeutics and the discovery of new mechanisms and clinical applications for existing therapeutics. PMID:25775521

Design, synthesis, and evaluation of cyclic amide/imide-bearing hydroxamic acid derivatives as class-selective histone deacetylase (HDAC) inhibitors.

PubMed

Shinji, Chihiro; Maeda, Satoko; Imai, Keisuke; Yoshida, Minoru; Hashimoto, Yuichi; Miyachi, Hiroyuki

2006-11-15

A series of hydroxamic acid derivatives bearing a cyclic amide/imide group as a linker and/or cap structure, prepared during our structural development studies based on thalidomide, showed class-selective potent histone deacetylase (HDAC)-inhibitory activity. Structure-activity relationship studies indicated that the steric character of the substituent introduced at the cyclic amide/imide nitrogen atom, the presence of the amide/imide carbonyl group, the hydroxamic acid structure, the shape of the linking group, and the distance between the zinc-binding hydroxamic acid group and the cap structure are all important for HDAC-inhibitory activity and class selectivity. A representative compound (30w) showed potent p21 promoter activity, comparable with that of trichostatin A (TSA), and its cytostatic activity against cells of the human prostate cell line LNCaP was more potent than that of the well-known HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA).

Immunomodulatory drugs disrupt the cereblon-CD147-MCT1 axis to exert antitumor activity and teratogenicity.

PubMed

Eichner, Ruth; Heider, Michael; Fernández-Sáiz, Vanesa; van Bebber, Frauke; Garz, Anne-Kathrin; Lemeer, Simone; Rudelius, Martina; Targosz, Bianca-Sabrina; Jacobs, Laura; Knorn, Anna-Maria; Slawska, Jolanta; Platzbecker, Uwe; Germing, Ulrich; Langer, Christian; Knop, Stefan; Einsele, Herrmann; Peschel, Christian; Haass, Christian; Keller, Ulrich; Schmid, Bettina; Götze, Katharina S; Kuster, Bernhard; Bassermann, Florian

2016-07-01

Immunomodulatory drugs (IMiDs), such as thalidomide and its derivatives lenalidomide and pomalidomide, are key treatment modalities for hematologic malignancies, particularly multiple myeloma (MM) and del(5q) myelodysplastic syndrome (MDS). Cereblon (CRBN), a substrate receptor of the CRL4 ubiquitin ligase complex, is the primary target by which IMiDs mediate anticancer and teratogenic effects. Here we identify a ubiquitin-independent physiological chaperone-like function of CRBN that promotes maturation of the basigin (BSG; also known as CD147) and solute carrier family 16 member 1 (SLC16A1; also known as MCT1) proteins. This process allows for the formation and activation of the CD147-MCT1 transmembrane complex, which promotes various biological functions, including angiogenesis, proliferation, invasion and lactate export. We found that IMiDs outcompete CRBN for binding to CD147 and MCT1, leading to destabilization of the CD147-MCT1 complex. Accordingly, IMiD-sensitive MM cells lose CD147 and MCT1 expression after being exposed to IMiDs, whereas IMiD-resistant cells retain their expression. Furthermore, del(5q) MDS cells have elevated CD147 expression, which is attenuated after IMiD treatment. Finally, we show that BSG (CD147) knockdown phenocopies the teratogenic effects of thalidomide exposure in zebrafish. These findings provide a common mechanistic framework to explain both the teratogenic and pleiotropic antitumor effects of IMiDs.

Significance of Fractionated Administration of Thalidomide Combined With γ-Ray Irradiation in Terms of Local Tumor Response and Lung Metastasis

PubMed Central

Masunaga, Shin-ichiro; Sanada, Yu; Moriwaki, Takahiro; Tano, Keizo; Sakurai, Yoshinori; Tanaka, Hiroki; Suzuki, Minoru; Kondo, Natsuko; Narabayashi, Masaru; Watanabe, Tsubasa; Nakagawa, Yosuke; Maruhashi, Akira; Ono, Koji

2014-01-01

Background The aim of this study was to evaluate the significance of fractionated administration of thalidomide combined with γ-ray irradiation in terms of local tumor response and lung metastatic potential, referring to the response of intratumor quiescent (Q) cells. Methods B16-BL6 melanoma tumor-bearing C57BL/6 mice were continuously given 5-bromo-2’-deoxyuridine (BrdU) to label all proliferating (P) cells. The tumor-bearing mice then received γ-ray irradiation after thalidomide treatment through a single or two consecutive daily intraperitoneal administrations up to a total dose of 400 mg/kg in combination with an acute hypoxia-releasing agent (nicotinamide) or mild temperature hyperthermia (MTH). Immediately after the irradiation, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (= P + Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumor-bearing mice, 17 days after irradiation, macroscopic lung metastases were enumerated. Results Thalidomide raised the sensitivity of the total cell population more remarkably than Q cells in both single and daily administrations. Daily administration of thalidomide elevated the sensitivity of both the total and Q cell populations, but especially the total cell population, compared with single administration. Daily administration, especially combined with MTH, decreased the number of lung metastases. Conclusion Daily fractionated administration of thalidomide in combination with γ-ray irradiation was thought to be more promising than single administration because of its potential to enhance local tumor response and repress lung metastatic potential. PMID:29147396

Thalidomide Accelerates the Degradation of Extracellular Matrix in Rat Hepatic Cirrhosis via Down-Regulation of Transforming Growth Factor-β1

PubMed Central

Meng, Qingshun; Liu, Jie; Wang, Chuanfang

2015-01-01

Purpose The degradation of the extracellular matrix has been shown to play an important role in the treatment of hepatic cirrhosis. In this study, the effect of thalidomide on the degradation of extracellular matrix was evaluated in a rat model of hepatic cirrhosis. Materials and Methods Cirrhosis was induced in Wistar rats by intraperitoneal injection of carbon tetrachloride (CCl4) three times weekly for 8 weeks. Then CCl4 was discontinued and thalidomide (100 mg/kg) or its vehicle was administered daily by gavage for 6 weeks. Serum hyaluronic acid, laminin, procollagen type III, and collagen type IV were examined by using a radioimmunoassay. Matrix metalloproteinase-13 (MMP-13), tissue inhibitor of metalloproteinase-1 (TIMP-1), and α-smooth muscle actin (α-SMA) protein in the liver, transforming growth factor β1 (TGF-β1) protein in cytoplasm by using immunohistochemistry and Western blot analysis, and MMP-13, TIMP-1, and TGF-β1 mRNA levels in the liver were studied using reverse transcriptase polymerase chain reaction. Results Liver histopathology was significantly better in rats given thalidomide than in the untreated model group. The levels of TIMP-1 and TGF-β1 mRNA and protein expressions were decreased significantly and MMP-13 mRNA and protein in the liver were significantly elevated in the thalidomide-treated group. Conclusion Thalidomide may exert its effects on the regulation of MMP-13 and TIMP-1 via inhibition of the TGF-β1 signaling pathway, which enhances the degradation of extracellular matrix and accelerates the regression of hepatic cirrhosis in rats. PMID:26446639

Synergistic Inhibition of Thalidomide and Icotinib on Human Non-Small Cell Lung Carcinomas Through ERK and AKT Signaling.

PubMed

Sun, Xiang; Xu, Yang; Wang, Yi; Chen, Qian; Liu, Liu; Bao, Yangyi

2018-05-15

BACKGROUND Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been widely used in the treatment of non-small cell lung cancer (NSCLC) patients with sensitive EGFR mutations. However, the survival of patients with EGFR-TKI administration is limited by the inevitable development of acquired drug resistance. Recently, multi-targeted drugs combination has been shown to be a promising strategy to improve the efficacy of EGFR-TKI treatment and enable the reduction of drug resistance in NSCLC. MATERIAL AND METHODS Humanized NSCLC cell lines PC9 and A549 were co-cultured with thalidomide and/or icotinib to test for anti-tumor efficiency. Cell proliferation was measured by MTT assay, cell apoptosis by flow cytometry and cell migration by wound healing assay. Western blot was performed to determine the expression of caspase-3, -8, -9, Bax, EGFR, VEGF-R, AKT, ERK, MMP2, MMP9, and NF-κB. The xenograft mouse model was used to explore the effects of thalidomide and icotinib in vivo. Immunohistochemical testing was used to determine the expression of Ki-67 and TUNEL staining in tumor tissues. RESULTS Treatments of thalidomide and/or icotinib reduced cell viability, induced apoptosis, and suppressed migration. Attenuation of pEGFR and pVEGF-R resulted in deactivation of ERK and AKT pathways, which eventually increased the anti-proliferative response. In PC9 xenograft model, combined administration of thalidomide and icotinib restrained tumor growth with remarkable reduced Ki-67 index and increased TUNEL positive cells. CONCLUSIONS Thalidomide sensitizes icotinib to increase apoptosis and prevent migration, and it may be a potentially promising anti-tumor drug in lung cancer multi-modality therapy.

Health-related quality-of-life in patients with newly diagnosed multiple myeloma in the FIRST trial: lenalidomide plus low-dose dexamethasone versus melphalan, prednisone, thalidomide

PubMed Central

Delforge, Michel; Minuk, Leonard; Eisenmann, Jean-Claude; Arnulf, Bertrand; Canepa, Letizia; Fragasso, Alberto; Leyvraz, Serge; Langer, Christian; Ezaydi, Yousef; Vogl, Dan T.; Giraldo-Castellano, Pilar; Yoon, Sung-Soo; Zarnitsky, Charles; Escoffre-Barbe, Martine; Lemieux, Bernard; Song, Kevin; Bahlis, Nizar Jacques; Guo, Shien; Monzini, Mara Silva; Ervin-Haynes, Annette; Houck, Vanessa; Facon, Thierry

2015-01-01

We compared the health-related quality-of-life of patients with newly diagnosed multiple myeloma aged over 65 years or transplant-ineligible in the pivotal, phase III FIRST trial. Patients received: i) continuous lenalidomide and low-dose dexamethasone until disease progression; ii) fixed cycles of lenalidomide and low-dose dexamethasone for 18 months; or iii) fixed cycles of melphalan, prednisone, thalidomide for 18 months. Data were collected using the validated questionnaires (QLQ-MY20, QLQ-C30, and EQ-5D). The analysis focused on the EQ-5D utility value and six domains pre-selected for their perceived clinical relevance. Lenalidomide and low-dose dexamethasone, and melphalan, prednisone, thalidomide improved patients’ health-related quality-of-life from baseline over the duration of the study across all pre-selected domains of the QLQ-C30 and EQ-5D. In the QLQ-MY20, lenalidomide and low-dose dexamethasone demonstrated a significantly greater reduction in the Disease Symptoms domain compared with melphalan, prednisone, thalidomide at Month 3, and significantly lower scores for QLQ-MY20 Side Effects of Treatment at all post-baseline assessments except Month 18. Linear mixed-model repeated-measures analyses confirmed the results observed in the cross-sectional analysis. Continuous lenalidomide and low-dose dexamethasone delays disease progression versus melphalan, prednisone, thalidomide and has been associated with a clinically meaningful improvement in health-related quality-of-life. These results further establish continuous lenalidomide and low-dose dexamethasone as a new standard of care for initial therapy of myeloma by demonstrating superior health-related quality-of-life during treatment, compared with melphalan, prednisone, thalidomide. PMID:25769541

Health-related quality-of-life in patients with newly diagnosed multiple myeloma in the FIRST trial: lenalidomide plus low-dose dexamethasone versus melphalan, prednisone, thalidomide.

PubMed

Delforge, Michel; Minuk, Leonard; Eisenmann, Jean-Claude; Arnulf, Bertrand; Canepa, Letizia; Fragasso, Alberto; Leyvraz, Serge; Langer, Christian; Ezaydi, Yousef; Vogl, Dan T; Giraldo-Castellano, Pilar; Yoon, Sung-Soo; Zarnitsky, Charles; Escoffre-Barbe, Martine; Lemieux, Bernard; Song, Kevin; Bahlis, Nizar Jacques; Guo, Shien; Monzini, Mara Silva; Ervin-Haynes, Annette; Houck, Vanessa; Facon, Thierry

2015-06-01

We compared the health-related quality-of-life of patients with newly diagnosed multiple myeloma aged over 65 years or transplant-ineligible in the pivotal, phase III FIRST trial. Patients received: i) continuous lenalidomide and low-dose dexamethasone until disease progression; ii) fixed cycles of lenalidomide and low-dose dexamethasone for 18 months; or iii) fixed cycles of melphalan, prednisone, thalidomide for 18 months. Data were collected using the validated questionnaires (QLQ-MY20, QLQ-C30, and EQ-5D). The analysis focused on the EQ-5D utility value and six domains pre-selected for their perceived clinical relevance. Lenalidomide and low-dose dexamethasone, and melphalan, prednisone, thalidomide improved patients' health-related quality-of-life from baseline over the duration of the study across all pre-selected domains of the QLQ-C30 and EQ-5D. In the QLQ-MY20, lenalidomide and low-dose dexamethasone demonstrated a significantly greater reduction in the Disease Symptoms domain compared with melphalan, prednisone, thalidomide at Month 3, and significantly lower scores for QLQ-MY20 Side Effects of Treatment at all post-baseline assessments except Month 18. Linear mixed-model repeated-measures analyses confirmed the results observed in the cross-sectional analysis. Continuous lenalidomide and low-dose dexamethasone delays disease progression versus melphalan, prednisone, thalidomide and has been associated with a clinically meaningful improvement in health-related quality-of-life. These results further establish continuous lenalidomide and low-dose dexamethasone as a new standard of care for initial therapy of myeloma by demonstrating superior health-related quality-of-life during treatment, compared with melphalan, prednisone, thalidomide. Copyright© Ferrata Storti Foundation.

Ligand-mediated protein degradation reveals functional conservation among sequence variants of the CUL4-type E3 ligase substrate receptor cereblon.

PubMed

Akuffo, Afua A; Alontaga, Aileen Y; Metcalf, Rainer; Beatty, Matthew S; Becker, Andreas; McDaniel, Jessica M; Hesterberg, Rebecca S; Goodheart, William E; Gunawan, Steven; Ayaz, Muhammad; Yang, Yan; Karim, Md Rezaul; Orobello, Morgan E; Daniel, Kenyon; Guida, Wayne; Yoder, Jeffrey A; Rajadhyaksha, Anjali M; Schönbrunn, Ernst; Lawrence, Harshani R; Lawrence, Nicholas J; Epling-Burnette, Pearlie K

2018-04-20

Upon binding to thalidomide and other immunomodulatory drugs, the E3 ligase substrate receptor cereblon (CRBN) promotes proteosomal destruction by engaging the DDB1-CUL4A-Roc1-RBX1 E3 ubiquitin ligase in human cells but not in mouse cells, suggesting that sequence variations in CRBN may cause its inactivation. Therapeutically, CRBN engagers have the potential for broad applications in cancer and immune therapy by specifically reducing protein expression through targeted ubiquitin-mediated degradation. To examine the effects of defined sequence changes on CRBN's activity, we performed a comprehensive study using complementary theoretical, biophysical, and biological assays aimed at understanding CRBN's nonprimate sequence variations. With a series of recombinant thalidomide-binding domain (TBD) proteins, we show that CRBN sequence variants retain their drug-binding properties to both classical immunomodulatory drugs and dBET1, a chemical compound and targeting ligand designed to degrade bromodomain-containing 4 (BRD4) via a CRBN-dependent mechanism. We further show that dBET1 stimulates CRBN's E3 ubiquitin-conjugating function and degrades BRD4 in both mouse and human cells. This insight paves the way for studies of CRBN-dependent proteasome-targeting molecules in nonprimate models and provides a new understanding of CRBN's substrate-recruiting function. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

A TAD better for myeloma therapy?

PubMed

Giralt, Sergio

2010-02-11

In this issue of Blood, Lokhorst and colleagues report on the results of HOVON-50, a phase 3 randomized trial designed to evaluate the effects of thalidomide during induction treatment and as maintenance in patients with multiple myeloma. There were 556 patients randomly assigned either to 3 cycles of VAD or to TAD. All patients were to receive high-dose melphalan with autologous stem cell support followed by maintenance with interferon for the VAD arm or thalidomide for the TAD arm.(1) This study together with other randomized and nonrandomized trials establish a definitive role for thalidomide as induction therapy in conjunction with dexamethasone, anthracyclines, and alkylating agents.

Combining Chimeric Mice with Humanized Liver, Mass Spectrometry, and Physiologically-Based Pharmacokinetic Modeling in Toxicology.

PubMed

Yamazaki, Hiroshi; Suemizu, Hiroshi; Mitsui, Marina; Shimizu, Makiko; Guengerich, F Peter

2016-12-19

Species differences exist in terms of drug oxidation activities, which are mediated mainly by cytochrome P450 (P450) enzymes. To overcome the problem of species extrapolation, transchromosomic mice containing a human P450 3A cluster or chimeric mice transplanted with human hepatocytes have been introduced into the human toxicology research area. In this review, drug metabolism and disposition mediated by humanized livers in chimeric mice are summarized in terms of biliary/urinary excretions of phthalate and bisphenol A and plasma clearances of the human cocktail probe drugs caffeine, warfarin, omeprazole, metoprolol, and midazolam. Simulation of human plasma concentrations of the teratogen thalidomide and its human metabolites is possible with a simplified physiologically based pharmacokinetic model based on data obtained in chimeric mice, in accordance with reported clinical thalidomide concentrations. In addition, in vivo nonspecific hepatic protein binding parameters of metabolically activated 14 C-drug candidate and hepatotoxic medicines in humanized liver mice can be analyzed by accelerator mass spectrometry and are useful for predictions in humans.

Combination therapy with thalidomide, temozolomide and tamoxifen improves quality of life in patients with malignant astrocytomas.

PubMed

Rabbani, Golam; Benzil, Deborah; Wallam, Mohammed N; Chen, Benjamin; Hoang, Albert; Kancherla, Ram; Ahmed, Tauseef

2007-01-01

Patients with malignant astrocytomas (MA) have a poor survival rate despite surgery, radiation therapy (RT), and chemotherapy (CT). Patients deteriorate rapidly with decreasing quality of life (QoL). The purpose of the current study was to determine the safety and efficacy, including QoL evaluation, of oral therapy with temozolomide, thalidomide, and tamoxifen (TTT) in patients with MA in an Institutional Review Board (IRB)-approved, prospective trial. Twenty-three patients met the eligibility requirements and were enrolled after informed consent was signed. After baseline testing, patients received temozolomide 75 mg/m2 orally (p.o.) for the first 21 days, thalidomide 100 mg p.o. daily, and tamoxifen 100 mg p.o. daily for each 28-day cycle. Treatment continued until disease progression. Primary outcome measurements were survival (Kaplan-Meier analysis), response to treatment, toxicity (National Cancer Institute's Common Toxicity Criterion) and QoL evaluation. The Kaplan-Meier analysis showed that survival time from diagnosis was 78.4+/-15 weeks with a median survival of 54.6 weeks and from date of enrollment was 46.1+/-10 weeks with median survival of 33.3 weeks. Toxicity was limited to 5 patients with deep venous thrombosis (DVT), 2 of whom had pulmonary emboli (PE). All recovered with anticoagulation therapy and none suffered long term sequelae. Several QoL measures, including the global health status scores (p=0.003), were significantly improved after 2 cycles of treatment compared to the baseline assessment. The combination of temozolomide, thalidomide and tamoxifen administered as outpatient oral therapy resulted in significantly improved QoL for patients with MA without significant toxicity.

Fifty Years of Predictive Testing for Human Developmental Toxicity: From Thalidomide to Virtual Embryos

EPA Science Inventory

The thalidomide tragedy of the early 1960s led to the three “Segment” tests promulgated by the United States Food and Drug Administration in 1966. The Segment II study involves exposing pregnant rodents or rabbits during organogenesis and examining fetuses prior to pa...

A New Series of Thalidomide Analogs That Have Potent Anti-Angiogenic Properties | NCI Technology Transfer Center | TTC

Cancer.gov

Researchers at the National Cancer Institute (NCI) have synthesized novel thalidomide derivatives that have therapeutic potential for a broad spectrum of cancer related diseases alone, or in combination with existing therapies. The compounds can also be useful for the treatment of autoimmune diseases.

Thalidomide‐induced teratogenesis: History and mechanisms

PubMed Central

2015-01-01

Nearly 60 years ago thalidomide was prescribed to treat morning sickness in pregnant women. What followed was the biggest man‐made medical disaster ever, where over 10,000 children were born with a range of severe and debilitating malformations. Despite this, the drug is now used successfully to treat a range of adult conditions, including multiple myeloma and complications of leprosy. Tragically, a new generation of thalidomide damaged children has been identified in Brazil. Yet, how thalidomide caused its devastating effects in the forming embryo remains unclear. However, studies in the past few years have greatly enhanced our understanding of the molecular mechanisms the drug. This review will look at the history of the drug, and the range and type of damage the drug caused, and outline the mechanisms of action the drug uses including recent molecular advances and new findings. Some of the remaining challenges facing thalidomide biologists are also discussed. Birth Defects Research (Part C) 105:140–156, 2015. © 2015 The Authors Birth Defects Research Part C: Embryo Today: Reviews Published by Wiley Periodicals, Inc. PMID:26043938

[Current therapeutic indications of thalidomide and lenalidomide].

PubMed

Ordi-Ros, Josep; Cosiglio, Francisco Javier

2014-04-22

Thalidomide is a synthetic glutamic acid derivative first introduced in 1956 in Germany as an over the counter medications. It was thought to be one of the safest sedatives ever produced as it was effective in small doses, was not addictive, and did not have acute side-effects such as motor impairment, but was quickly removed from market after it was linked to cases of severe birth defects. The Food and Drug Administration approved use in the treatment of erythema nodosum leprosum. Further, it was shown its effectiveness in unresponsive dermatological conditions such as actinic prurigo, adult Langerhans cell hystiocytosis, aphthous stomatitis, Behçet syndrome, graft-versus-host disease, cutaneous sarcoidosis, erythema multiforme, Jessner-Kanof lymphocytic infiltration of the skin, Kaposi sarcoma, lichen planus, lupus erythematosus, melanoma, prurigo nodularis, pyoderma gangrenosum and others. In May 2006, it was approved for the treating multiple myeloma. New thalidomide analogues have been developed but lack clinical experience. This paper is a review of the history, pharmacology, mechanism of action, clinical applications and side effects of thalidomide and its analogues. Copyright © 2013 Elsevier España, S.L. All rights reserved.

Possible mechanism of protective effect of thalidomide in STZ-induced-neuropathic pain behavior in rats.

PubMed

Taliyan, Rajeev; Sharma, Pyare Lal

2012-04-01

Diabetes-induced neuropathic pain is recognized as one of the most difficult type of pain to treat and conventional analgesics are well known to be partially effective or associated with potential toxicity. Recently, it has been demonstrated that thalidomide, besides its teratogenic potential, reduced chronic pain in an SNL experimental pain model. The present study was designed to investigate the effect of thalidomide on streptozotocin (STZ)-induced neuropathic pain in rats. Streptozotocin (20 mg/kg, i.p, daily × 4 days) was administered to induce diabetes in the rats. Nociceptive latency was measured using tail-flick and paw-withdrawal test. Thermal hyperalgesia and mechanical allodynia were measured using planter test and dynamic aesthesiometer (Ugo-Basile, Italy), respectively. Urinary and serum nitrite concentration was estimated using Greiss reagent method. Spleen homogenate supernatant was prepared from spleen of 28th day diabetic rats and administered to normal rats (400 ul, i.v) daily for 28 days. Pain threshold progressively decreased in STZ-treated rats, as compared with control rats. 3 weeks after induction of diabetes, the rat exhibited thermal hyperalgesia and mechanical allodynia. The analgesic effect of morphine (8 mg/kg, s.c.) was significantly decreased in both diabetic and in SHS-treated non-diabetic rats. Administration of thalidomide (25 and 50 mg/kg, i.p), a TNF-α inhibitor, significantly prevented hyperglycemia-induced thermal hyperalgesia and mechanical allodynia and also attenuated the increase in serum and urinary nitrite concentration, as compared with untreated diabetic rats. Also, thalidomide (25 and 50 mg/kg, i.p) 1 h before or concurrently with morphine significantly restored the analgesic effect of morphine in diabetic rats. It may be concluded that thalidomide has a beneficial effect in neuropathic pain by decreasing cytokines (TNF-α) and nitric oxide level and may provide a novel promising therapeutic approach for managing painful diabetic neuropathy.

Emerging role of thalidomide in the treatment of gastrointestinal bleeding.

PubMed

McFarlane, Michael; O'Flynn, Lauren; Ventre, Rachel; Disney, Benjamin R

2018-04-01

Thalidomide was initially synthesised in 1954 and marketed as a sedative and antiemetic for morning sickness. It was withdrawn in 1961 due to the realisation that it was teratogenic with over 10 000 children born with congenital abnormalities. Since then it has been used for treatment of dermatological and oncological conditions, including myeloma. In 1994, it was found to have a potent antiangiogenic effect via downregulation of vascular endothelial growth factor (VEGF). This has led to its use in gastrointestinal bleeding, as vascular abnormalities such as angiodysplasia have been found to have elevated VEGF levels. This article will review the current evidence of the use of thalidomide in bleeding associated with gastrointestinal vascular malformations, including angiodysplasia, gastric cancer and radiation-induced proctitis.

Effects of geldanamycin and thalidomide on the Th1/Th2 cytokine balance in mice subjected to operative trauma.

PubMed

Nakano, Takumi; Araki, Keijiro; Nakatani, Hajime; Kobayashi, Michiya; Sugimoto, Takeki; Furuya, Yasuo; Matsuoka, Takanori; Jin, Toufeng; Hanazaki, Kazuhiro

2007-04-01

Persistence of postoperative immune dysfunction is a critical problem because it increases the risk of serious infectious complications. The mechanisms of the immune dysfunction that occur initially after non-thermal operative injury remain to be fully elucidated. Two mouse models of operative trauma (simple laparotomy to represent minor operative injury and ileocecal resection to represent major operative injury) were used to define the characteristics of initial cytokine synthesis. Geldanamycin and thalidomide were independently added intraperitoneally before and after operative injury to examine the effect on postoperative immune dysfunction. Mice were sacrificed at scheduled times (3, 6, 12, and 24 h after operative injury) and TNF-alpha, IL-2, IL-4, and IL-10 were analyzed. Spleen was used for intracellular cytokines and RT-PCR. Sera were used for ELISA. Major operative injury caused an initial upregulation of IL-10 synthesis with delayed synthesis of TNF-alpha and IL-2. Minor operative injury caused an early induction of IL-2 synthesis preceded by an initial induction of IL-4 synthesis. GA caused a specific early upregulation of TNF-alpha mRNA expression and intracellular TNF-alpha synthesis. The GA and THD groups showed early serum IL-2 production with reduction of IL-10 mRNA expression and intracellular IL-10 synthesis in the early post-operative phase. Major and minor operative injury showed different Th1/Th2 cytokine patterns in the initial post-operative period. Geldanamycin and thalidomide improved the Th1/Th2 imbalance independently after major operative injury.

Tumor blood vessel "normalization" improves the therapeutic efficacy of boron neutron capture therapy (BNCT) in experimental oral cancer.

PubMed

Molinari, Ana J; Pozzi, Emiliano C C; Monti Hughes, Andrea; Heber, Elisa M; Garabalino, Marcela A; Thorp, Silvia I; Miller, Marcelo; Itoiz, Maria E; Aromando, Romina F; Nigg, David W; Trivillin, Verónica A; Schwint, Amanda E

2012-01-01

We previously demonstrated the efficacy of BNCT mediated by boronophenylalanine (BPA) to treat tumors in a hamster cheek pouch model of oral cancer with no normal tissue radiotoxicity and moderate, albeit reversible, mucositis in precancerous tissue around treated tumors. It is known that boron targeting of the largest possible proportion of tumor cells contributes to the success of BNCT and that tumor blood vessel normalization improves drug delivery to the tumor. Within this context, the aim of the present study was to evaluate the effect of blood vessel normalization on the therapeutic efficacy and potential radiotoxicity of BNCT in the hamster cheek pouch model of oral cancer. Blood vessel normalization was induced by two doses of thalidomide in tumor-bearing hamsters on 2 consecutive days. All studies in thalidomide-treated animals were performed 48 h after the first dose of thalidomide, previously established as the window of normalization. Biodistribution studies were performed with BPA at a dose of 15.5 mg (10)B/kg in thalidomide-treated (Th+) and untreated (Th-) tumor-bearing hamsters. The effect of blood vessel normalization prior to BPA administration on the efficacy of BNCT was assessed in in vivo BNCT studies at the RA-3 Nuclear Reactor in tumor-bearing hamsters. Group I was treated with BPA-BNCT after treatment with thalidomide (Th+ BPA-BNCT). Group II was treated with BPA-BNCT alone (Th- BPA-BNCT). Group III was treated with the beam only after treatment with thalidomide (Th+ BO), and Group IV was treated with the beam only (Th- BO). Groups I and II were given the same dose of BPA (15.5 mg (10)B/kg), and all groups (I-IV) were exposed to the same neutron fluence. Two additional groups were treated with the beam only at a higher dose to exacerbate mucositis in precancerous tissue and to explore the potential direct protective effect of thalidomide on radiation-induced mucositis in a scenario of more severe toxicity, i.e. Group V (Th+ hdBO) and Group VI (Th- hdBO). The animals were followed for 28 days. Biodistribution studies revealed no statistically significant differences in gross boron content between Th+ and Th- animals. Overall tumor control (complete response + partial response) at 28 days post-treatment was significantly higher for Group I (Th+ BPA-BNCT) than for Group II (Th- BPA-BNCT): 84 ± 3% compared to 67 ± 5%. Pretreatment with thalidomide did not induce statistically significant changes in overall tumor control induced by the beam only, i.e. 15 ± 5% in Group III (Th+ BO) and 18 ± 5% in Group IV (Th- BO), or in overall tumor control induced by the high-dose beam only, i.e. 60 ± 7% in Group V (Th+ hdBO) and 47 ± 10% in Group VI (Th- hdBO). BPA-BNCT alone (Group II) induced mucositis in precancerous tissue that reached Grades 3-4 in 80% of the animals, whereas pretreatment with thalidomide (Group I) prevented mucositis Grades 3 and 4 completely. Beam-only Group III (Th+ BO) exhibited only Grade 1 mucositis in precancerous tissue, whereas 17% of the animals in beam-only Group IV (Th- BO) reached Grade 2 mucositis. High-dose beam-only group V (Th+ hdBO) exhibited only Grade 2 mucositis, whereas high-dose beam-only group VI (Th- hdBO) reached Grade 3 mucositis in 83% of the animals. In all cases mucositis in precancerous tissue was reversible. No normal tissue radiotoxicity was observed with any of the protocols. Pretreatment with thalidomide enhanced the therapeutic efficacy of BNCT and reduced precancerous tissue toxicity.

[Effect of TNF-alpha gene polymorphism on outcome of thalidomide-based regimens for multiple myeloma].

PubMed

DU, Juan; Yuan, Zhen-Gang; Zhang, Chun-Yang; Fu, Wei-Jun; Jiang, Hua; Chen, Bao-An; Hou, Jian

2009-10-01

To evaluate the effect of polymorphism at the -238 and -308 position of the TNF-alpha promotor region on the clinical outcome of thalidomide (Thal)-based regimens for the treatment of multiple myeloma (MM). The polymorphism at the -238 and -308 position of the TNF-alpha promotor region of 168 MM patients treated with Thal-based regimens were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Genotypes were tested for association with overall response by logistic regression, and survival was evaluated by univariate and multivariate analysis. In TNF-alpha -238 position, 11 (6.5%) patients had GA genotype and 1 (0.6%) AA genotype. In TNF-alpha -308 position, 19 (11.3%) had GA genotype and 1 (0.6%) AA genotype. In univariate analysis, the TNF-alpha -238 GA + AA genotypes were associated with a significantly prolonged progression free survival (PFS) (P = 0.017), and a better overall survival (OS) (P = 0.150). Multivariate COX regression analysis showed that TNF-alpha -238 polymorphic status was an independent prognostic factor for prolonged PFS (P = 0.049). The TNF-alpha -238 polymorphic status is associated with a favorable clinical outcome in MM patients treated with thalidomide-based regimen. The polymorphism status of TNF-alpha gene might be of promise for developing a more informative stratification system for MM.

LC-MS/MS method for simultaneous determination of thalidomide, lenalidomide, cyclophosphamide, bortezomib, dexamethasone and adriamycin in serum of multiple myeloma patients.

PubMed

Shu, Chang; Zeng, Tianmei; Gao, Shouhong; Xia, Tianyi; Huang, Lifeng; Zhang, Feng; Chen, Wansheng

2016-08-15

Multiple myeloma (MM), a malignant neoplastic serum-cell disorder, has been a serious threat to human health. The determination of 6 commonly used drug concentrations, including thalidomide, lenalidomide, cyclophosphamide, bortezomib, dexamethasone and adriamycin, in MM patients was of great clinical interest. Herein, we reported a method for the rapid and simultaneous measurement of the above therapeutics by liquid chromatography-tandem mass spectroscopy (LC-MS/MS) method with solid phase extraction. Analysis was performed on a Waters XBridge(®) BEH C18 column (2.5μm, 2.1 mm×50mm), with formic acid aqueous solution and acetonitrile as the mobile phase at flow rate 0.3mL/min. All analytes showed good correlation coefficients (r>0.996), and LLOQ of thalidomide, lenalidomide, cyclophosphamide, bortezomib, dexamethasone and adriamycin were 4, 2, 2, 2, 2 and 2ng/mL, respectively. The inter- and intra-day precisions and stability were expressed as variation coefficients within 15% and relative error less than 15%. Dilution effect, carryover and incurred sample reanalysis were investigated according to the 2015 edition Chinese Pharmacopoeia guidelines, as US FDA (2013, revision 1) required. The LC-MS/MS based assay described in this article may improve future clinical studies evaluating common therapeutics for MM treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

Frances Kelsey and Thalidomide in the US: A Case Study Relating to Pharmaceutical Regulations.

ERIC Educational Resources Information Center

Seidman, Lisa A.; Warren, Noreen

2002-01-01

Presents a case study on the story of Dr. Frances Kelsey and the drug thalidomide, which was widely used in Europe for its therapeutic effects in the 1960s and later identified as having multiple effects on the body during development by the Food and Drug Administration (FDA). Describes the drug approval process in the United States and…

Analysis of circulating angiogenic biomarkers from patients in two phase III trials in lung cancer of chemotherapy alone or chemotherapy and thalidomide

PubMed Central

Young, R J; Tin, A W; Brown, N J; Jitlal, M; Lee, S M; Woll, P J

2012-01-01

Background: Thalidomide has potent anti-inflammatory and anti-angiogenic properties. It was evaluated in combination with chemotherapy in two randomised placebo-controlled trials in patients with small cell lung cancer (SCLC, n=724) and advanced non-small cell lung cancer (NSCLC, n=722). Neither study demonstrated an improvement in overall survival with the addition of thalidomide to chemotherapy. This study investigated circulating angiogenic biomarkers in a subset of these patients. Methods: Serial plasma samples were collected in a cohort of patients enrolled in these two trials (n=95). Vascular endothelial growth factor (VEGF), soluble truncated form of VEGF receptor-2 (sVEGFR-2), interleukin-8 (IL-8), tumour necrosis factor-α (TNF-α), basic fibroblast growth factor (bFGF) and soluble intercellular adhesion molecule-1 (sICAM-1) levels were measured by enzyme-linked immunosorbent assays. Results were correlated with patient clinical data including stage, response rate and progression-free survival (PFS). Results: Baseline biomarker levels were not significantly different between SCLC and NSCLC. For pooled treatment groups, limited stage SCLC was associated with lower baseline VEGF (P=0.046), sICAM-1 (P=0.008) and IL-8 (P=0.070) than extensive stage disease. Low baseline IL-8 was associated with a significantly improved PFS in both SCLC and NSCLC (P=0.028), and a greater reduction in IL-8 was associated with a significantly improved tumour response (P=0.035). Baseline angiogenic factor levels, however, did not predict response to thalidomide. Conclusion: Circulating angiogenic biomarkers did not identify patients who benefited from thalidomide treatment. PMID:22353811

Thalidomide for inflammatory bowel disease

PubMed Central

Bramuzzo, Matteo; Ventura, Alessandro; Martelossi, Stefano; Lazzerini, Marzia

2016-01-01

Abstract Background: Thalidomide is an immunomodulatory drug used in the experimental treatment of refractory Crohn disease and ulcerative colitis. We aimed to review the existing evidence on the efficacy and safety of thalidomide in the treatment of inflammatory bowel diseases. Methods: CENTRAL, MEDLINE, LILACS, POPLINE, CINHAL, and Web of Science were searched in March 2016. Manual search included conference and reference lists. All types of studies, except single case reports, were included. Outcomes evaluated were: induction of remission; maintenance of remission; steroid reduction; effect on penetrating Crohn disease; endoscopic remission; adverse events. Results: The research strategies retrieved 722 papers. Two randomized controlled trials and 29 uncontrolled studies for a total of 489 patients matched the inclusion criteria. Thalidomide induced a clinical response in 296/427 (69.3%) patients. Clinical remission was achieved in 220/427 (51.5%) cases. Maintenance of remission was reported in 128/160 (80.0%) patients at 6 months and in 96/133 (72.2%) at 12 months. Reduction in steroid dosage was reported in 109/152 (71.7%) patients. Fistulas improved in 49/81 (60.5%) cases and closed in 28/81 (34.6%). Endoscopic improvement was observed in 46/66 (69.7%) and complete mucosal healing in 35/66 (53.0%) patients. Cumulative incidence of total adverse events and of those leading to drug suspension was 75.6 and 19.7/1000 patient-months, respectively. Neurological disturbances accounted for 341/530 (64.3%) adverse events and were the most frequent cause of drug withdrawal. Conclusion: Existing evidence suggests that thalidomide may be a valid treatment option for patients with inflammatory bowel diseases refractory to other first- and second-line treatments. PMID:27472695

The protective effect of thalidomide on left ventricular function in a rat model of diabetic cardiomyopathy.

PubMed

Kim, Dae-Hee; Kim, Yong-Jin; Chang, Sung-A; Lee, Hye-Won; Kim, Ha-Na; Kim, Hyung-Kwan; Chang, Hyuk-Jae; Sohn, Dae-Won; Park, Young-Bae

2010-10-01

To evaluate the protective effect of thalidomide, a potent anti-inflammatory drug, on the development of diabetic cardiomyopathy (DMCMP). We induced type 1 diabetes using streptozocin in 8-week-old Sprague-Dawley rats, divided them into two groups-a thalidomide treatment group (DM-T, n = 15) and a non-treatment group (DM-N, n = 15)-and compared them with a normal control (n = 10). Ten weeks after diabetes induction, heart and lung mass indices were higher in the DM-N group compared with the control group. In the DM-T group, increases in heart and lung mass indices were attenuated compared with the DM-N group. On echocardiographic examination, systolic and diastolic mitral annulus velocities were impaired in the DM-N group, but they remained normal in the DM-T group. On haemodynamic analyses, left ventricular (LV) systolic function, represented by end-systolic elastance (0.35 ± 0.14 vs. 0.18 ± 0.07 mmHg/μl, P < 0.001) and preload-recruitable stroke work (90.5 ± 24.3 vs. 51.8 ± 22.0 mmHg, P < 0.001), was preserved in the DM-T group compared with the DM-N group. Likewise, deterioration of LV diastolic function was attenuated in the DM-T group. Increases in serum levels of TNF-α were attenuated in the DM-T group compared with the DM-N group. On histological analysis, thalidomide treatment lowered total myocardial collagen content and the expression of TNF-α, IL-1β, ICAM-1, and VCAM-1. In an animal model of DMCMP, deterioration of LV systolic and diastolic function was partially prevented by thalidomide treatment.

Preparation, characterization, in vitro and in vivo anti-tumor effect of thalidomide nanoparticles on lung cancer.

PubMed

Chen, Long Xia; Ni, Xiao Ling; Zhang, Heng; Wu, Min; Liu, Jing; Xu, Shan; Yang, Ling Lin; Fu, Shao Zhi; Wu, Jingbo

2018-01-01

Thalidomide (THA) is an angiogenesis inhibitor and an efficient inhibitor of the tumor necrosis factor-α (TNF-α). However, the clinical application of THA has been limited due to hydrophobicity of the compound. To increase the water solubility of THA and in order to evaluate the anticancer abilities of this material on human lung carcinoma, methoxy poly(ethylene glycol)-poly(ε-caprolactone) nanoparticles loaded with THA (THA-NPs) were prepared. The synthesis of THA-NPs was carried out via a dialysis method with relative satisfactory encapsulation efficiency, loading capacity, size distribution, and zeta potential. A cytotoxicity assay demonstrated that THA-NPs inhibited the growth of cells in a dose-dependent manner. The evaluation of anti-tumor activity in vivo showed that THA-NPs could inhibit tumor growth and prolong the survival rate of tumor-bearing mice. Immunohistochemical analysis indicated that THA-NPs inhibited cell proliferation (Ki-67 positive rate, 32.8%±4.2%, P <0.01), and resulted in a decreased rate of the tumor tissue microvessel density (3.87%±0.77%, P <0.01), VEGF (26.67%±4.02%, P <0.01), and TNF-α (75.21±6.85 ng/mL, P <0.01). In general, the drug delivery system reported herein may shed light on future targeted therapy in lung cancer treatment.

How to select among available options for the treatment of multiple myeloma.

PubMed

Harousseau, J L

2012-09-01

The introduction of novel agents (thalidomide, bortezomib and lenalidomide) in the frontline therapy of multiple myeloma has markedly improved the outcome both in younger patients who are candidates for high-dose therapy plus autologous stem-cell transplantation (HDT/ASCT) and in elderly patients. In the HDT/ASCT paradigm, novel agents may be used as induction therapy or after HDT/ASCT as consolidation and/or maintenance therapy. It is now possible to achieve up to 70% complete plus very good partial remission after HDT/ASCT and 70% 3-year progression-free survival (PFS). However long-term non-intensive therapy may also yield high response rates and prolonged PFS. Randomized trials comparing these two strategies are underway. In elderly patients, six randomized studies show the benefit of adding thalidomide to melphalan-prednisone (MP). a large randomized trial has also shown that the combination of bortezomib-MP is superior to MP for all parameters measuring the response and outcome. Finally, the role of maintenance is currently evaluated and a randomized trial shows that low-dose lenalidomide maintenance prolongs PFS.

Thalidomide for steroid-dependent chronic disseminated candidiasis after stem cell transplantation: A case report.

PubMed

Rammaert, Blandine; Candon, Sophie; Maunoury, Christophe; Bougnoux, Marie-Elisabeth; Jouvion, Grégory; Braun, Thorsten; Correas, Jean-Michel; Lortholary, Olivier

2017-02-01

Chronic disseminated candidiasis (CDC) is a rare and difficult-to-treat invasive fungal disease occurring mainly after prolonged and profound neutropenia. We describe the case of a 59-year-old man successfully treated with thalidomide for CDC recurrences after an autologous transplantation. We add evidence of the effectiveness of immunomodulatory drugs to manage inflammatory reconstitution immune syndrome-related refractory CDC. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Prediction of peripheral neuropathy in multiple myeloma patients receiving bortezomib and thalidomide: a genetic study based on a single nucleotide polymorphism array.

PubMed

García-Sanz, Ramón; Corchete, Luis Antonio; Alcoceba, Miguel; Chillon, María Carmen; Jiménez, Cristina; Prieto, Isabel; García-Álvarez, María; Puig, Noemi; Rapado, Immaculada; Barrio, Santiago; Oriol, Albert; Blanchard, María Jesús; de la Rubia, Javier; Martínez, Rafael; Lahuerta, Juan José; González Díaz, Marcos; Mateos, María Victoria; San Miguel, Jesús Fernando; Martínez-López, Joaquín; Sarasquete, María Eugenia

2017-12-01

Bortezomib- and thalidomide-based therapies have significantly contributed to improved survival of multiple myeloma (MM) patients. However, treatment-induced peripheral neuropathy (TiPN) is a common adverse event associated with them. Risk factors for TiPN in MM patients include advanced age, prior neuropathy, and other drugs, but there are conflicting results about the role of genetics in predicting the risk of TiPN. Thus, we carried out a genome-wide association study based on more than 300 000 exome single nucleotide polymorphisms in 172 MM patients receiving therapy involving bortezomib and thalidomide. We compared patients developing and not developing TiPN under similar treatment conditions (GEM05MAS65, NCT00443235). The highest-ranking single nucleotide polymorphism was rs45443101, located in the PLCG2 gene, but no significant differences were found after multiple comparison correction (adjusted P = .1708). Prediction analyses, cytoband enrichment, and pathway analyses were also performed, but none yielded any significant findings. A copy number approach was also explored, but this gave no significant results either. In summary, our study did not find a consistent genetic component associated with TiPN under bortezomib and thalidomide therapies that could be used for prediction, which makes clinical judgment essential in the practical management of MM treatment. Copyright © 2016 John Wiley & Sons, Ltd.

Successful treatment of myelodysplastic syndrome-induced pyoderma gangrenosum.

PubMed

Koca, E; Duman, A E; Cetiner, D; Buyukasik, Y; Haznedaroglu, I C; Uner, A; Demirhan, B; Kerimoglu, U; Barista, I; Calguneri, M; Ozcebe, O I

2006-12-01

We report successful treatment of a refractory myelodysplastic syndrome-associated pyoderma gangrenosum with the combination of thalidomide and interferon-alpha2a in a single patient. A non-healing wound developed on a 40-year-old woman's left thumb after minor trauma. Massive ulcerovegetative lesions developed after reconstruction surgery. Histopathological examination of the bone marrow and cytogenetic studies revealed an atypical myeloproliferative/myelodysplastic syndrome. The skin lesions resolved dramatically after two months of thalidomide and interferon-alpha2a combination therapy and the haematological status improved.

Immunomodulation of multiple myeloma.

PubMed

Tohnya, Tanyifor M; Figg, William D

2004-11-01

Multiple myeloma is a multi-process disease, and these different processes are responsible for the reduced sensitivity to chemotherapy and radiotherapy, hence the relapse and refractory nature of multiple myeloma. Emphasis is now placed on the hypothesis that myeloma cell growth, inhibition of apoptosis and drug resistance are dependent on immunomodulatory cytokines such as IL-6 and pro-angiogenic factors such as VEGF. In addition to its anti-angiogenic effects, the immunomodulatory properties of thalidomide make it a possible therapy for patients with advanced multiple myeloma. This has lead to the clinical development of a number of immunomodulatory thalidomide analogues (IMiDs) which are more potent and have less side effects than the parent drug, thalidomide. In the August 15(th) issue of Journal of Clinical Oncology, Schey SA et al. suggested that an IMiD (CC-4047) maybe efficacious due to T-cell co-stimulation, and safe in patients with relapsed or refractory multiple myeloma. This article demonstrates a supporting role for IMiDs as immunomodulatory adjuvant therapy.

Dental status and oral function in an adult group of subjects with thalidomide embryopathy - a clinical and questionnaire study.

PubMed

Ekfeldt, Anders; Carlsson, Gunnar E

2008-10-01

The purpose of the study was to present the results of an oral examination of individuals with thalidomide embryopathy in relation to dental conditions and functional aspects of the masticatory system, with a special focus on tooth wear. All 108 subjects with thalidomide embryopathy living in Sweden were invited to participate in a comprehensive investigation, and approximately one-third, 31 subjects (13 F and 18 M, aged 45-49 years), took part. The methods included a questionnaire and clinical and radiographic examinations. Most of the subjects had regular dental care, which they in general considered sufficient. All except one always brushed their teeth themselves. One subject had limited mouth opening (25 mm). There were no great deviations from normal anatomy and function of the masticatory system. Caries and periodontal conditions were also normal. Regurgitation was reported by 42% of the subjects. Tooth wear was more extensive than in comparable age groups. About a third of the subjects had Class III or edge-to-edge occlusion. In general, subjects with thalidomide embryopathy had no great deviations in dental conditions from people of the same age in the general population except for an increased rate of tooth wear and a higher prevalence of prenormal jaw relations. Tooth wear was related less to use of the teeth as tools and more to dental erosion associated, among other things, with a high rate of regurgitation.

Therapeutic experience of vincristine/cyclophosphamide/melphalan or mitoxantrone/prednisone combination therapy plus thalidomide as first-line induction therapy for newly diagnosed multiple myeloma in a single institution of China.

PubMed

Wang, Xiaoning; He, Pengcheng; Guo, Caili; Sun, Chunhong; Zhang, Mei

2017-10-01

To investigate the safety and efficacy of the combination regimen vincristine, cyclophosphamide, melphalan or mitoxantrone and prednisone (VCMP) plus thalidomide as first-line induction therapy for newly diagnosed multiple myeloma (MM). Three hundred and ninety-six symptomatic, newly diagnosed MM patients were treated with VCMP plus thalidomide in our hospital for the past 11 years, and clinical data of these patients were retrospectively analyzed. Of the 396 patients enrolled, the total response rate was 77.3%. Forty-three patients relapsed after sCR and CR. Mean cycles to first response were six cycles (range 1-16 cycles). A total of 53% of patients achieved at least a PR within the first cycle of therapy. The actuarial 1-year, 3-year and 5-year overall survival of all patients were 89.4%, 29.5% and 10.6%, respectively. The probabilities of 1-year, 3-year and 5-year progression-free survival of all patients were 84.0%, 23.1% and 8.4%, respectively. The major adverse events were gastrointestinal symptoms, electrolytes and glucose metabolism disorders, hypertension, infection, peripheral nerve disease and hematological adverse events, which were mostly below grade 3 and could be alleviated by symptomatic treatment. We concluded that VCMP plus thalidomide is an effective regimen with manageable side effects in the treatment of symptomatic, newly diagnosed MM including elderly patients and patients with renal failure. © 2016 John Wiley & Sons Australia, Ltd.

Immunomodulatory drugs in multiple myeloma: mechanisms of action and clinical experience

PubMed Central

Holstein, Sarah A.; McCarthy, Philip L.

2017-01-01

Over the last two decades, the outcomes for patients with multiple myeloma, a plasma cell malignancy, have dramatically improved. The development of the immunomodulatory drugs (IMiDs) which include thalidomide, lenalidomide, and pomalidomide, has contributed significantly to these improved outcomes. While thalidomide is now less commonly prescribed, lenalidomide is widely used in the treatment of newly diagnosed transplant-eligible and transplant-ineligible patients, in the maintenance setting post-transplant and in the relapsed/refractory setting, while pomalidomide is currently utilized in the relapsed/refractory setting. The IMiDs have been reported to have a multitude of activities, including anti-angiogenic, cytotoxic, and immunomodulatory, however, the more recent discoveries that the IMiDs bind to cereblon and thus regulate the ubiquitination of key transcription factors including IKZF1 and IKZF3, have provided greater insight into their mechanism of action. Here the clinical efficacy of these agents in myeloma is reviewed as well as discussion of structure-function relationship, the molecular mechanisms of action, and the association of IMiDs with second primary malignancies and thrombosis. PMID:28205024

Anti-inflammatory effect of α,β-amyrin, a triterpene from Protium heptaphyllum, on cerulein-induced acute pancreatitis in mice.

PubMed

Melo, Caroline M; Morais, Talita C; Tomé, Adriana R; Brito, Gerly Anne C; Chaves, Mariana H; Rao, Vietla S; Santos, Flávia A

2011-07-01

To evaluate the anti-inflammatory effect of α,β-amyrin, a pentacyclic triterpenoid from Protium heptaphyllum, on cerulein-induced acute pancreatitis in mice. Acute pancreatitis was induced in Swiss mice by five intraperitoneal injections of cerulein (50 μg/kg), at 1 h intervals. Mice received α,β-amyrin (10, 30 and 100 mg/kg), thalidomide (200 mg/kg), or vehicle (3% Tween 80) orally 1 h before and 12 h after the cerulein challenge. The severity of pancreatitis was evaluated 24 h after cerulein by assessing serum pro-inflammatory cytokines and amylase activity, pancreatic myeloperoxidase (MPO), and thiobarbituric acid-reactive substances (TBARS), as well as by histology. α,β-Amyrin and thalidomide significantly attenuated the cerulein-induced increase in tumor necrosis factor (TNF)-α, interleukin-6, lipase, amylase, MPO, and TBARS. Moreover, α,β-amyrin greatly suppressed the pancreatic edema, inflammatory cell infiltration, acinar cell necrosis, and expressions of TNFα and inducible nitric oxide synthase. α,β-Amyrin ameliorates cerulein-induced acute pancreatitis by acting as an anti-inflammatory and antioxidant agent.

A Reevaluation of X-Irradiation Induced Phocomelia and Proximodistal Limb Patterning

PubMed Central

Galloway, Jenna L.; Delgado, Irene; Ros, Maria A.; Tabin, Clifford J.

2009-01-01

Phocomelia is a devastating, rare congenital limb malformation in which the long bones are shorter than normal, with the upper portion of the limb being most severely affected. In extreme cases, the hands or fingers are attached directly to the shoulder and the most proximal elements (those closest to the shoulder) are entirely missing. This disorder, previously known in both autosomal recessive and sporadic forms, showed a dramatic increase in incidence in the early 1960’s due to the tragic toxicological effects of the drug thalidomide, which had been prescribed as a mild sedative1, 2. This human birth defect is mimicked in developing chick limb buds exposed to X-irradiation3-5. Both X-irradiation5 and thalidomide-induced phocomelia5, 6 have been interpreted as patterning defects in the context of the Progress Zone Model, which states that a cell’s proximodistal (PD) identity is determined by the length of time spent in a distal limb region termed the “Progress Zone” 7. Indeed, studies of X-irradiation induced phocomelia have served as one of the two major experimental lines of evidence supporting the validity of the Progress Zone Model. Here, using a combination of molecular analysis and lineage tracing, we show that X-irradiation-induced phocomelia is fundamentally not a patterning defect, but rather results from a time-dependent loss of skeletal progenitors. As skeletal condensation proceeds from the shoulder to fingers (in a proximal to distal direction), the proximal elements are differentially affected in limb buds exposed to radiation at early stages. This conclusion changes the framework for considering the effect of thalidomide and other forms of phocomelia, suggesting the possibility that the etiology lies not in a defect in the patterning process, but rather in progenitor cell survival and differentiation. Moreover, molecular evidence that PD patterning is unaffected following X-irradiation does not support the predictions of the Progress Zone Model. PMID:19553938

A reevaluation of X-irradiation-induced phocomelia and proximodistal limb patterning.

PubMed

Galloway, Jenna L; Delgado, Irene; Ros, Maria A; Tabin, Clifford J

2009-07-16

Phocomelia is a devastating, rare congenital limb malformation in which the long bones are shorter than normal, with the upper portion of the limb being most severely affected. In extreme cases, the hands or fingers are attached directly to the shoulder and the most proximal elements (those closest to the shoulder) are entirely missing. This disorder, previously known in both autosomal recessive and sporadic forms, showed a marked increase in incidence in the early 1960s due to the tragic toxicological effects of the drug thalidomide, which had been prescribed as a mild sedative. This human birth defect is mimicked in developing chick limb buds exposed to X-irradiation. Both X-irradiation and thalidomide-induced phocomelia have been interpreted as patterning defects in the context of the progress zone model, which states that a cell's proximodistal identity is determined by the length of time spent in a distal limb region termed the 'progress zone'. Indeed, studies of X-irradiation-induced phocomelia have served as one of the two major experimental lines of evidence supporting the validity of the progress zone model. Here, using a combination of molecular analysis and lineage tracing in chick, we show that X-irradiation-induced phocomelia is fundamentally not a patterning defect, but rather results from a time-dependent loss of skeletal progenitors. Because skeletal condensation proceeds from the shoulder to fingers (in a proximal to distal direction), the proximal elements are differentially affected in limb buds exposed to radiation at early stages. This conclusion changes the framework for considering the effect of thalidomide and other forms of phocomelia, suggesting the possibility that the aetiology lies not in a defect in the patterning process, but rather in progenitor cell survival and differentiation. Moreover, molecular evidence that proximodistal patterning is unaffected after X-irradiation does not support the predictions of the progress zone model.

Thalidomide for Control Delayed Vomiting in Cancer Patients Receiving Chemotherapy.

PubMed

Han, Zhengxiang; Sun, Xuan; Jiang, Guan; Du, Xiuping

2016-11-01

To explore the efficacy and safety of thalidomide for the treatment of delayed vomiting, induced by chemotherapy in cancer patients. Randomized, double-blind controlled study. The Oncology Department of Affiliated Hospital of Xuzhou Medical University, Jiangsu Xuzhou, China, from January 2012 to January 2014. A total of 78 cancer patients, who had delayed vomiting observed from 24 hours to 1 week after chemotherapy, were included in the study. Patients were divided in a treatment group (40 patients, 51.28%) and a control group (38 patients, 48.71%). The treatment group received thalidomide at an oral dose of 100 mg per night; 50 mg was added daily up to a dose of 200 mg per night, if the curative effect was suboptimal and the medicine was tolerated. Both the treatment and the control groups received a drip of 10 mg azasetron 30 minutes before chemotherapy. The control group only proportions of antiemetic effects and adverse reactions were compared using the c2 test. Antiemetic effects and adverse reactions were assessed from Odds Ratios (OR) with 95% Confidence Intervals(95% CI). The effective control rate of delayed vomiting in the treatment group was significantly higher than that in the control group (c2=5.174, p=0.023). No significant difference was found between the two groups in other adverse effects of chemotherapy. Karnofsky scores or the overall self-evaluation of the patients (p>0.05). Thalidomide can effectively control the delayed vomiting of cancer patients receiving chemotherapy and the adverse reactions of the agent can be tolerated.

Effects of thalidomide on angiogenesis and tumor growth and metastasis of human hepatocellular carcinoma in nude mice

PubMed Central

Zhang, Zhong-Lin; Liu, Zhi-Su; Sun, Quan

2005-01-01

AIM: To investigate the effects of thalidomide on angiogenesis, tumor growth and metastasis of hepatocellular carcinoma in nude mice. METHODS: Twenty-four nude mice were randomly divided into therapy group and control group, 12 mice in each group. Thalidomide dissolved in 0.5% sodium carboxyl methyl cellulose (CMC) suspension was administered intraperitoneally once a day at the dose of 200 mg/kg in therapy group, and an equivalent volume of 0.5% CMC in control group. Mice were sacrificed on the 30th d, tumor size and weight and metastases in liver and lungs were measured. CD34 and VEGF mRNA in tumor tissue were detected by immunohistochemistry and semi-quantitative RT-PCR respectively and microvessel density (MVD) was counted. Serum concentrations of TNF-α and ALT and AFP were also tested. RESULTS: MVD and VEGF mRNA in therapy group were less than those in control group (31.08±16.23 vessels/HP vs 80.00±26.27 vessels/HP, 0.0538±0.0165 vs 0.7373±0.1297, respectively, P<0.05). No statistical difference was observed in tumor size and weight and metastases in liver and lungs. TNF-α was significantly lower in therapy group than in control group (28.64±4.64 ng/L vs 42.69±6.99 ng/L, P<0.05). No statistical difference in ALT and AFP was observed between groups. CONCLUSION: Thalidomide can significantly inhibit angiogenesis and metastasis of hepatocellular carcinoma. It also has inhibitory effects on circulating TNF-α. PMID:15633219

Stochastic detection of enantiomers.

PubMed

Kang, Xiao-Feng; Cheley, Stephen; Guan, Xiyun; Bayley, Hagan

2006-08-23

The rapid quantification of the enantiomers of small chiral molecules is very important, notably in pharmacology. Here, we show that the enantiomers of drug molecules can be distinguished by stochastic sensing, a single-molecule detection technique. The sensing element is an engineered alpha-hemolysin protein pore, fitted with a beta-cyclodextrin adapter. By using the approach, the enantiomeric composition of samples of ibuprofen and thalidomide can be determined in less than 1 s.

European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma

PubMed Central

Engelhardt, Monika; Terpos, Evangelos; Kleber, Martina; Gay, Francesca; Wäsch, Ralph; Morgan, Gareth; Cavo, Michele; van de Donk, Niels; Beilhack, Andreas; Bruno, Benedetto; Johnsen, Hans Erik; Hajek, Roman; Driessen, Christoph; Ludwig, Heinz; Beksac, Meral; Boccadoro, Mario; Straka, Christian; Brighen, Sara; Gramatzki, Martin; Larocca, Alessandra; Lokhorst, Henk; Magarotto, Valeria; Morabito, Fortunato; Dimopoulos, Meletios A.; Einsele, Hermann; Sonneveld, Pieter; Palumbo, Antonio

2014-01-01

Multiple myeloma management has undergone profound changes in the past thanks to advances in our understanding of the disease biology and improvements in treatment and supportive care approaches. This article presents recommendations of the European Myeloma Network for newly diagnosed patients based on the GRADE system for level of evidence. All patients with symptomatic disease should undergo risk stratification to classify patients for International Staging System stage (level of evidence: 1A) and for cytogenetically defined high- versus standard-risk groups (2B). Novel-agent-based induction and up-front autologous stem cell transplantation in medically fit patients remains the standard of care (1A). Induction therapy should include a triple combination of bortezomib, with either adriamycin or thalidomide and dexamethasone (1A), or with cyclophosphamide and dexamethasone (2B). Currently, allogeneic stem cell transplantation may be considered for young patients with high-risk disease and preferably in the context of a clinical trial (2B). Thalidomide (1B) or lenalidomide (1A) maintenance increases progression-free survival and possibly overall survival (2B). Bortezomib-based regimens are a valuable consolidation option, especially for patients who failed excellent response after autologous stem cell transplantation (2A). Bortezomib-melphalan-prednisone or melphalan-prednisone-thalidomide are the standards of care for transplant-ineligible patients (1A). Melphalan-prednisone-lenalidomide with lenalidomide maintenance increases progression-free survival, but overall survival data are needed. New data from the phase III study (MM-020/IFM 07-01) of lenalidomide-low-dose dexamethasone reached its primary end point of a statistically significant improvement in progression-free survival as compared to melphalan-prednisone-thalidomide and provides further evidence for the efficacy of lenalidomide-low-dose dexamethasone in transplant-ineligible patients (2B). PMID:24497560

Avascular necrosis of femoral and/or humeral heads in multiple myeloma: results of a prospective study of patients treated with dexamethasone-based regimens and high-dose chemotherapy.

PubMed

Talamo, Giampaolo; Angtuaco, Edgardo; Walker, Ronald C; Dong, Li; Miceli, Marisa H; Zangari, Maurizio; Tricot, Guido; Barlogie, Bart; Anaissie, Elias

2005-08-01

To assess the prevalence, time of onset, risk factors, and outcome of avascular necrosis (AVN) of bone in patients with multiple myeloma undergoing antineoplastic therapy. A total of 553 consecutive assessable patients were enrolled onto a treatment protocol consisting of dexamethasone-containing induction chemotherapy, autologous stem-cell transplantation, consolidation chemotherapy, and maintenance with interferon alfa. Patients were randomly assigned to receive thalidomide (269 patients) or no thalidomide (284 patients) throughout the study period. With a median follow-up of 33 months (range, 5 to 114 months), AVN of the femoral head(s) developed in 49 patients (9%). Median time to onset of AVN was 12 months (range, 2 to 41 months). Three risk factors for AVN were identified by multivariate analysis: cumulative dexamethasone dose (odds ratio [OR], 1.028; 95% CI, 1.012 to 1.044; P = .0006 [per 40 mg dexamethasone]), male sex (OR, 0.390; 95% CI, 0.192 to 0.790; P = .009), and younger age (OR, 0.961; 95% CI, 0.934 to 0.991 per year; P = .0122). Thalidomide-treated patients had a prevalence of AVN similar to that of the control group (8% v 10%, respectively; P = .58). AVN-related pain and limited range of motion of the affected joint were present in only nine and four patients, respectively, and four patients underwent hip replacement because of AVN. Fluorine-18 fluorodeoxyglucose positron emission tomography failed to detect abnormal uptake in the AVN-affected bones. AVN is a rare and usually asymptomatic complication during myeloma therapy. Cumulative dexamethasone dose, male sex, and younger age, but not thalidomide, increase the risk of AVN.

The immunosuppressant drug, thalidomide, improves hepatic alterations induced by a high-fat diet in mice.

PubMed

Pinto, Livia de Fraia; Compri, Cecília Melleti; Fornari, João Victor; Bartchewsky, Waldemar; Cintra, Dennys Eduardo; Trevisan, Miriam; Carvalho, Patrícia de Oliveira; Ribeiro, Marcelo Lima; Velloso, Licio A; Saad, Mario J; Pedrazzoli, José; Gambero, Alessandra

2010-04-01

Pro-inflammatory cytokines, such as tumour necrosis factor (TNF)-alpha, are known to be involved in the establishment of insulin resistance. Insulin resistance plays a key role in the development of obesity-related pathologies, such as type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). The state of chronic inflammation associated with obesity led us to hypothesize that TNF-alpha blockade may have an effect on experimentally obese animals. We studied the effects of thalidomide, an immunosuppressant and anti-TNF-alpha drug, on hepatic alterations that were induced by a high-fat diet (HFD) in mice. Obesity was induced in Swiss mice using a HFD for 12 weeks. Thalidomide-treated animals received thalidomide i.p. (100 mg/kg/day, 10 days). Glucose, aspartate aminotransferases and alanine aminotransferases levels were assessed in the blood. Insulin and glucose tolerance tests were performed. The liver was excised for histological, triglyceride, gene and protein expression analyses. We found improvements in both the basal glucose blood levels and the response to insulin administration in the treated animals. The molecular analysis of insulin signalling revealed a restoration of the hepatic insulin receptor substrate (IRS)-1 and AKT phosphorylation. The hepatic expression of TNF-alpha was inhibited and the levels correlated with a significant reduction in the steatosis area. Other hepatic inflammatory markers, such as iNOS and suppressor of cytokine signalling (SOCS-3), were also reduced. We suggest that immunosuppressant drugs that target TNF-alpha and that may also contribute to reductions in the inflammatory markers that are associated with obesity could be a therapeutic option in NAFLD and type 2 diabetes.

Modulation of Regulatory T Cell Activity by TNF Receptor Type II-Targeting Pharmacological Agents

PubMed Central

Zou, Huimin; Li, Ruixin; Hu, Hao; Hu, Yuanjia; Chen, Xin

2018-01-01

There is now compelling evidence that tumor necrosis factor (TNF)–TNF receptor type II (TNFR2) interaction plays a decisive role in the activation, expansion, and phenotypical stability of suppressive CD4+Foxp3+ regulatory T cells (Tregs). In an effort to translate this basic research finding into a therapeutic benefit, a number of agonistic or antagonistic TNFR2-targeting biological agents with the capacity to activate or inhibit Treg activity have been developed and studied. Recent studies also show that thalidomide analogs, cyclophosphamide, and other small molecules are able to act on TNFR2, resulting in the elimination of TNFR2-expressing Tregs. In contrast, pharmacological agents, such as vitamin D3 and adalimumab, were reported to induce the expansion of Tregs by promoting the interaction of transmembrane TNF (tmTNF) with TNFR2. These studies clearly show that TNFR2-targeting pharmacological agents represent an effective approach to modulating the function of Tregs and thus may be useful in the treatment of major human diseases such as autoimmune disorders, graft-versus-host disease (GVHD), and cancer. In this review, we will summarize and discuss the latest progress in the study of TNFR2-targeting pharmacological agents and their therapeutic potential based on upregulation or downregulation of Treg activity. PMID:29632537

Drug therapy in pregnancy: the lessons of diethylstilbestrol, thalidomide, and bendectin.

PubMed

Saunders, E J; Saunders, J A

1990-01-01

A pregnant woman and the fetus she carries face health risks from many sources. One risk that requires ongoing vigilance is the use of prescription drugs during pregnancy. The international health care community has been sensitized to the risks of drug use during pregnancy because of three pharmaceuticals that have caused widespread crises for mothers and their offspring. The crises that diethylstilbestrol, thalidomide, and, to a lesser extent, Bendectin have created in the past four decades are reviewed in this article. The lessons these drug crises can teach us are articulated in the belief that similar crises may be averted in the future.

Assessing advantages of sequential boron neutron capture therapy (BNCT) in an oral cancer model with normalized blood vessels.

PubMed

Molinari, Ana J; Thorp, Silvia I; Portu, Agustina M; Saint Martin, Gisela; Pozzi, Emiliano C C; Heber, Elisa M; Bortolussi, Silva; Itoiz, Maria E; Aromando, Romina F; Monti Hughes, Andrea; Garabalino, Marcela A; Altieri, Saverio; Trivillin, Verónica A; Schwint, Amanda E

2015-01-01

We previously demonstrated the therapeutic success of sequential boron neutron capture therapy (Seq-BNCT) in the hamster cheek pouch oral cancer model. It consists of BPA-BNCT followed by GB-10-BNCT 24 or 48 hours later. Additionally, we proved that tumor blood vessel normalization with thalidomide prior to BPA-BNCT improves tumor control. The aim of the present study was to evaluate the therapeutic efficacy and explore potential boron microdistribution changes in Seq-BNCT preceded by tumor blood vessel normalization. Tumor bearing animals were treated with thalidomide for tumor blood vessel normalization, followed by Seq-BNCT (Th+ Seq-BNCT) or Seq-Beam Only (Th+ Seq-BO) in the window of normalization. Boron microdistribution was assessed by neutron autoradiography. Th+ Seq-BNCT induced overall tumor response of 100%, with 87 (4)% complete tumor response. No cases of severe mucositis in dose-limiting precancerous tissue were observed. Differences in boron homogeneity between tumors pre-treated and not pre-treated with thalidomide were observed. Th+ Seq-BNCT achieved, for the first time, response in all treated tumors. Increased homogeneity in tumor boron microdistribution is associated to an improvement in tumor control.

LASSBio-468: a new achiral thalidomide analogue which modulates TNF-alpha and NO production and inhibits endotoxic shock and arthritis in an animal model.

PubMed

Alexandre-Moreira, Magna S; Takiya, Christina M; de Arruda, Luciana B; Pascarelli, Bernardo; Gomes, Raquel N; Castro Faria Neto, Hugo C; Lima, Lídia M; Barreiro, Eliezer J

2005-03-01

As part of a program researching the synthesis and immunopharmacological evaluation of novel synthetic compounds, we have described the immune modulatory profile of the new achiral thalidomide analogue LASSBio-468 in the present work. This compound was planned as an N-substituted phthalimide derivate, structurally designed as a hybrid of thalidomide and aryl sulfonamides, which were previously described as tumor necrosis factor-alpha (TNF-alpha) and PDE4 inhibitors. LASSBio-468 was recently demonstrated to inhibit the TNF-alpha production induced by lipopolysaccharide (LPS), in vivo. Here, we investigated whether this compound would affect chronic inflammation processes associated with the production of this pro-inflammatory cytokine. Treatment with LASSBio-468 before a lethal dose injection of LPS in animals greatly inhibited endotoxic shock. This effect seems to be mediated by a specific down regulation of TNF-alpha and nitric oxide production, regulated mainly at the RNA level. In another model, histopathological analysis indicated that this compound also inhibited adjuvant-induced arthritis in rats. Taken together, our data demonstrated a potent anti-inflammatory effect of LASSBio-468, suggesting its use as a potential drug against chronic inflammatory diseases.

Metabolic profiles of pomalidomide in human plasma simulated with pharmacokinetic data in control and humanized-liver mice.

PubMed

Shimizu, Makiko; Suemizu, Hiroshi; Mitsui, Marina; Shibata, Norio; Guengerich, F Peter; Yamazaki, Hiroshi

2017-10-01

1. Pomalidomide has been shown to be potentially teratogenic in thalidomide-sensitive animal species such as rabbits. Screening for thalidomide analogs devoid of teratogenicity/toxicity - attributable to metabolites formed by cytochrome P450 enzymes - but having immunomodulatory properties is a strategic pathway towards development of new anticancer drugs. 2. In this study, plasma concentrations of pomalidomide, its primary 5-hydroxylated metabolite, and its glucuronide conjugate(s) were investigated in control and humanized-liver mice. Following oral administration of pomalidomide (100 mg/kg), plasma concentrations of 7-hydroxypomalidomide and 5-hydroxypomalidomide glucuronide were slightly higher in humanized-liver mice than in control mice. 3. Simulations of human plasma concentrations of pomalidomide were achieved with simplified physiologically-based pharmacokinetic models in both groups of mice in accordance with reported pomalidomide concentrations after low dose administration in humans. 4. The results indicate that pharmacokinetic profiles of pomalidomide were roughly similar between control mice and humanized-liver mice and that control and humanized-liver mice mediated pomalidomide 5-hydroxylation in vivo. Introducing one aromatic amino group into thalidomide resulted in less species differences in in vivo pharmacokinetics in control and humanized-liver mice.

Gastric damage and granulocyte infiltration induced by indomethacin in tumour necrosis factor receptor 1 (TNF-R1) or inducible nitric oxide synthase (iNOS) deficient mice

PubMed Central

Souza, M H L P; Lemos, H. Paula; Oliveira, R B; Cunha, F Q

2004-01-01

Background: Tumour necrosis factor α (TNF-α) is involved in non-steroidal anti-inflammatory drug induced gastropathy. Nitric oxide (NO) is a mediator of gastrointestinal mucosal defence but, paradoxically, it also contributes to mucosal damage. Aims: We optimised the C57BL/6 mouse model of indomethacin induced gastropathy to evaluate the role of TNF-α and inducible nitric oxide synthase (iNOS) generated NO in gastric damage and granulocyte infiltration using tumour necrosis factor receptor 1 (TNF-R1−/−) or iNOS (iNOS−/−) deficient mice. Methods: Different doses of indomethacin (2.5, 5, 10, 20 mg/kg) were administered and animals were assessed 6, 12, or 24 hours later. Gastric damage was measured by the sum of all erosions in the gastric mucosa, and gastric granulocyte infiltration was determined by myeloperoxidase (MPO) activity. Other groups of wild-type mice received thalidomide, dexamethasone, fucoidin, l-NAME, or 1400W, and then indomethacin was administered. Additionally, indomethacin was administered to TNF-R1−/− or iNOS−/−. Gastric damage and MPO activity were evaluated 12 hours later. Results: Indomethacin induced dose and time dependent gastric damage and increase in MPO activity in wild-type mice, with the greatest effect at a dose of 10 mg/kg and after 12 hours. Treatment with thalidomide, dexamethasone, or fucoidin reduced gastric damage and MPO activity induced by indomethacin. After indomethacin administration, TNF-R1−/− had less gastric damage and MPO activity than controls. Genetic (knockout mice) or pharmacological (1400W and l-NAME) inhibition of iNOS activity reduced indomethacin induced gastric damage, despite no reduction in MPO activity. Conclusion: TNF-α, acting via TNF-R1, is involved in indomethacin induced gastric damage and granulocyte infiltration. Furthermore, iNOS generated NO is involved in gastric damage induced by indomethacin. PMID:15138204

Real-time measurement of blood pressure with Nexfin in a patient with thalidomide-related phocomelia.

PubMed

Earle, Rosie; Vaghadia, Himat; Shanahan, Enda; Tang, Raymond; Sawka, Andrew

2016-11-01

We report the novel application of photoplethysmographic technology with the Nexfin HD monitor for real-time measurement of blood pressure (BP) in a patient with tetraamelia. The patient was a 58-year-old man with tetraamelia secondary to thalidomide exposure in utero, who presented for surgical excision of a maxillary schwannoma. Because difficulty of cuff use on rudimentary limbs and failure to gain invasive arterial access due to abnormalities of limb vasculature, this population is known to pose some unique challenges for BP measurement. Nexfin may offer an alternative noninvasive method to detect BP in patients with phocomelia during the perioperative period. Copyright © 2016 Elsevier Inc. All rights reserved.

The penumbra of thalidomide, the litigation culture and the licensing of pharmaceuticals

PubMed Central

2012-01-01

Fifty years ago several thousand children were born with severe limb defects after their mothers had been given thalidomide in pregnancy. This tragedy caused procedures for licensing new medicines to become much stricter. Where, nevertheless, significant side effects were found it became common to sue for damages. These consequences have caused possibly an even greater disaster damaging many more people and threatening ruin to health services everywhere. The huge increase in both time and cost in bringing medicines to market is increasing their price to unsupportable levels; and only wealthy companies are now able to do so. This requires reform as does litigation for ‘statistical’ harmful effects. PMID:22908318

Thalidomide in Treating Patients With Recurrent or Persistent Endometrial Cancer

ClinicalTrials.gov

2013-01-23

Endometrial Adenoacanthoma; Endometrial Adenocarcinoma; Endometrial Adenosquamous Cell Carcinoma; Endometrial Clear Cell Carcinoma; Endometrial Papillary Serous Carcinoma; Recurrent Endometrial Carcinoma

The Applicability of the International Staging System in Chinese Patients with Multiple Myeloma Receiving Bortezomib or Thalidomide-Based Regimens as Induction Therapy: A Multicenter Analysis

PubMed Central

Lu, Jing; Lu, Jin; Liu, Aijun; Fu, Weijun; Du, Juan; Huang, Xiaojun; Chen, Wenming; Hou, Jian

2015-01-01

The International Staging System (ISS) is the most important prognostic system for multiple myeloma (MM). It was identified in the era of conventional agents. The outcome of MM has significantly changed by novel agents. Thus the applicability of ISS system in the era of novel agents in Chinese patients needs to be demonstrated. We retrospectively analyzed the clinical outcomes and prognostic significance of ISS system in 1016 patients with newly diagnosed multiple myeloma in Chinese patients between 2008 and 2012, who received bortezomib- or thalidomide-based regimens as first-line therapy. The median overall survival (OS) of patients for ISS stages I/II/III was not reached/55.4 months/41.7 months (p < 0.001), and the median progression-free survival (PFS) was 30/29.5/25 months (p = 0.072), respectively. Statistically significant difference in survival was confirmed among three ISS stages in thalidomide-based group, but not between ISS stages I and II in bortezomib-based group. These findings suggest that ISS system can predict the survival in the era of novel agents in Chinese MM patients, and bortezomib may have the potential to partially overcome adverse effect of risk factors on survival, especially in higher stage of ISS system. PMID:26640799

Development and characterization of parenteral nanoemulsions containing thalidomide.

PubMed

Araújo, F A; Kelmann, R G; Araújo, B V; Finatto, R B; Teixeira, H F; Koester, L S

2011-02-14

This study reports the development of nanoemulsions intended for intravenous administration of thalidomide (THD). The formulations were prepared by spontaneous emulsification method and optimized with respect to thalidomide (0.01-0.05%, w/w), and hydrophilic emulsifier (polysorbate 80; 0.5-4.0%, w/w) content. The formulations were evaluated concerning physical appearance and drug crystallization; droplet size; zeta potential and drug assay. Only the formulation containing 0.01% THD and 0.5% polysorbate kept its properties in a satisfactory range over the evaluated period (60 days), i.e. droplet size around 200nm, drug content around 95% and zeta potential around -30mV. The transmission electron microscopy revealed emulsion droplets almost spherical in shape confirming the results obtained by photon correlation spectroscopy. Drug crystallization observed for higher content (THD 0.05%, w/w) nanoemulsions was investigated. The crystals observed at optical microscopy presented a different crystal habit compared to that of the raw material used. It was speculated whether the kind of THD polymorph employed could influence nanoemulsion formulation. Formulations were prepared with either one of THD polymorphs (β- or α-) and crystals were characterized by fourier transformed infrared spectroscopy (FTIR) and X-ray diffraction (XRD). It was observed that regardless of the polymorph employed (β- or α-), drug crystallization occurs in the α-form. THD solubility in oils was not influenced by the polymorphic form. In addition, the in vitro dissolution profile of the selected formulation (THD 0.01%, w/w; polysorbate 0.5%, w/w) was assessed by bulk-equilibrium reverse dialysis sac technique and demonstrated a release profile similar to that of a THD acetonitrile solution, with around 95% THD being dissolved within 4h. Finally, a pharmacokinetic simulation of an intravenous infusion of 250mL of the selected nanoemulsion suggests that the parenteral administration of a dose as low as 25mg might lead to therapeutic plasma concentrations of thalidomide. Copyright © 2010 Elsevier B.V. All rights reserved.

Effect of TNF-α production inhibitors on the production of pro-inflammatory cytokines by peripheral blood mononuclear cells from HTLV-1-infected individuals.

PubMed

Luna, T; Santos, S B; Nascimento, M; Porto, M A F; Muniz, A L; Carvalho, E M; Jesus, A R

2011-11-01

Human T lymphotropic virus type 1 (HTLV-1) is the causal agent of myelopathy/tropical spastic paraparesis (HAM/TSP), a disease mediated by the immune response. HTLV-1 induces a spontaneous proliferation and production of pro-inflammatory cytokines by T cells, and increasing interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) levels are potentially involved in tissue damage in diseases related to HTLV-1. This exaggerated immune response is also due to an inability of the natural regulatory mechanisms to down-modulate the immune response in this group of patients. TNF-α inhibitors reduce inflammation and have been shown to improve chronic inflammatory diseases in clinical trials. The aim of this study was to evaluate the ability of pentoxifylline, forskolin, rolipram, and thalidomide to decrease in vitro production of TNF-α and IFN-γ in cells of HTLV-1-infected subjects. Participants of the study included 19 patients with HAM/TSP (mean age, 53 ± 11; male:female ratio, 1:1) and 18 HTLV-1 carriers (mean age, 47 ± 11; male:female ratio, 1:2.6). Cytokines were determined by ELISA in supernatants of mononuclear cell cultures. Pentoxifylline inhibited TNF-α and IFN-γ synthesis with the minimum dose used (50 µM). The results with forskolin were similar to those observed with pentoxifylline. The doses of rolipram used were 0.01-1 µM and the best inhibition of TNF-α production was achieved with 1 µM and for IFN-γ production it was 0.01 µM. The minimum dose of thalidomide used (1 µM) inhibited TNF-α production but thalidomide did not inhibit IFN-γ production even when the maximum dose (50 µM) was used. All drugs had an in vitro inhibitory effect on TNF-α production and, with the exception of thalidomide, all of them also decreased IFN-γ production.

Nuclear cereblon modulates transcriptional activity of Ikaros and regulates its downstream target, enkephalin, in human neuroblastoma cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wada, Takeyoshi; Asahi, Toru; Research Organization for Nano & Life Innovation, Waseda University #03C309, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo, 162-8480

2016-08-26

The gene coding cereblon (CRBN) was originally identified in genetic linkage analysis of mild autosomal recessive nonsyndromic intellectual disability. CRBN has broad localization in both the cytoplasm and nucleus. However, the significance of nuclear CRBN remains unknown. In the present study, we aimed to elucidate the role of CRBN in the nucleus. First, we generated a series of CRBN deletion mutants and determined the regions responsible for the nuclear localization. Only CRBN protein lacking the N-terminal region was localized outside of the nucleus, suggesting that the N-terminal region is important for its nuclear localization. CRBN was also identified as amore » thalidomide-binding protein and component of the cullin-4-containing E3 ubiquitin ligase complex. Thalidomide has been reported to be involved in the regulation of the transcription factor Ikaros by CRBN-mediated degradation. To investigate the nuclear functions of CRBN, we performed co-immunoprecipitation experiments and evaluated the binding of CRBN to Ikaros. As a result, we found that CRBN was associated with Ikaros protein, and the N-terminal region of CRBN was required for Ikaros binding. In luciferase reporter gene experiments, CRBN modulated transcriptional activity of Ikaros. Furthermore, we found that CRBN modulated Ikaros-mediated transcriptional repression of the proenkephalin gene by binding to its promoter region. These results suggest that CRBN binds to Ikaros via its N-terminal region and regulates transcriptional activities of Ikaros and its downstream target, enkephalin. - Highlights: • We found that CRBN is a nucleocytoplasmic shutting protein and identified the key domain for nucleocytoplasmic shuttling. • CRBN associates with the transcription factor Ikaros via the N-terminal domain. • CRBN modulates Ikaros-mediated transcriptional regulation and its downstream target, enkephalin.« less

Rational combination treatment with histone deacetylase inhibitors and immunomodulatory drugs in multiple myeloma.

PubMed

Hideshima, T; Cottini, F; Ohguchi, H; Jakubikova, J; Gorgun, G; Mimura, N; Tai, Y-T; Munshi, N C; Richardson, P G; Anderson, K C

2015-05-15

Immunomodulatory drugs (IMiDs) thalidomide, lenalidomide (Len) and pomalidomide trigger anti-tumor activities in multiple myeloma (MM) by targetting cereblon and thereby impacting IZF1/3, c-Myc and IRF4. Histone deacetylase inhibitors (HDACi) also downregulate c-Myc. We therefore determined whether IMiDs with HDACi trigger significant MM cell growth inhibition by inhibiting or downregulating c-Myc. Combination treatment of Len with non-selective HDACi suberoylanilide hydroxamic acid or class-I HDAC-selective inhibitor MS275 induces synergic cytotoxicity, associated with downregulation of c-Myc. Unexpectedly, we observed that decreased levels of cereblon (CRBN), a primary target protein of IMiDs, was triggered by these agents. Indeed, sequential treatment of MM cells with MS275 followed by Len shows less efficacy than simultaneous treatment with this combination. Importantly ACY1215, an HDAC6 inhibitor with minimal effects on class-I HDACs, together with Len induces synergistic MM cytotoxicity without alteration of CRBN expression. Our results showed that only modest class-I HDAC inhibition is able to induce synergistic MM cytotoxicity in combination with Len. These studies may provide the framework for utilizing HDACi in combination with Len to both avoid CRBN downregulation and enhance anti-MM activities.

Extramedullary (EMP) relapse in unusual locations in multiple myeloma: Is there an association with precedent thalidomide administration and a correlation of special biological features with treatment and outcome?

PubMed

Katodritou, E; Gastari, V; Verrou, E; Hadjiaggelidou, C; Varthaliti, M; Georgiadou, S; Laschos, K; Xirou, P; Yiannaki, E; Constantinou, N; Markala, D; Zervas, K

2009-08-01

Extramedullary relapse constitutes an uncommon manifestation of multiple myeloma (MM), characterized by highly malignant histology, special biological features, resistance to treatment and poor outcome. Its incidence has been increased during the last years, probably due to the introduction of novel strategies in the management of MM, including intensified treatment and immunomodulatory drugs. Here we report nine cases of extramedullary relapse of MM, presented in unusual locations, seven of which had previously been treated with thalidomide-containing regimens (TCR). Our aim was to explore the morphological, immunophenotypical, molecular and laboratory characteristics accompanying EMP-relapse and seek possible correlations with treatment and clinical outcome.

Tumor Cell Gene Expression Changes Following Short-term In vivo Exposure to Single Agent Chemotherapeutics are Related to Survival in Multiple Myeloma

PubMed Central

Burington, Bart; Barlogie, Bart; Zhan, Fenghuang; Crowley, John; Shaughnessy, John D.

2013-01-01

Changes in global gene expression patterns in tumor cells following in vivo therapy may vary by treatment and provide added or synergistic prognostic power over pretherapy gene expression profiles (GEP). This molecular readout of drug-cell interaction may also point to mechanisms of action/resistance. In newly diagnosed patients with multiple myeloma (MM), microarray data were obtained on tumor cells prior to and 48 hours after in vivo treatment using dexamethasone (n = 45) or thalidomide (n = 42); in the case of relapsed MM, microarray data were obtained prior to (n = 36) and after (n = 19) lenalidomide administration. Dexamethasone and thalidomide induced both common and unique GEP changes in tumor cells. Combined baseline and 48-hour changes in GEP in a subset of genes, many related to oxidative stress and cytoskeletal dynamics, were predictive of outcome in newly diagnosed MM patients receiving tandem transplants. Thalidomide-altered genes also changed following lenalidomide exposure and predicted event-free and overall survival in relapsed patients receiving lenalidomide as a single agent. Combined with baseline molecular features, changes in GEP following short-term single-agent exposure may help guide treatment decisions for patients with MM. Genes whose drug-altered expression were found to be related to survival may point to molecular switches related to response and/or resistance to different classes of drugs. PMID:18676754

Drug-induced tremor

MedlinePlus

... Drugs that can cause tremor include the following: Cancer medicines such as thalidomide and cytarabine Seizure medicines such as valproic acid (Depakote) and sodium valproate (Depakene) Asthma medicines such as theophylline and ...

Induction regimens for transplant-eligible patients with newly diagnosed multiple myeloma: a network meta-analysis of randomized controlled trials

PubMed Central

Zeng, Zi-Hang; Chen, Jia-Feng; Li, Yi-Xuan; Zhang, Ran; Xiao, Ling-Fei; Meng, Xiang-Yu

2017-01-01

Objective The aim of this study was to compare the early efficacy and survivals of induction regimens for transplant-eligible patients with untreated multiple myeloma. Materials and methods A comprehensive literature search in electronic databases was conducted for relevant randomized controlled trials (RCTs). Eligible studies were selected according to the predefined selection criteria, before they were evaluated for methodological quality. Basic characteristics and data for network meta-analysis (NMA) were extracted from included trials and pooled in our meta-analysis. The end points were the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results A total of 14 RCTs that included 4,763 patients were analyzed. The post-induction ORR was higher with bortezomib plus thalidomide plus dexamethasone (VTD) regimens, and VTD was better than the majority of other regimens. For OS, VTD plus cyclophosphamide (VTDC) regimens showed potential superiority over other regimens, but the difference was not statistically significant. The PFS was longer with thalidomide plus doxorubicin plus dexamethasone (TAD) regimens for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). Conclusion The NMA demonstrated that the VTD, VTDC, and TAD regimens are most beneficial in terms of ORR, OS, and PFS for transplant-eligible patients with NDMM, respectively. PMID:28744159

Thalidomide

MedlinePlus

... biology of immunomodulatory drugs (IMiDs) in cancer. Pharmacology & Therapeutics. 2012;136:56. Thalomid (prescribing information). Summit, N. ... Behcet disease. In: Treatment of Skin Disease: Comprehensive Therapeutic Strategies. 4th ed. Philadelphia, Pa.: Saunders Elsevier; 2014. ...

The thalidomide analogue CC-3052 inhibits HIV-1 and tumour necrosis factor-alpha (TNF-α) expression in acutely and chronically infected cells in vitro

PubMed Central

La Maestra, L; Zaninoni, A; Marriott, J B; Lazzarin, A; Dalgleish, A G; Barcellini, W

2000-01-01

We investigated the in vitro effect of the water-soluble, highly stable thalidomide analogue CC-3052 on HIV-1 expression and TNF-α production in latently infected promonocytic U1 cells, acutely infected T cells and monocyte-derived human macrophages (MDM), and in mitogen-stimulated ex vivo cultures from patients with primary acute HIV-1 infection. HIV-1 expression was assessed by Northern blot analysis of RNAs, and ELISA for p24 antigen release and reverse transcriptase (RT) activity. TNF-α expression was evaluated by RT-polymerase chain reaction (PCR)-ELISA for mRNA and ELISA for protein secretion. We demonstrated that CC-3052 is able to inhibit HIV-1 expression, as evaluated by mRNA, p24 release and RT activity, in phorbol myristate acetate (PMA)- and cytokine-stimulated U1 cells. Furthermore, CC-3052 inhibited HIV-1 expression, as evaluated by p24 and RT activity, in acutely infected MDM and T cells. As far as TNF-α is concerned, CC-3052 significantly reduced TNF-α mRNA and protein secretion in PMA-stimulated U937 and U1 cells, and in PMA-stimulated uninfected and acutely infected MDM. Consistently, the addition of CC-3052 reduced TNF-α production in phytohaemagglutinin (PHA) and lipopolysaccharide (LPS)-stimulated whole blood cultures from patients during the primary acute phase of HIV-1 infection. Since TNF-α is among the most potent enhancers of HIV-1 expression, the effect of CC-3052 on TNF-α may account for its inhibitory activity on HIV-1 expression. Given the well documented immunopathological role of TNF-α and its correlation with viral load, advanced disease and poor prognosis, CC-3052 could be an interesting drug for the design of therapeutic strategies in association with anti-retroviral agents. PMID:10606973

The thalidomide analogue CC-3052 inhibits HIV-1 and tumour necrosis factor-alpha (TNF-alpha) expression in acutely and chronically infected cells in vitro.

PubMed

La Maestra, L; Zaninoni, A; Marriott, J B; Lazzarin, A; Dalgleish, A G; Barcellini, W

2000-01-01

We investigated the in vitro effect of the water-soluble, highly stable thalidomide analogue CC-3052 on HIV-1 expression and TNF-alpha production in latently infected promonocytic U1 cells, acutely infected T cells and monocyte-derived human macrophages (MDM), and in mitogen-stimulated ex vivo cultures from patients with primary acute HIV-1 infection. HIV-1 expression was assessed by Northern blot analysis of RNAs, and ELISA for p24 antigen release and reverse transcriptase (RT) activity. TNF-alpha expression was evaluated by RT-polymerase chain reaction (PCR)-ELISA for mRNA and ELISA for protein secretion. We demonstrated that CC-3052 is able to inhibit HIV-1 expression, as evaluated by mRNA, p24 release and RT activity, in phorbol myristate acetate (PMA)- and cytokine-stimulated U1 cells. Furthermore, CC-3052 inhibited HIV-1 expression, as evaluated by p24 and RT activity, in acutely infected MDM and T cells. As far as TNF-alpha is concerned, CC-3052 significantly reduced TNF-alpha mRNA and protein secretion in PMA-stimulated U937 and U1 cells, and in PMA-stimulated uninfected and acutely infected MDM. Consistently, the addition of CC-3052 reduced TNF-alpha production in phytohaemagglutinin (PHA) and lipopolysaccharide (LPS)-stimulated whole blood cultures from patients during the primary acute phase of HIV-1 infection. Since TNF-alpha is among the most potent enhancers of HIV-1 expression, the effect of CC-3052 on TNF-alpha may account for its inhibitory activity on HIV-1 expression. Given the well documented immunopathological role of TNF-alpha and its correlation with viral load, advanced disease and poor prognosis, CC-3052 could be an interesting drug for the design of therapeutic strategies in association with anti-retroviral agents.

Role of cytokines (TNF-alpha, IL-1beta and KC) in the pathogenesis of CPT-11-induced intestinal mucositis in mice: effect of pentoxifylline and thalidomide.

PubMed

Melo, Maria Luisa P; Brito, Gerly A C; Soares, Rudy C; Carvalho, Sarah B L M; Silva, Johan V; Soares, Pedro M G; Vale, Mariana L; Souza, Marcellus H L P; Cunha, Fernando Q; Ribeiro, Ronaldo A

2008-04-01

Irinotecan (CPT-11) is an inhibitor of DNA topoisomerase I and is clinically effective against several cancers. A major toxic effect of CPT-11 is delayed diarrhea; however, the exact mechanism by which the drug induces diarrhea has not been established. Elucidate the mechanisms of induction of delayed diarrhea and determine the effects of the cytokine production inhibitor pentoxifylline (PTX) and thalidomide (TLD) in the experimental model of intestinal mucositis, induced by CPT-11. Intestinal mucositis was induced in male Swiss mice by intraperitoneal administration of CPT-11 (75 mg/kg) daily for 4 days. Animals received subcutaneous PTX (1.7, 5 and 15 mg/kg) or TLD (15, 30, 60 mg/kg) or 0.5 ml of saline daily for 5 and 7 days, starting 1 day before the first CPT-11 injection. The incidence of delayed diarrhea was monitored by scores and the animals were sacrificed on the 5th and 7th experimental day for histological analysis, immunohistochemistry for TNF-alpha and assay of myeloperoxidase (MPO) activity, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and KC ELISA. CPT-11 caused significant diarrhea, histopathological alterations (inflammatory cell infiltration, loss of crypt architecture and villus shortening) and increased intestinal tissue MPO activity, TNF-alpha, IL-1beta and KC level and TNF-alpha immuno-staining. PTX inhibited delayed diarrhea of mice submitted to intestinal mucositis and reduced histopathological damage, intestinal MPO activity, tissue level of TNF-alpha, IL-1beta and KC and TNF-alpha immuno-staining. TLD significantly reduced the lesions induced by CPT-11 in intestinal mucosa, decreased MPO activity, TNF-alpha tissue level and TNF-alpha immuno-staining, but did not reduce the severity of diarrhea. These results suggest an important role of TNF-alpha, IL-1beta and KC in the pathogenesis of intestinal mucositis induced by CPT-11.

Canadian Thalidomide Experience

PubMed Central

Webb, Jean F.

1963-01-01

Data are presented on 115 children, including three sets of twins, born in Canada in 1961 and 1962 with congenital malformations associated with the use of thalidomide by their mothers in early pregnancy. The epidemiological method is described. Of the 115 children, 74 were alive at the time of reporting, 41 of these being severely handicapped; 8 had been stillborn; 33 had died. Limb involvement was usually bilateral, affecting the upper limbs alone in 42 cases, and the upper and lower limbs in 41. Of 112 mothers, only 60 had had the drug prescribed by the physician providing maternity care; 87 were estimated to have first taken the drug before their last menstrual period or within 56 days thereafter. A plea is made for the development of better methods of collecting information on the occurrence of congenital malformations, with the aid of practising physicians. PMID:14076167

Mutations in STN1 cause Coats plus syndrome and are associated with genomic and telomere defects

PubMed Central

Simon, Amos J.; Lev, Atar; Zhang, Yong; Weiss, Batia; Rylova, Anna; Eyal, Eran; Kol, Nitzan; Cesarkas, Keren; Rhodes, Michele; Schiby, Ginette; Barshack, Iris; Katz, Shulamit; Reznik-Wolf, Haike; Ribakovsky, Elena; Simon, Carlos; Hazou, Wadi; Katzir, Hagar; Sagie, Shira; Amariglio, Ninette; Rechavi, Gideon

2016-01-01

The analysis of individuals with telomere defects may shed light on the delicate interplay of factors controlling genome stability, premature aging, and cancer. We herein describe two Coats plus patients with telomere and genomic defects; both harbor distinct, novel mutations in STN1, a member of the human CTC1–STN1–TEN1 (CST) complex, thus linking this gene for the first time to a human telomeropathy. We characterized the patients’ phenotype, recapitulated it in a zebrafish model and rescued cellular and clinical aspects by the ectopic expression of wild-type STN1 or by thalidomide treatment. Interestingly, a significant lengthy control of the gastrointestinal bleeding in one of our patients was achieved by thalidomide treatment, exemplifying a successful bed-to-bench-and-back approach. PMID:27432940

Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study.

PubMed

Rosiñol, Laura; Oriol, Albert; Teruel, Ana Isabel; Hernández, Dolores; López-Jiménez, Javier; de la Rubia, Javier; Granell, Miquel; Besalduch, Joan; Palomera, Luis; González, Yolanda; Etxebeste, María Asunción; Díaz-Mediavilla, Joaquín; Hernández, Miguel T; de Arriba, Felipe; Gutiérrez, Norma C; Martín-Ramos, María Luisa; Cibeira, María Teresa; Mateos, María Victoria; Martínez, Joaquín; Alegre, Adrián; Lahuerta, Juan José; San Miguel, Jesús; Bladé, Joan

2012-08-23

The Spanish Myeloma Group conducted a trial to compare bortezomib/thalidomide/dexamethasone (VTD) versus thalidomide/dexamethasone (TD) versus vincristine, BCNU, melphalan, cyclophosphamide, prednisone/vincristine, BCNU, doxorubicin, dexamethasone/bortezomib (VBMCP/VBAD/B) in patients aged 65 years or younger with multiple myeloma. The primary endpoint was complete response (CR) rate postinduction and post-autologous stem cell transplantation (ASCT). Three hundred eighty-six patients were allocated to VTD (130), TD (127), or VBMCP/VBAD/B (129). The CR rate was significantly higher with VTD than with TD (35% vs 14%, P = .001) or with VBMCP/VBAD/B (35% vs 21%, P = .01). The median progression-free survival (PFS) was significantly longer with VTD (56.2 vs 28.2 vs 35.5 months, P = .01). In an intention-to-treat analysis, the post-ASCT CR rate was higher with VTD than with TD (46% vs 24%, P = .004) or with VBMCP/VBAD/B (46% vs 38%, P = .1). Patients with high-risk cytogenetics had a shorter PFS and overall survival in the overall series and in all treatment groups. In conclusion, VTD resulted in a higher pre- and posttransplantation CR rate and in a significantly longer PFS although it was not able to overcome the poor prognosis of high-risk cytogenetics. Our results support the use of VTD as a highly effective induction regimen prior to ASCT. The study was registered with http://www.clinicaltrials.gov (NCT00461747) and Eudra CT (no. 2005-001110-41).

After thalidomide - do we have the right balance between public health and intellectual property.

PubMed

Feldschreiber, Peter; Breckenridge, Alasdair

2015-01-01

The current European regulatory and consumer protection legal framework is the legacy of Thalidomide. The disaster led to the introduction of systematic biological and clinical data to endorse the safety and efficacy of new medicines. The European Medicines Directive outlined the pre-clinical, clinical data and product information to evaluate an appropriate benefit. Risk profile of new medicines and also allowed innovative companies to extend patent protection and data/marketing exclusivity periods to compensate for the cost for research and development. However in recent years it has become apparent that the costs and time for research and development are becoming increasingly burdensome, particularly for new drugs with recently discovered mechanisms of action for cancers and neurodegenerative disorders. The costs of development and the commercial uncertainty of such products is reducing commercialisation of these medicines. There is now considerable debate in the regulatory community as to how this regulatory burden may be eased by making earlier review of benefit risk and hence earlier access to authorised medicines. The Courts are moving away from the wide definition of medicinal product to a more nuanced view of the biological and clinical therapeutic mechanisms to satisfy the 'functional' limb definition in the Directive. This may be a move away from the rigorous scientific methodology generated after thalidomide. We discuss the ethical and public health implications of this shift in policy and the implications for intellectual property mechanisms currently available to protect the commercial needs of companies.

p97/VCP promotes degradation of CRBN substrate glutamine synthetase and neosubstrates

PubMed Central

Nguyen, Thang Van; Li, Jing; Lu, Chin-Chun (Jean); Mamrosh, Jennifer L.; Lu, Gang; Cathers, Brian E.; Deshaies, Raymond J.

2017-01-01

Glutamine synthetase (GS) plays an essential role in metabolism by catalyzing the synthesis of glutamine from glutamate and ammonia. Our recent study showed that CRBN, a direct protein target for the teratogenic and antitumor activities of immunomodulatory drugs such as thalidomide, lenalidomide, and pomalidomide, recognizes an acetyl degron of GS, resulting in ubiquitylation and degradation of GS in response to glutamine. Here, we report that valosin-containing protein (VCP)/p97 promotes the degradation of ubiquitylated GS, resulting in its accumulation in cells with compromised p97 function. Notably, p97 is also required for the degradation of all four known CRBN neo-substrates [Ikaros family zinc finger proteins 1 (IKZF1) and 3 (IKZF3), casein kinase 1α (CK1α), and the translation termination factor GSPT1] whose ubiquitylation is induced by immunomodulatory drugs. Together, these data point to an unexpectedly intimate relationship between the E3 ubiquitin ligase CRL4CRBN and p97 pathways. PMID:28320958

An Adult with Polyneuropathy and Hypogonadism due to Poems Syndrome.

PubMed

Zaidi, Saba; Sattar, Sidra; Asumal, Khealani Bhojo

2017-10-01

POEMS (acronym for polyneuropathy, organomegaly, endocrinopathy, M protein myeloma and skin changes), is a rare disease which occurs in the setting of plasma cell dyscrasias. We describe a case of an adult lady who presented with gradual onset weakness of all four limbs and multisystem involvement characterized by pedal edema, ascites, hyperpigmentation and hypogonadism. Nerve conduction study showed severe sensorimotor polyneuropathy. Serum immunofixation showed lambda light chain restricted monoclonal gammopathy. Bone marrow biopsy consistent with plasma cell dyscrasia. Hormonal assay showed decreased FSH, LH and estradiol levels which led us to diagnosis of hypogonadotrophic hypogonadism. The patient responded well to combination therapy of thalidomide, melphalan and dexamethasone. Eight months after the therapy, she noted decreased paresthesias and increased strength. She had reduced edema and ascites.

[Effect of thalidomide combined with dexamethasone on multiple myeloma KM3 cells].

PubMed

He, Bin; Zhang, Yu; Zhou, Wei; Gao, Na; Gao, Bo; Gu, Jian; Li, Jian-Yong

2009-08-01

The purpose of this study was to investigate the effect of thalidomide (THD) combined with dexamethasone (Dx) on multiple myeloma KM3 cells and its mechanism. The effect of the different concentrations and treatment time of THD or THD + Dx on KM3 cells was assayed by cytotoxicity test (MTT method), the inhibitory ratio of THD or THD + Dx on the KM3 cell growth was detected for choosing the best intervention condition. The expression levels of IL-6, TNF-alpha, VEGF, ES, survivin in supernatant of cells treated with best intervention condition were measured by indirect ELISA. The results indicated that an enhancement of cell growth inhibition was observed in treated KM3 cells along with increasing of drug concentrations and prolonging of treatment times, at the same time the THD combined with Dx could significantly inhibit the KM3 cell growth. The combination of THD in concentration of 80 or 100 microg/ml with Dx in concentration of 4 microg/ml decreased the expression of IL-6, TNF-alpha and survivin, increased the expression of ES, while no influence on VEGF expression was found. It is concluded that THD combined with Dx shows the synergistic inhibitory effect on KM3 cells, they bring the effect resistant to multiple myeloma probably through down-regulating the expression of IL-6, TNF-alpha and survivin, and up-regulating the expression of ES in KM3 cell.

Mechanism of immunomodulatory drugs' action in the treatment of multiple myeloma

PubMed Central

Chang, Xiubao; Zhu, Yuanxiao; Shi, Changxin; Stewart, A. Keith

2014-01-01

Although immunomodulatory drugs (IMiDs), such as thalidomide, lenalidomide, and pomalidomide, are widely used in the treatment of multiple myeloma (MM), the molecular mechanism of IMiDs' action is largely unknown. In this review, we will summarize recent advances in the application of IMiDs in MM cancer treatment as well as their effects on immunomodulatory activities, anti-angiogenic activities, intervention of cell surface adhesion molecules between myeloma cells and bone marrow stromal cells, anti-inflammatory activities, anti-proliferation, pro-apoptotic effects, cell cycle arrest, and inhibition of cell migration and metastasis. In addition, the potential IMiDs' target protein, IMiDs' target protein's functional role, and the potential molecular mechanisms of IMiDs resistance will be discussed. We wish, by presentation of our naive discussion, that this review article will facilitate further investigation in these fields. PMID:24374776

Pathophysiology of drug-induce peripheral neuropathy in patients with multiple myeloma.

PubMed

Luczkowska, K; Litwinska, Z; Paczkowska, E; Machalinski, B

2018-04-01

Multiple myeloma (MM) is a disease of unknown, complex etiology that affects primarily older adults. The course of the disease and the patients' survival time are very heterogeneous, but over the last decade, clear progress in the treatment of this incurable disease has been observed. Therapeutics that have proven to be highly effective include the immunomodulatory drug thalidomide and its newer analogs, lenalidomide and pomalidomide, as well as the proteasome inhibitors bortezomib and carfilzomib. However, the administration of some of the treatments, e.g., thalidomide or bortezomib, has also been associated with the occurrence of a serious and common adverse effect, drug-induced peripheral neuropathy. The mechanism of the development of the peripheral neuropathy is poorly understood. Nevertheless, one of its potential causes could be inadequate concentrations of crucial trophic factors, including neurotrophic and/or angiogenic factors, which are responsible for the proliferation, differentiation, survival and death of neuronal and nonneuronal cells.

Enantioseparation of thalidomide and its hydroxylated metabolites using capillary electrophoresis with various cyclodextrins and their combinations as chiral buffer additives.

PubMed

Meyring, M; Chankvetadze, B; Blaschke, G

1999-09-01

The separation of thalidomide (TD) and its hydroxylated metabolites including their simultaneous enantioseparation was studied in capillary electrophoresis (CE) using four different randomly substituted charged cyclodextrin (CD) derivatives, the combinations of some of them with each other, and beta-CD. TD, as well as two metabolites recently found in incubations of human liver microsomes and human blood, 5-hydroxythalidomide (5-OH-TD) and one of the diastereomeric 5'-hydroxythalidomides (5'-OH-TD), are neutral compounds. Therefore, they were resolved using charged chiral selectors in CE. Two different separation modes (normal polarity and carrier mode) and two different capillaries (fused-silica and polyacrylamide-coated) were tested. Based on the behavior of the individual CDs, their designed combinations were selected in order to improve the separation selectivity and enantioselectivity. Under optimized conditions all three chiral compounds and their enantiomers were resolved simultaneously.

Electroacupuncture for thalidomide/bortezomib-induced peripheral neuropathy in multiple myeloma: a feasibility study

PubMed Central

2014-01-01

Background This single-arm study evaluated feasibility, safety, and initial efficacy of electroacupuncture for thalidomide/bortezomib-induced peripheral neuropathy (PN) in cancer patients with multiple myeloma. Methods Patients with neuropathy ≥ grade 2 received 20 acupuncture treatments over 9 weeks. Results For the 19 evaluable patients, Functional Assessment of Cancer Therapy/Gynecological Oncology Group-Neurotoxicity (FACT/GOG/NTX) mean (SD) scores improved significantly between baseline and week 13 (20.8 [9.6] vs 13.2 [8.5], p = 0.0002). Moderate effect size differences began on week 4, with the largest effect size differences found at week 9 for FACT/GOG/NTX scores, worst pain in the last 24 hours, and pain severity (Cohen’s d = 1.43, 1.19, and 1.08, respectively) and continuing through week 13 (Cohen’s d = 0.86, 0.88, and 0.90, respectively). From baseline to week 13, additional significant improvements were seen as follows: postural stability (1.0 [0.6] vs 0.8 [0.4], p = 0.02); coin test (10.0 [7.4] vs 5.6 [1.9], p < 0.0001); button test (96.1 [144.4] vs 54.9 [47.3], p < 0.0001); and walking test (21.6 [10.0] vs 17.2 [7.7], p = 0.0003). No significant changes were seen with NCS. Conclusions Acupuncture may help patients experiencing thalidomide- or bortezomib-induced PN. Larger, randomized, clinical trials are needed. Trial registration ClinicalTrials.gov Identifier: NCT00891618. PMID:24886772

Analysis of a ToxCast™ HTS Toxicity Signature for putative Vascular Disruptor Compounds

EPA Science Inventory

Recent studies have shown the importance of blood vessel formation during embryo development and the strong correlation to developmental toxicity. Several developmental toxicants, such as thalidomide, have been identified which specifically target the forming embryonic vasculatur...

Identification of phototransformation products of thalidomide and mixture toxicity assessment: an experimental and quantitative structural activity relationships (QSAR) approach.

PubMed

Mahmoud, Waleed M M; Toolaram, Anju P; Menz, Jakob; Leder, Christoph; Schneider, Mandy; Kümmerer, Klaus

2014-02-01

The fate of thalidomide (TD) was investigated after irradiation with a medium-pressure Hg-lamp. The primary elimination of TD was monitored and structures of phototransformation products (PTPs) were assessed by LC-UV-FL-MS/MS. Environmentally relevant properties of TD and its PTPs as well as hydrolysis products (HTPs) were predicted using in silico QSAR models. Mutagenicity of TD and its PTPs was investigated in the Ames microplate format (MPF) aqua assay (Xenometrix, AG). Furthermore, a modified luminescent bacteria test (kinetic luminescent bacteria test (kinetic LBT)), using the luminescent bacteria species Vibrio fischeri, was applied for the initial screening of environmental toxicity. Additionally, toxicity of phthalimide, one of the identified PTPs, was investigated separately in the kinetic LBT. The UV irradiation eliminated TD itself without complete mineralization and led to the formation of several PTPs. TD and its PTPs did not exhibit mutagenic response in the Salmonella typhimurium strains TA 98, and TA 100 with and without metabolic activation. In contrast, QSAR analysis of PTPs and HTPs provided evidence for mutagenicity, genotoxicity and carcinogenicity using additional endpoints in silico software. QSAR analysis of different ecotoxicological endpoints, such as acute toxicity towards V. fischeri, provided positive alerts for several identified PTPs and HTPs. This was partially confirmed by the results of the kinetic LBT, in which a steady increase of acute and chronic toxicity during the UV-treatment procedure was observed for the photolytic mixtures at the highest tested concentration. Moreover, the number of PTPs within the reaction mixture that might be responsible for the toxification of TD during UV-treatment was successfully narrowed down by correlating the formation kinetics of PTPs with QSAR predictions and experimental toxicity data. Beyond that, further analysis of the commercially available PTP phthalimide indicated that transformation of TD into phthalimide was not the cause for the toxification of TD during UV-treatment. These results provide a path for toxicological assessment of complex chemical mixtures and in detail show the toxic potential of TD and its PTPs as well as its HTPs. This deserves further attention as UV irradiation might not always be a green technology, because it might pose a toxicological risk for the environment in general and specifically for water compartments. Copyright © 2013 Elsevier Ltd. All rights reserved.

Effect of 13q deletion on IL-6 production in patients with multiple myeloma: a hypothesis may hold true.

PubMed

Neemat, Kassem; Rania, Khalifa; Tarek, Mohamed; Hamdy, Abdel Azim

2014-01-01

Numerous studies have shown a correlation between 13q deletion and poor prognosis in multiple myeloma (MM), but the mechanisms are not fully understood. Earlier studies suggest that this lesion involves large segments or the entire long arm involving the retinoblastoma (Rb) gene. In myeloma, Rb gene is believed to down regulate interleukin-6 (IL-6) which plays a central role in the pathogenesis of MM. Therefore, it has been hypothesized that loss of the Rb gene might be associated with very high expression of IL-6 and subsequent bad prognosis. Hence this study evaluates IL-6 production in MM patients with and without 13q deletions and assesses their response to conventional and new therapeutic regimens. Forty MM patients and 20 matched controls were included in this study. Interphase fluorescence in situ hybridization (FISH) analysis was performed using LSI 13q14-specific probe. Serum levels of IL-6 were determined by ELISA. All patients received conventional chemotherapy. Refractory patients received other therapeutic regimens of Thalidomide or Bortezomib. Significant increase (p < 0.001) of IL-6 production was recorded in patients with a 13q deletion compared to patients with normal chromosome 13q status. These patients were also refractory to conventional chemotherapy but showed striking response to Thalidomide or Bortezomib. This study suggests that 13q deletions are associated with increased production of IL-6 in MM and this could be a possible cause of the associated bad prognosis. In addition, the results also show the potential to improve responses in patients with refractory MM with the introduction of novel therapies.

BSG and MCT1 Genetic Variants Influence Survival in Multiple Myeloma Patients.

PubMed

Łacina, Piotr; Butrym, Aleksandra; Mazur, Grzegorz; Bogunia-Kubik, Katarzyna

2018-04-24

Multiple myeloma (MM) is a haematologic malignancy characterized by the presence of atypical plasma cells. Basigin (BSG, CD147) controls lactate export through the monocarboxylic acid transporter 1 (MCT1, SLC16A1) and supports MM survival and proliferation. Additionally, BSG is implicated in response to treatment with immunomodulatory drugs (thalidomide and its derivatives). We investigated the role of single nucleotide polymorphisms (SNPs) in the gene coding for BSG and SLC16A1 in MM. Following an in silico analysis, eight SNPs (four in BSG and four in SLC16A1 ) predicted to have a functional effect were selected and analyzed in 135 MM patients and 135 healthy individuals. Alleles rs4919859 C, rs8637 G, and haplotype CG were associated with worse progression-free survival ( p = 0.006, p = 0.017, p = 0.002, respectively), while rs7556664 A, rs7169 T and rs1049434 A (all in linkage disequilibrium (LD), r ² > 0.98) were associated with better overall survival ( p = 0.021). Similar relationships were observed in thalidomide-treated patients. Moreover, rs4919859 C, rs8637 G, rs8259 A and the CG haplotype were more common in patients in stages II⁻III of the International Staging System ( p < 0.05), while rs8259 A correlated with higher levels of β-2-microglobulin and creatinine ( p < 0.05). Taken together, our results show that BSG and SLC16A1 variants affect survival, and may play an important role in MM.

[Producing technical drawings using the feet--a special work site for a thalidomide-damaged technical draftswoman].

PubMed

Fischbach, F

1989-05-01

Persons with upper limb deficiency do not find it easy to lead a somewhat "normal" private, occupational and social life. True, society offers many kinds of assistance and support; it nevertheless is very much a matter of how the individual concerned reacts to the positive and negative influences and imponderabilities encountered. The present report sets out the efforts of a thalidomide-affected young woman who, in the face of numerous obstacles, left nothing untried to create a life basis of her own by obtaining a good vocational qualification as a technical draftswoman, regardless of her congenital upper limb amputation. Her success is proof enough that she chose the right course. This example, in more general terms, should perhaps be considered a prompting for society, on the one hand, to undertake the endeavour of providing quality assistance even in extreme situations and, on the other, to be prepared to have confidence even in those with very severe physical disablement to be able to accomplish goals which at the first glance may appear "nonsensical", such as a desire to be trained as a technical draftswoman even though one's hands are missing. The account not least shows the positive impact help and self-help may have in the rehabilitation of very severely disabled persons. The disabled person's reward primarily lies in the sense of independence achieved and in financial self-reliance, which in turn generate a sense of feeling free inwardly and outwardly.

[PET-CT documented remission of multicentric Castleman disease after treatment with rituximab: case report and review].

PubMed

Adam, Zdeněk; Szturz, Petr; Koukalová, Renata; Řehák, Zdeněk; Pour, Luděk; Krejčí, Marta; Šmardová, Lenka; Eid, Michal; Volfová, Pavlína; Čermáková, Zdeňka; Křen, Leoš; Sokol, Filip; Hanke, Ivo; Michalková, Eva; Král, Zdeněk; Mayer, Jiří

2015-03-01

We describe a case of multicentric Castleman disease with generalized lymphadenopathy and splenomegaly, accompanied by typical B symptoms - loss of 15 kg, fever of non-infectious origin, night sweats, symptoms of anemia. Histological examination of the nodes with the highest accumulation of fluorodeoxyglucose, taken from mediastinum by thoracoscopy, revealed plasmocellular type of Castleman disease. Tests for HIV and human herpesvirus 8 (HHV-8) were negative. Three recurrences of herpes zoster indicating an alteration of immunity preceded the dia-gnosis of disease. Treatment was initiated with combination of thalidomide, dexamethasone, and cyclophosphamide. The response after 2 months therapy was not clear and patient doesn't tolerated the therapy well. Therefore, this treatment was terminated and R-CHOP (Mabthera - rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone) was selected as a second-line therapy. Lymphadenopathy and splenomegaly were reduced during the 2 cycles of treatment, however, serious infectious complications accompanied the therapy. Therefore, only use of Mabthera monotherapy 375 mg /m2 was administered in 28-day intervals. This treatment has shown efficacy and tolerability. PET-CT scan has demonstrated disappearance of lymphadenopathy and splenomegaly, in addition, normalized accumulation of fluorodeoxyglucose. Monotherapy with Mabthera has proved to be effective and well tolerated drug in this case. Currently, there are more effective therapeutic alternatives in multicentric Castleman disease: treatment with monotherapy of rituximab or in combination therapy with immunomodulatory drugs (thalidomide or lenalidomide, treatment with anti-IL-6 (siltuximab) or against its receptor (tocilizumab). In the case of ineffectiveness of one treatment option must be tested other alternative. In this case the therapy based on thalidomide wasn't successful, whereas the treatment with Mabthera has achieved disappearance of disease symptoms.

Semi-Microscale Williamson Ether Synthesis and Simultaneous Isolation of an Expectorant from Cough Tablets

NASA Astrophysics Data System (ADS)

Stabile, Ryan G.; Dicks, Andrew P.

2003-03-01

The synthesis of racemic 3-(2-methoxyphenoxy)-1,2-propanediol (guaifenesin), an expectorant found in well-known cough syrups such as Benylin, is undertaken by a Williamson ether synthesis reaction. The same compound is simultaneously isolated and characterized from commercially available Guai-Aid cough tablets. The experiment is well-suited towards the introductory part of an advanced organic laboratory course and complements typical lecture topics in a stimulating manner. Consideration is given towards reaction mechanisms, stereochemistry, optical activity, pharmaceutical synthesis, and spectroscopic analysis. Discussion of the merits or disadvantages of marketing a drug as a racemic mixture, with reference to the notorious thalidomide case study, and the concept of enantioselective synthesis is possible.

Blood Vessel Normalization in the Hamster Oral Cancer Model for Experimental Cancer Therapy Studies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ana J. Molinari; Romina F. Aromando; Maria E. Itoiz

Normalization of tumor blood vessels improves drug and oxygen delivery to cancer cells. The aim of this study was to develop a technique to normalize blood vessels in the hamster cheek pouch model of oral cancer. Materials and Methods: Tumor-bearing hamsters were treated with thalidomide and were compared with controls. Results: Twenty eight hours after treatment with thalidomide, the blood vessels of premalignant tissue observable in vivo became narrower and less tortuous than those of controls; Evans Blue Dye extravasation in tumor was significantly reduced (indicating a reduction in aberrant tumor vascular hyperpermeability that compromises blood flow), and tumor bloodmore » vessel morphology in histological sections, labeled for Factor VIII, revealed a significant reduction in compressive forces. These findings indicated blood vessel normalization with a window of 48 h. Conclusion: The technique developed herein has rendered the hamster oral cancer model amenable to research, with the potential benefit of vascular normalization in head and neck cancer therapy.« less

A risk assessment of topical tretinoin as a potential human developmental toxin based on animal and comparative human data.

PubMed

Johnson, E M

1997-03-01

Although topically applied all-trans-retinoic acid (tretinoin) undergoes minimal absorption and adds negligibly to normal endogenous levels, its safety in humans is occasionally questioned because oral ingestion of retinoids at therapeutic levels is known to entail teratogenic risks. To assess the actual potential for developmental toxicity from treatment with topical tretinoin. Risk assessments were conducted on four known human developmental toxicants (valproic acid, methotrexate, thalidomide, and isotretinoin) and a potential developmental toxicant (acetylsalicylic acid). The margin of safety for each chemical was calculated from the ratio of animal no-observed adverse effect levels to human lowest-observed adverse effect levels or estimated exposure doses. The derived safety margin of more than 100 for topical tretinoin (with 2% absorption) contrasted sharply with the near unity values for valproic acid, methotrexate, thalidomide, and isotretinoin and was larger than that for acetylsalicylic acid. These data support other epidemiologic and animal data that topical tretinoin is not a potential human developmental toxicant.

Versican is a potential therapeutic target in docetaxel-resistant prostate cancer

PubMed Central

Arichi, Naoko; Mitsui, Yozo; Hiraki, Miho; Nakamura, Sigenobu; Hiraoka, Takeo; Sumura, Masahiro; Hirata, Hiroshi; Tanaka, Yuichiro; Dahiya, Rajvir; Yasumoto, Hiroaki; Shiina, Hiroaki

2015-01-01

In the current study, we investigated a combination of docetaxel and thalidomide (DT therapy) in castration-resistant prostate cancer (CRPC) patients. We identified marker genes that predict the effect of DT therapy. Using an androgen-insensitive PC3 cell line, we established a docetaxel-resistant PC-3 cell line (DR-PC3). In DR-PC3 cells, DT therapy stronger inhibited proliferation/viability than docetaxel alone. Based on gene ontology analysis, we found versican as a selective gene. This result with the findings of cDNA microarray and validated by quantitative RT-PCR. In addition, the effect of DT therapy on cell viability was the same as the effect of docetaxel plus versican siRNA. In other words, silencing of versican can substitute for thalidomide. In the clinical setting, versican expression in prostate biopsy samples (before DT therapy) correlated with PSA reduction after DT therapy (p<0.05). Thus targeting versican is a potential therapeutic strategy in docetaxel-resistant prostate cancer. PMID:25859560

Medical and Psychosocial Aspects of the Habilitation of Thalidomide Children

PubMed Central

Mongeau, M.; Gingras, G.; Sherman, E. D.; Hebert, B.; Hutchison, J.; Corriveau, C.

1966-01-01

The habilitation of 34 thalidomide children, begun in 1963 at the Rehabilitation Institute of Montreal, involved the contribution of many medical and paramedical disciplines. These individual contributions are described. Habilitation of congenitally deformed children must be initiated at an early age. The early prescription of a prosthesis is desirable. Their care involves a broad range of services that must be continued over many years. Parents require support before they can accept the misfortune that has befallen them and their deformed child. Despite the necessity of frequent hospitalizations, children should be reared in a home setting. From their experience, the authors conclude that children born with malformations, and their parents, should be thoroughly evaluated and followed up for many years; and recommend that governments should finance programs for the complete habilitation of all children born with congenital malformations. National registries for the compulsory recording of birth deformities should also be established. ImagesFig. 1Fig. 2Fig. 3 PMID:5923651

Fetal exposure to teratogens: evidence of genes involved in autism.

PubMed

Dufour-Rainfray, Diane; Vourc'h, Patrick; Tourlet, Sébastien; Guilloteau, Denis; Chalon, Sylvie; Andres, Christian R

2011-04-01

Environmental challenges during the prenatal period can result in behavioral abnormalities and cognitive deficits that appear later in life such as autism. Prenatal exposure to valproic acid, ethanol, thalidomide and misoprostol has been shown to be associated with an increased incidence of autism. In addition, rodents exposed in utero to some of these drugs show autism-like abnormalities, including brain changes and lifelong behavior dysfunction. Our aim is to summarize current understanding of the relationship between in utero exposure to these drugs and autism in humans and in autism-like animal model phenotypes. It also highlights the importance of these models to understanding the neurobiology of autism, particularly in the identification of susceptibility genes. These drugs are able to modulate the expression of many genes involved in processes such as proliferation, apoptosis, neuronal differentiation and migration, synaptogenesis and synaptic activity. It seems essential to focus research on genes expressed during early neurodevelopment which may be the target of mutations or affected by drugs such as those included in this review. Copyright © 2011. Published by Elsevier Ltd.

Pyoderma Gangranosum of the Penis

PubMed Central

Kim, Tae Heung; Oh, Seung Young

2009-01-01

We report a patient who developed pyoderma gangrenosum in the penis with invasion of the distal urethra. The patient was treated with prednisolone and thalidomide, followed by a reconstructive surgical repair using a scrotal island flap. We report this case with a brief review of the literature. PMID:19949683

TERATOLOGY SOCIETY 1998 PUBLIC AFFAIRS COMMITTEE SYMPOSIUM: THE NEW THALIDOMIDE ERA: DEALING WITH THE RISKS

EPA Science Inventory

The Teratology Society Public Affairs Committee Symposium was held on June 21, 1998, during the Society's annual meeting in San Diego, California. The symposium was organized and chaired by Dr. Carole Kimmel. The sysmposium was designed to consider the medical, social, and ethi...

Engineered Bio-Molecular Nano-Devices/Systems

DTIC Science & Technology

2009-03-01

molecules with proper size will be captured by BCD and produce current blockage events, including, e.g., ibuprofen and thalidomide [37]. However, since...detection of enantiomers ," J. Am. Chem. Soc, vol. 128, pp. 10684-10685, 2006. [38] F. Sachs, J. Neil, and N. Barkakati, "The Automated-Analysis of

Complex Anatomic Abnormalities of the Lower Leg Muscles and Tendons Associated With Phocomelia: A Case Report.

PubMed

Hodo, Thomas; Hamrick, Mark; Melenevsky, Yulia

Musculoskeletal anatomy is widely known to have components that stray from the norm in the form of variant muscle and tendon presence, absence, origin, insertion, and bifurcation. Although these variant muscles and tendons might be deemed incidental and insignificant findings by most, they can be important contributors to pathologic physiology or, more importantly, an option for effective treatment. In the present case report, we describe a patient with phocomelia and Müllerian abnormalities secondary to in utero thalidomide exposure. The patient had experienced recurrent bilateral foot pain accompanied by numbness, stiffness, swelling, and longstanding pes planus. These symptoms persisted despite conservative treatment with orthotics, steroids, and nonsteroidal anti-inflammatory drugs. Radiographic imaging showed dysmorphic and degenerative changes of the ankle and foot joints. Further investigation with magnetic resonance imaging revealed complex anatomic abnormalities, including the absence of the posterior tibialis and peroneus brevis, lateralization of the peroneus longus, and the presence of a variant anterior compartment muscle. The variant structure was likely a previously described anterior compartment variant, anterior fibulocalcaneus, and might have been a source of the recurrent pain. Also, the absence of the posterior tibialis might have caused the pes planus in the present patient, considering that posterior tibialis tendon dysfunction is the most common cause of acquired pes planus. Although thalidomide infrequently affects the lower extremities, its effects on growth and development were likely the cause of this rare array of anatomic abnormalities and resulting ankle and foot pathologic features. Copyright © 2017 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.

Characteristics, Treatment, and Long-Term Outcome of Gastrointestinal Involvement in Behcet's Syndrome

PubMed Central

Hatemi, Ibrahim; Esatoglu, Sinem Nihal; Hatemi, Gulen; Erzin, Yusuf; Yazici, Hasan; Celik, Aykut Ferhat

2016-01-01

Abstract Gastrointestinal involvement is rare in Behçet's syndrome (BS) patients from the Mediterranean basin. We report the demographic and disease characteristics, treatment modalities, and outcome of patients with gastrointestinal involvement in BS (GIBS). We retrospectively reviewed the charts of all BS patients in our BS clinic with a diagnosis of GIBS. Patients were invited to the clinic to assess their outcome. Among 8763 BS patients, we identified 60 with GIBS (M/F: 32/28, mean age at diagnosis: 34 ± 10, mean follow-up: 7.5 ± 4 years), after excluding 22 patients with mimicking symptoms. Six (10%) had juvenile-onset BS. The most common intestinal localization was ileocecal region (36/59, 61%) mainly as big oval ulcer/s. Initial treatment was azathioprine for moderate to severe (n = 37) and 5-ASA for mild cases (n = 16). Anti-TNFs and/or thalidomide provided remission in 12 of 18 (67%) refractory patients. Emergency surgery was required in 22 patients. Nine patients did not receive postoperative immunomodulators and 8 relapsed. Overall, 48 of 60 (80%) patients were in remission (29/48 without treatment) at the time of survey. Three recently treated and 2 refractory patients were still active, 3 had died due to non-GI-related reasons, and 4 were lost to follow-up. Careful evaluation for excluding mimickers is important during the diagnosis of GIBS. Azathioprine seems to be a good choice as first-line treatment with high remission rates and few adverse events. Thalidomide and/or TNF-alpha antagonists may be preferred in resistant cases. Surgery may be required for perforations or massive bleeding, and postoperative immunosuppressive treatment is necessary for preventing postoperative recurrences. PMID:27100417

Evaluating Drugs and Food Additives for Public Use: A Case Studies Approach.

ERIC Educational Resources Information Center

Merritt, Sheridan V.

1980-01-01

Described is a case study used in an introductory college biology course that provides a basis for generating debate on an issue concerning the regulation of controversial food additives and prescription drugs. The case study contained within this article deals with drug screening, specifically with information related to thalidomide. (CS)

New pharmacotherapy options for multiple myeloma.

PubMed

Mina, Roberto; Cerrato, Chiara; Bernardini, Annalisa; Aghemo, Elena; Palumbo, Antonio

2016-01-01

Novel agents and the availability of autologous stem-cell transplantation have revolutionized the treatment of patients with multiple myeloma. First-generation novel agents namely thalidomide, lenalidomide, and bortezomib have significantly improved response and survival of patients. Second-generation novel agents such as pomalidomide, carfilzomib, and monoclonal antibodies are being tested both in the newly diagnosed and relapse settings, and results are promising. In this review article, the main results derived from Phase III trials with thalidomide, lenalidomide, and bortezomib for the treatment of myeloma patients, both at diagnosis and at relapse, are summarized. Data about second-generation novel agents such as pomalidomide and carfilzomib are also reported. Newer effective drugs currently under investigation and the promising results with monoclonal antibodies are described. The availability of new effective drugs has considerably increased the treatment options for myeloma patients. A sequential approach including induction, transplantation (when possible), consolidation, and maintenance is an optimal strategy to achieve disease control and prolong survival. Despite these improvements, the best combination, the optimal sequence, and the proper target of newer drugs need to be defined.

Habilitation of Patients with Congenital Malformations Associated with Thalidomide: Prosthetic Aspects

PubMed Central

Gilpin, R. E.

1963-01-01

The types of prostheses available for treatment of congenital amputations in children, and the assistance in habilitation which can be expected from their use, are described in this communication. The limb deformities in children commonly associated with the drug thalidomide are phocomelia and amelia. Prosthetic treatment of these is difficult, but in almost every case some assistance can be offered. The degree of this assistance will depend to a large extent on (1) the number of limbs involved, (2) the site of the deformity, (3) the intellectual capacity of the child. These factors are evaluated by a clinic team, consisting of a prosthetist, a therapist, a social worker, and a doctor, who acts as the clinical chief. They are also embodied into a prescription for a prosthesis and into a program of management. Subsequently, the clinic team also carry out an assessment of the result. The prosthetist makes available his knowledge of present-day appliances, and assures that the way is left open for use of new, and perhaps revolutionary prostheses, in the future. ImagesFig. 1(a)-1(b)Fig. 2Fig. 3Fig. 4 PMID:13947980

Habilitation of Patients with Congenital Malformations Associated with Thalidomide: Surgery of Limb Defects

PubMed Central

Hall, John E.

1963-01-01

The deformities commonly seen in “thalidomide babies” are described. These vary from relatively uncomplicated radial-ray defects to complete phocomelia of all four extremities. It is suggested that the care of these children is best carried out in a clinic accustomed to dealing with juvenile amputee problems. A plea is made for very early fitting of upper-extremity prostheses (at approximately three months of age) in cases of unilateral upper-limb deficiencies. A “bucket” for sitting should be supplied for children with quadrilateral phocomelia to sit in when they reach seven or eight months of age. Children with severe upper-limb malformations will be candidates for some form of externally powered prostheses. ImagesFig. 1a and 1bFig. 2a and 2bFig. 3a and 3bFig. 4a and 4bFig. 5a, b and cFig. 6a and 6bFig. 7Fig. 8Fig. 9a and 9bFig. 10a,bFig. 10c and d PMID:13952105

Peripheral Nerve Dysfunction in Middle-Aged Subjects Born with Thalidomide Embryopathy

PubMed Central

Nicotra, Alessia; Newman, Claus; Johnson, Martin; Eremin, Oleg; Friede, Tim; Malik, Omar; Nicholas, Richard

2016-01-01

Background Phocomelia is an extremely rare congenital malformation that emerged as one extreme of a range of defects resulting from in utero exposure to thalidomide. Individuals with thalidomide embryopathy (TE) have reported developing symptoms suggestive of peripheral nervous system dysfunction in the mal-developed limbs in later life. Methods Case control study comparing TE subjects with upper limb anomalies and neuropathic symptoms with healthy controls using standard neurophysiological testing. Other causes of a peripheral neuropathy were excluded prior to assessment. Results Clinical examination of 17 subjects with TE (aged 50.4±1.3 [mean±standard deviation] years, 10 females) and 17 controls (37.9±9.0 years; 8 females) demonstrated features of upper limb compressive neuropathy in three-quarters of subjects. Additionally there were examination findings suggestive of mild sensory neuropathy in the lower limbs (n = 1), L5 radiculopathic sensory impairment (n = 1) and cervical myelopathy (n = 1). In TE there were electrophysiological changes consistent with a median large fibre neuropathic abnormality (mean compound muscle action potential difference -6.3 mV ([-9.3, -3.3], p = 0.0002) ([95% CI], p-value)) and reduced sympathetic skin response amplitudes (-0.8 mV ([-1.5, -0.2], p = 0.0089)) in the affected upper limbs. In the lower limbs there was evidence of sural nerve dysfunction (sensory nerve action potential -5.8 μV ([-10.7, -0.8], p = 0.0232)) and impaired warm perception thresholds (+3.0°C ([0.6, 5.4], p = 0.0169)). Conclusions We found a range of clinical features relevant to individuals with TE beyond upper limb compressive neuropathies supporting the need for a detailed neurological examination to exclude other treatable pathologies. The electrophysiological evidence of large and small fibre axonal nerve dysfunction in symptomatic and asymptomatic limbs may be a result of the original insult and merits further investigation. PMID:27100829

Multiple myeloma associated with an Evan’s syndrome

PubMed Central

Bechir, Achour; Haifa, Regaieg; Nesrine, Ben Sayed; Emna, Bouslema; Senda, Mejdoub; Asma, Achour; Amina, Bouatay Bouzouita; Mrabet, Senda; Yosra, Ben Youssef; Mondher, Kortas; Abderrahim, Khelif

2016-01-01

Auto-immun events are rare in multiple myeloma (MM). Here, we report one MM case complicated by Evans syndrome (Autoimmun hemolytic anemia (AIHA) associated with thrombocytopenia). A 52-year-old man was admitted in nephrology department with severe anemia, renal insufficiency and hypergamma globulinemia. Laboratory exams showed acute hemolysis due to an IgG warm autoantibody. Serum electrophoresis revealed the presence of a monoclonal IgG protein and urinary M protein was 2g/day. A whole body CT-Scan showed osteolytic lesions of vertebral body of C5, D4, L3, L4 and the left iliac wing. The diagnosis of multiple myeloma and Evan's syndrome was made, we underwent chemotherapy by BTD (bortezomib-thalidomide-dexamethasone) and continuous corticosteroid therapy but unfortunately the patient died secondary of a Lactic acidosis. The relationship between MM and hemolysis remain unclear. PMID:28292089

LINKING ETIOLOGIES IN HUMANS AND ANIMAL MODELS: STUDIES OF AUTISM. (R824758)

EPA Science Inventory

Abstract

Thalidomide has been shown to lead to a high rate of autism when exposure occurs during the 20th to 24th d of gestation. Both the critical period and the neurological deficits of the autistic cases indicate that they have sustained injuries to the cranial nerv...

Solid dispersions enhance solubility, dissolution, and permeability of thalidomide.

PubMed

Barea, Silvana A; Mattos, Cristiane B; Cruz, Ariadne C C; Chaves, Vitor C; Pereira, Rafael N; Simões, Claudia M O; Kratz, Jadel M; Koester, Letícia S

2017-03-01

Thalidomide (THD) is a BCS class II drug with renewed and growing therapeutic applicability. Along with the low aqueous solubility, additional poor biopharmaceutical properties of the drug, i.e. chemical instability, high crystallinity, and polymorphism, lead to a slow and variable oral absorption. In this view, we developed solid dispersions (SDs) containing THD dispersed in different self-emulsifying carriers aiming at an enhanced absorption profile for the drug. THD was dispersed in lauroyl macrogol-32 glycerides (Gelucire ® 44/14) and α-tocopherol polyethylene glycol succinate (Kolliphor ® TPGS), in the presence or absence of the precipitation inhibitor polyvinylpyrrolidone K30 (PVP K30), by means of the solvent method. Physicochemical analysis revealed the formation of semicrystalline SDs. X-ray diffraction and infrared spectroscopy analyses suggest that the remaining crystalline fraction of the drug in the SDs did not undergo polymorphic transition. The impact of the solubility-enhancing formulations on the THD biopharmaceutical properties was evaluated by several in vitro techniques. The developed SDs were able to increase the apparent solubility of the drug (up to 2-3x the equilibrium solubility) for a least 4 h. Dissolution experiments (paddle method, 75 rpm) in different pHs showed that around 80% of drug dissolved after 120 min (versus 40% of pure crystalline drug). Additionally, we demonstrated the enhanced solubility obtained via SDs could be translated into increased flux in a parallel artificial membrane permeability assay (PAMPA). In summary, the results demonstrate that SDs could be considered an interesting and unexplored strategy to improve the biopharmaceutical properties of THD, since SDs of this important drug have yet to be reported.

Perception of teratogenic and foetotoxic risk by health professionals: a survey in Midi-Pyrenees area.

PubMed

Damase-Michel, Christine; Pichereau, Juliette; Pathak, Atul; Lacroix, Isabelle; Montastruc, Jean Louis

2008-01-01

Counselling or prescribing drugs during pregnancy requires health professionals to assess risk/benefit ratio for women and their baby. A misperception of the risk may lead to inappropriate decisions for pregnancy outcomes. The aim of the present study was to assess teratogenic and/or foetotoxic risk perception of common medications by general practitioners (GPs) and community pharmacists (CPs) from the Midi-Pyrenees area. 103 GPs and 104 CPs were interviewed. For 21 given drugs, a visual-analogue scale was used to evaluate the risk to give birth to a malformed infant if the mother had taken the drug during first trimester of pregnancy. For 9 drugs, health professionals had to say if they thought there was a potential foetotoxic and/or neonatal risk when drugs were administered during late pregnancy. 97% and 91% of GPs and CPs respectively thought that isotretinoin and thalidomide are teratogenic and more than 80% thought that amoxicillin and acetaminophen are safe in early pregnancy. However, 19% of the GPs and 33% of CPs answered there were no teratogenic risk for valproate. Around 11% of both GPs and CPs said that warfarin was safe during pregnancy. For 22% of GPs and for 13% and 27% of CPs respectively, ibuprofen and enalapril were safe on late pregnancy. For each drug, mean value of perceived teratogenic risk by health professionals was higher than values that can be found in scientific references. Concerning isotretinoin, thalidomide and metoclopramide, perceived teratogenic risk was higher for CPs. These data show that the potential teratogenic and foetotoxic risk of several commonly used drugs is unknown by health professionals. Conversely, GPs and CPs who think that a risk exists, overestimate it. This misperception can lead to inappropriate decisions for pregnancy outcomes.

Differential Angiogenic Regulation of Experimental Colitis

PubMed Central

Chidlow, John H.; Langston, Will; Greer, James J.M.; Ostanin, Dmitry; Abdelbaqi, Maisoun; Houghton, Jeffery; Senthilkumar, Annamalai; Shukla, Deepti; Mazar, Andrew P.; Grisham, Matthew B.; Kevil, Christopher G.

2006-01-01

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders of the intestinal tract with unknown multifactorial etiology that, among other things, result in alteration and dysfunction of the intestinal microvasculature. Clinical observations of increased colon microvascular density during IBD have been made. However, there have been no reports investigating the physiological or pathological importance of angiogenic stimulation during the development of intestinal inflammation. Here we report that the dextran sodium sulfate and CD4+CD45RBhigh T-cell transfer models of colitis stimulate angiogenesis that results in increased blood vessel density concomitant with increased histopathology, suggesting that the neovasculature contributes to tissue damage during colitis. We also show that leukocyte infiltration is an obligatory requirement for the stimulation of angiogenesis. The angiogenic response during experimental colitis was differentially regulated in that the production of various angiogenic mediators was diverse between the two models with only a small group of molecules being similarly controlled. Importantly, treatment with the anti-angiogenic agent thalidomide or ATN-161 significantly reduced angiogenic activity and associated tissue histopathology during experimental colitis. Our findings identify a direct pathological link between angiogenesis and the development of experimental colitis, representing a novel therapeutic target for IBD. PMID:17148665

Case for diagnosis. Actinic prurigo.

PubMed

Daldon, Patricia Erica Christofoletti; Pascini, Mirella; Correa, Mariane

2010-01-01

A 13-year-old black boy had pruritic papular and nodular lesions on his forearms associated to edema of the lower lip, photophobia, conjunctivitis and pterygium. Skin biopsy of the lower lip revealed acanthosis, spongiosis with dermal perivascular mononuclear cell infiltration composed by lymphocytes, plasma cells and eosinophils consistent with actinic prurigo. Lesions improved considerably with the use of thalidomide 100mg/ day.

Prolonged Suppression of Neuropathic Pain by Sequential Delivery of Lidocaine and Thalidomide Drugs Using PEGylated Graphene Oxide.

PubMed

Song, Tieying; Gu, Kunfeng; Wang, Wenli; Wang, Hong; Yang, Yunliang; Yang, Lijun; Ma, Pengxu; Ma, Xiaojing; Zhao, Jianhui; Yan, Ruyu; Guan, Jiao; Wang, Chunping; Qi, Yan; Ya, Jian

2015-11-01

The management of patients with neuropathic pain is challenging. Monotherapy with a single pain relief drug may encounter different difficulties, such as short duration of efficacy and hence too many times of drug administration, and inadequate drug delivery. Recently, nanocarrier-based drug delivery systems have been proved to provide promising strategies for efficient drug loading, delivery, and release. In the present study, we developed poly(ethylene glycol) methyl ether functionalized graphene oxide (GO) bearing two commonly used drugs of lidocaine (LDC) and thalidomide (THD) as an agent for the treatment of neuropathic pain. The sequential drug release of LDC and THD from the developed LDC-THD-GO nanosheets exhibited a synergistic effect on neuropathic pain in vitro and in vivo, as evidenced by the increased pain threshold in mechanical allodynia and hyperalgesic response tests, and the improved inhibition of proinflammatory cytokines TNF-α, IL-1β, IL-6, and nitric oxide. We believed that the present study herein would hold promise for future development of a new generation of potent agents for neuropathic pain relief. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Update on the use of defibrotide.

PubMed

Guglielmelli, Tommasina; Bringhen, Sara; Palumbo, Antonio

2012-03-01

Defibrotide is a polydisperse oligonucleotide obtained from porcine intestinal mucosa and prepared by controlled depolymerization of DNA. It is a nucleic acid polymer, predominantly single-stranded, which has anti-ischemic and anti-thrombotic properties. The efficacy and safety of defibrotide in the treatment of veno-occlusive disease (VOD) occurring after high-dose chemotherapy and hematopoietic stem-cell transplantation is now well established in Phase II - III trials. A recent randomized, Phase III trial in pediatric patients has also demonstrated its role in the prevention of VOD. Preclinical studies reported the inhibitory effects of defibrotide on myeloma cells' growth through an antiangiogenic action and a regulation of the tumor-microenvironment interactions. A recent Phase II trial underlines the efficacy and safety of defibrotide-thalidomide-melphalan combination in the treatment of relapsed/refractory multiple myeloma. Defibrotide may be effective in the prophylaxis and the treatment of veno-occlusive disease. Recent experimental results suggest that defibrotide may belong to the new generation of anti-cancer drugs that can prevent tumor angiogenesis. In multiple myeloma, defibrotide may overcome the prothrombotic effect of thalidomide on endothelial cells. Further preclinical and clinical investigations are needed to assess the precise role of defibrotide in the treatment of patients with multiple myeloma.

Thalidomide and its analogues have distinct and opposing effects on TNF-α and TNFR2 during co-stimulation of both CD4+ and CD8+ T cells

PubMed Central

MARRIOTT, J B; CLARKE, I A; DREDGE, K; MULLER, G; STIRLING, D; DALGLEISH, A G

2002-01-01

Thalidomide (Thd) is clinically useful in a number of conditions where its efficacy is probably related to its anti-TNF-α activity. More recently, Thd has also been shown to co-stimulate T cells and second generation co-stimulatory (IMiD™) analogues are currently being assessed in the treatment of cancer patients. However, in contrast to their known suppressive effects during inflammatory stimuli, the effects of Thd/IMiDs on TNF-α and TNF receptors (TNFRs) during T cell co-stimulation are not known. We sought to determine the effect of Thd, two clinically relevant IMiDs (CC-4047, ACTIMID™ and CC-5013, REVIMID™) and a non-stimulatory SelCID analogue (CC-3052) on TNF-α production and on the expression and shedding of TNFRs during co-stimulation. We found that co-stimulation of PBMC with Thd/IMiDs, but not CC-3052, prevented αCD3-induced T cell surface expression of TNFR2 and thereby reduced soluble TNFR2 (sTNFR2) levels. However, there was no effect on total (surface/intracellular) TNFR2 protein expression, suggesting inhibition of trafficking to the cell membrane. The extent of co-stimulation by Thd/IMiDs (assessed by CD69/CD25 expression and IL-2/sIL-2Rα production) was similar for CD4+ and CD8+ T lymphocytes and correlated with TNFR2 inhibition. Co-stimulation, but not the early inhibitory effect on TNFR2, was IL-2-dependent and led to increased TNF-α production by both CD4+ and CD8+ T lymphocytes. The clinical relevance of this observation was confirmed by the elevation of serum TNF-α during REVIMID™ treatment of patients with advanced cancer. Together, these results suggest a possible role for TNF-mediated events during co-stimulation and contrast with the TNF inhibitory effects of Thd and its analogues during inflammatory stimuli. PMID:12296856

Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation

PubMed Central

Davies, Faith E.; Gregory, Walter M.; Russell, Nigel H.; Bell, Sue E.; Szubert, Alexander J.; Coy, Nuria Navarro; Cook, Gordon; Feyler, Sylvia; Byrne, Jenny L.; Roddie, Huw; Rudin, Claudius; Drayson, Mark T.; Owen, Roger G.; Ross, Fiona M.; Jackson, Graham H.; Child, J. Anthony

2011-01-01

As part of the randomized MRC Myeloma IX trial, we compared an attenuated regimen of cyclophosphamide, thalidomide, and dexamethasone (CTDa; n = 426) with melphalan and prednisolone (MP; n = 423) in patients with newly diagnosed multiple myeloma ineligible for autologous stem-cell transplantation. The primary endpoints were overall response rate, progression-free survival, and overall survival (OS). The overall response rate was significantly higher with CTDa than MP (63.8% vs 32.6%; P < .0001), primarily because of increases in the rate of complete responses (13.1% vs 2.4%) and very good partial responses (16.9% vs 1.7%). Progression-free survival and OS were similar between groups. In this population, OS correlated with the depth of response (P < .0001) and favorable interphase fluorescence in situ hybridization profile (P < .001). CTDa was associated with higher rates of thromboembolic events, constipation, infection, and neuropathy than MP. In elderly patients with newly diagnosed multiple myeloma (median age, 73 years), CTDa produced higher response rates than MP but was not associated with improved survival outcomes. We highlight the importance of cytogenetic profiling at diagnosis and effective management of adverse events. This trial was registered at International Standard Randomized Controlled Trials Number as #68454111. PMID:21652683

Angiogenesis inhibitors: current strategies and future prospects.

PubMed

Cook, Kristina M; Figg, William D

2010-01-01

Angiogenesis has become an attractive target for drug therapy because of its key role in tumor growth. An extensive array of compounds is currently in preclinical development, with many now entering the clinic and/or achieving approval from the US Food and Drug Administration. Several regulatory and signaling molecules governing angiogenesis are of interest, including growth factors (eg, vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factor, and epidermal growth factor), receptor tyrosine kinases, and transcription factors such as hypoxia inducible factor, as well as molecules involved in mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling. Pharmacologic agents have been identified that target these pathways, yet for some agents (notably thalidomide), an understanding of the specific mechanisms of antitumor action has proved elusive. The following review describes key molecular mechanisms and novel therapies that are on the horizon for antiangiogenic tumor therapy. (c) 2010 American Cancer Society, Inc.

Therapy for immunoglobulin light chain amyloidosis: the new and the old.

PubMed

Gertz, Morie A; Lacy, Martha Q; Dispenzieri, Angela

2004-03-01

An accurate diagnosis of amyloidosis and its subtype classification are essential for disease prognostication and treatment. In primary amyloidosis, overall median survival is approximately 2 years and may be less in patients with cardiomyopathy. Current therapy for primary amyloidosis is suboptimal. Controlled studies suggest that treatment with melphalan and prednisone may provide marginal survival benefit. A more aggressive approach such as autologous hematopoietic stem cell transplantation may offer potential for long-term benefit. Although patients undergoing autologous hematopoietic stem cell transplantation are highly selected, response rates can approach 60%, and patients with amyloidosis who respond to treatment have potential for long-term survival. New treatment modalities that were shown to have antitumor activity in multiple myeloma (high-dose dexamethasone and thalidomide) may also be of therapeutic value in primary amyloidosis. Systemic chemotherapy would not be expected to have any beneficial effect on other forms of amyloid and carries significant risk.

Phocomelia: Report of Three Cases

PubMed Central

Coodin, Fischel J.; Uchida, Irene A.; Murphy, Claude H.

1962-01-01

Three infants were born with phocomelia in Winnipeg during the period from May 1961 to May 1962. In one case thalidomide had been administered to the mother early in the pregnancy. No etiological agent was discovered in the other two, both of whom died. Known teratogenic agents capable of causing phocomelia are reviewed, but no clear association with the two cases described in this report is evident. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5 PMID:14022756

Bortezomib in multiple myeloma and lymphoma: a systematic review and clinical practice guideline.

PubMed

Reece, D; Imrie, K; Stevens, A; Smith, C A

2006-10-01

In patients with multiple myeloma, Waldenström macroglobulinemia, or lymphoma, what is the efficacy of bortezomib alone or in combination as measured by survival, quality of life, disease control (for example, time to progression), response duration, or response rate?What is the toxicity associated with the use of bortezomib?Which patients are more or less likely to benefit from treatment with bortezomib? Evidence was selected and reviewed by two members of the Hematology Disease Site Group and by methodologists from the Program in Evidence-based Care (pebc) at Cancer Care Ontario. The practice guideline report was reviewed and approved by the Hematology Disease Site Group, which comprises hematologists, medical and radiation oncologists, and a patient representative. As part of an external review process, the report was disseminated to practitioners throughout Ontario to obtain their feedback. Outcomes of interest were overall survival, quality of life, response rates and duration, and rates of adverse events. A systematic search was conducted of the medline, embase, HealthStar, cinahl, and Cochrane Library databases for primary articles and practice guidelines. The resulting evidence informed the development of clinical practice recommendations. Those recommendations were appraised by a sample of practitioners in Ontario and modified in response to the feedback received. The systematic review and modified recommendations were approved by a review body w theithin pebc. The literature review found one randomized controlled trial (rct)-the only published rct of bortezomib in relapsed myeloma. A number of phase ii studies were also retrieved, including a randomized phase ii study. No randomized trials were retrieved for lymphoma. The rct found bortezomib to be superior to high-dose dexamethasone for median time to progression and 1-year survival in patients with relapsed myeloma, although grade 3 adverse events were more common in the bortezomib arm. Bortezomib is recommended as the preferred treatment option in patients with myeloma relapsing within 1 year of the conclusion of initial treatment; it may also be a reasonable option in patients relapsing at least 1 year after autologous stem-cell transplantation. This evidence-based series applies to adult patients with myeloma, Waldenström macroglobulinemia, or lymphoma of any type, stage, histology, or performance status. Based on the results of a large well-conducted rct, which represents the only published randomized study in relapsed myeloma, the Hematology Disease Site Group (dsg) offers the following recommendations: For patients with myeloma refractory to or relapsing within 1 year of the conclusion of initial or subsequent treatment or treatments, including autologous stem-cell transplantation, and who are candidates for further chemotherapy, bortezomib is recommended as the preferred treatment option.Bortezomib is also a reasonable option for patients relapsing at least 1 year after autologous stem-cell transplantation. The dsg is aware that thalidomide, alkylating agents, or repeat transplantation may also be options for these patients. However, evaluation of these other options is beyond the scope of this practice guideline.For patients with myeloma relapsing at least 1 year after the conclusion of alkylating agent-based chemotherapy who are candidates for further chemotherapy, further treatment with alkylating agent-based chemotherapy is recommended.Evidence is insufficient to support the use of bortezomib in patients with non-Hodgkin lymphoma or Waldenström macroglobulinemia outside of clinical trials. Limited evidence supports the appropriateness of a specific time-to-relapse period as being indicative of treatment-insensitive disease. The 1-year threshold provided in the foregoing recommendations is based on the opinion of the Hematology dsg. For specific details related to the administration of bortezomib therapy, the dsg suggests that clinicians refer to the protocols used in major trials. Some of those details are provided here for informational purposes. Bortezomib 1.3,g/m(2) is given as a rapid intravenous bolus over 3-5 seconds on days 1, 4, 8, and 11 of a 21-day cycle; a minimum of 72 hours between doses is required to allow for recovery of normal proteasome function. Vital signs should be checked before and after each dose. A complete blood count is recommended before each dose, with blood chemistries (including electrolyte and creatinine levels) monitored at a minimum on days 1 and 8 of each cycle. The dose of bortezomib should be reduced or held immediately upon development of painful neuropathy, as described in the product monograph; dose modification may also be required for peripheral sensory neuropathy without pain or for other toxicities. Most toxicities are reversible if dose modification guidelines are followed. RESPONSE TO TREATMENT: Responses are usually apparent by 6 weeks (2 cycles). For patients achieving complete remission (determined by negative electrophoresis and immunofixation), bortezomib should be given for 2 additional cycles beyond the date of confirmed complete remission. In patients with progressive disease after 2 cycles or stable disease after 4 cycles, dexamethasone added to the bortezomib regimen (20 mg by mouth the day of and the day after each bortezomib dose) may produce an objective response. Bortezomib (with or without dexamethasone) should be continued in patients showing benefit from therapy (excluding those in complete remission) unless disease progression or significant toxicity is observed. Therapy should be discontinued in patients who do not respond to bortezomib alone if disease progression is seen within 2 cycles of the addition of dexamethasone. The Hematology dsg recognizes that thalidomide is an active agent in multiple myeloma patients who have relapsed after autologous stem-cell transplantation or who are refractory to alkylating agent-based chemotherapy. To date, no reported rcts have evaluated thalidomide in this role, and specifically, no trials have compared thalidomide with bortezomib. Given these limitations, the members of the Hematology dsg regard thalidomide or bortezomib as therapy alternatives to dexamethasone.

High Prevalence of Personality Disorders in Skin-restricted Lupus Patients.

PubMed

Jalenques, Isabelle; Rondepierre, Fabien; Massoubre, Catherine; Bonnefond, Sophie; Schwan, Raymond; Labeille, Bruno; Perrot, Jean-Luc; Collange, Marianne; Mulliez, Aurelien; D'Incan, Michel

2017-08-31

Psychiatric and personality disorders have been extensively documented in patients with systemic lupus erythematosus (SLE). However, the prevalence of personality disorders in skin-restricted lupus (SRL) patients remains unknown. The aim of this study was to assess the prevalence of personality disorders in SRL outpatients and to examine the associated factors. We evaluated 60 SRL outpatients and 118 controls matched for sex, age and education level. On the basis of the Personality Diagnostic Questionnaire 4+, 38% of patients vs 20% of controls fulfilled the criteria for at least one personality disorder (OR 2.2 [95% CI 1.01-4.6], p = 0.048). Only one patient with a personality disorder had specialised mental health care. Late lupus onset and more frequent past treatments by thalidomide were associated factors. This study evidences a high prevalence of personality disorders in SRL patients and shows that most SRL patients with personality disorder do not receive specialised mental health care.

Depressive-like behavior induced by tumor necrosis factor-α in mice.

PubMed

Kaster, Manuella P; Gadotti, Vinícius M; Calixto, João B; Santos, Adair R S; Rodrigues, Ana Lúcia S

2012-01-01

Pro-inflammatory cytokines are implicated in the pathogenesis of depression. However, few animal models of cytokine-induced depression well characterized regarding its response to antidepressants are available. Hence, the aim of this study was to propose a model of depressive-like behavior induced by the administration of tumor necrosis factor-α (TNF-α) responsive to antidepressant treatments. TNF-α administered by i.c.v. route produced a depressive-like behavior in the forced swimming test (FST) and tail suspension test (TST) (0.1-1 fg/site and 0.001 fg/site, respectively), without altering the locomotor activity in the open-field test. In addition, anti-TNF-α antibody (0.1-1 pg/site, i.c.v.), but not the inhibitor of TNF-α synthesis thalidomide (3-30 mg/kg, s.c.) produced an antidepressant-like response in the FST. Moreover, either anti-TNF-α antibody (0.01 pg/site, i.c.v) or thalidomide (30 mg/kg, s.c.) reversed the depressive-like behavior induced by TNF- (0.1 fg/site, i.c.v.) in the FST. TNF-α receptor 1 (TNFR1) knockout mice exhibited an antidepressant-like behavior in the FST and in the TST as compared with the wild type mice. Treatment with fluoxetine (32 mg/kg, i.p), imipramine (15 mg/kg, i.p.) and desipramine (16 mg/kg, i.p) prevented the depressant-like effect induced by TNF-α (0.1 fg/site, i.c.v.) in the FST. In addition, TNF-α (0.1 fg/site, i.c.v.) administration produced an anhedonic response in a sucrose intake test, which was prevented by anti-TNF-α antibody (0.01 pg/site, i.c.v) or fluoxetine (32 mg/kg, i.p). Taken together, these results indicate that TNF-α produces a depressive-like state in mice, reinforcing the notion that an inflammatory component may play an important role in the pathophysiology of depression and suggesting that the central administration of TNF-α may be a novel approach to study the inflammatory component of depressive disorder. This article is part of a Special Issue entitled 'Anxiety and Depression'. Copyright © 2011 Elsevier Ltd. All rights reserved.

Thalidomide and its analogues have distinct and opposing effects on TNF-alpha and TNFR2 during co-stimulation of both CD4(+) and CD8(+) T cells.

PubMed

Marriott, J B; Clarke, I A; Dredge, K; Muller, G; Stirling, D; Dalgleish, A G

2002-10-01

Thalidomide (Thd) is clinically useful in a number of conditions where its efficacy is probably related to its anti-TNF-alpha activity. More recently, Thd has also been shown to co-stimulate T cells and second generation co-stimulatory (IMiD trade mark ) analogues are currently being assessed in the treatment of cancer patients. However, in contrast to their known suppressive effects during inflammatory stimuli, the effects of Thd/IMiDs on TNF-alpha and TNF receptors (TNFRs) during T cell co-stimulation are not known. We sought to determine the effect of Thd, two clinically relevant IMiDs (CC-4047, ACTIMID trade mark and CC-5013, REVIMID trade mark ) and a non-stimulatory SelCID analogue (CC-3052) on TNF-alpha production and on the expression and shedding of TNFRs during co-stimulation. We found that co-stimulation of PBMC with Thd/IMiDs, but not CC-3052, prevented alphaCD3-induced T cell surface expression of TNFR2 and thereby reduced soluble TNFR2 (sTNFR2) levels. However, there was no effect on total (surface/intracellular) TNFR2 protein expression, suggesting inhibition of trafficking to the cell membrane. The extent of co-stimulation by Thd/IMiDs (assessed by CD69/CD25 expression and IL-2/sIL-2Ralpha production) was similar for CD4+ and CD8+ T lymphocytes and correlated with TNFR2 inhibition. Co-stimulation, but not the early inhibitory effect on TNFR2, was IL-2-dependent and led to increased TNF-alpha production by both CD4+ and CD8+ T lymphocytes. The clinical relevance of this observation was confirmed by the elevation of serum TNF-alpha during REVIMID trade mark treatment of patients with advanced cancer. Together, these results suggest a possible role for TNF-mediated events during co-stimulation and contrast with the TNF inhibitory effects of Thd and its analogues during inflammatory stimuli.

[Drug surveillance and adverse reactions to drugs. The literature and importance of historical data].

PubMed

Mariani, L; Minora, T; Ventresca, G P

1996-12-01

The authors highlight the essential role of pharmacovigilance and the need for a simple, efficient and low-cost system of adverse reaction (AR) reporting which could cover the whole population and all marketed drugs, and suggest that the only one presently viable is based on spontaneous reporting. To support their proposal the authors provide a definition of AR and of the different monitoring system, and list as many drugs as possible to find in the literature that have been associated with a specific AR, together with the active molecule, the therapeutic indication, the features of the AR and the regulatory actions (withdrawal from the market, restriction of use). Moreover, by describing the "history" behind some of these drugs the authors highlight the contribution that pharmacovigilance and spontaneous reporting have had to the development of regulations for approval and marketing of new drugs. It is also highlighted how some of these unexpected events (thalidomide, DES) have had a significant and important contribution to pharmacological and toxicological knowledge.

The impact of toceranib, piroxicam and thalidomide with or without hypofractionated radiation therapy on clinical outcome in dogs with inflammatory mammary carcinoma.

PubMed

Rossi, F; Sabattini, S; Vascellari, M; Marconato, L

2018-05-27

In dogs, inflammatory mammary carcinoma is a clinicopathological entity characterized by rapid progression and aggressive behavior from onset of disease. Reported median survival time is short, with no effective treatment options. The aims of this prospective, noncontrolled clinical trial were to investigate outcome variables and safety profile of toceranib, thalidomide and piroxicam with or without hypofractionated radiation therapy in dogs with measurable histologically confirmed inflammatory mammary carcinoma that underwent a complete staging. Eighteen dogs were enrolled: 14 received medical treatment, and 4 were treated with hypofractionated radiation therapy and medical therapy. Overall, median time to progression was 34 days and median survival time was 109 days. In dogs treated with medical therapy, overall response rate was 21%, and clinical benefit rate (CBR) was 64%; median time to progression was 28 days and median survival time was 59 days. In dogs receiving medical therapy and undergoing radiation therapy, overall response rate and clinical benefit rate were 100%, with significantly longer time to progression (156 days) and survival time (180 days). Overall, treatment was well tolerated, with mild gastrointestinal and dermatological adverse events. Although the optimal treatment to this disease remains uncertain, the current approach consisting of systemic anti-angiogenic drugs with or without hypofractionated radiation therapy, provided clinical benefit in a significant proportion of dogs and should, therefore, be further explored. © 2018 John Wiley & Sons Ltd.

Impact of concomitant dexamethasone dosing schedule on bortezomib-induced peripheral neuropathy in multiple myeloma.

PubMed

Kumar, Shaji K; Laubach, Jacob P; Giove, Thomas J; Quick, Maureen; Neuwirth, Rachel; Yung, Godwin; Rajkumar, S Vincent; Richardson, Paul G

2017-09-01

Peripheral neuropathy (PN) is the most troublesome adverse event associated with the proteasome inhibitor bortezomib. Studies suggest an inflammatory aetiology for bortezomib-induced PN (BiPN) and it has been hypothesized that reducing inflammation with concomitant dexamethasone may reduce BiPN incidence and/or severity. We retrospectively analysed PN rates from 32 studies (2697 patients with previously untreated multiple myeloma) incorporating bortezomib and differing dexamethasone schedules: partnered dosing (days of and after bortezomib), weekly dosing, and other dosing schedules (e.g. days 1-4, 8-11). Pooled overall PN rates were 45·5%, 63·9%, and 47·5%, respectively, with 5·3%, 11·0%, and 9·6% grade ≥3. Adjusting for potential confounders (age, gender, presence of thalidomide, bortezomib treatment duration), PN rates in patients on partnered dosing schedules appeared lower than in patients on weekly or other dosing schedules. Analyses conducted using patient-level data suggest that cumulative dexamethasone dose, a potential confounding factor, is unlikely to have influenced the analyses. Findings were similar in a separate pooled analysis excluding data from regimens incorporating thalidomide, when pooled overall PN rates were 50·1%, 63·9%, and 48·3%, respectively, with 4·2%, 11·0%, and 8·6% grade ≥3. These findings suggest that partnered dexamethasone dosing may result in less severe BiPN compared with alternative dexamethasone dosing schedules. © 2017 John Wiley & Sons Ltd.

Clinical features and outcomes of plasma cell leukemia: a single-institution experience in the era of novel agents.

PubMed

Talamo, Giampaolo; Dolloff, Nathan G; Sharma, Kamal; Zhu, Junjia; Malysz, Jozef

2012-06-26

Plasma cell leukemia (PCL) is a rare hematologic malignancy with aggressive clinical and biologic features. Data regarding its prognosis with the use of the novel agents, i.e., the immunomodulatory drugs thalidomide and lenalidomide, and the proteasome inhibitor bortezomib, are limited. We retrospectively reviewed clinical outcomes, response to therapy, and survival of 17 patients seen at the Penn State Hershey Cancer Institute since the availability of novel agents (2006-2011). Twelve patients had primary PCL (pPCL), and 5 secondary PCL (sPCL). PCL was associated with aggressive clinicobiological features, such as high-risk cytogenetics, elevated serum beta-2-microglobulin and lactate dehydrogenase, International Staging System stage III, and rapid relapse after therapy. With the use of thalidomide, lenalidomide, and bortezomib in 53%, 53%, and 88% patients, respectively, median overall survival (OS) was 18 months in the whole group (95% confidence interval, 11-21 months), and 21 and 4 months in pPCL and sPCL, respectively (P=0.015). OS was inferior to that of 313 consecutive patients with multiple myeloma (MM) treated in the same period, even when compared with a subset of 47 MM with high-risk cytogenetics. Although our data are limited by the small sample size, we conclude that novel agents may modestly improve survival in patients with PCL, when compared to historical controls. Novel therapies do not seem to overcome the negative prognosis of PCL as compared with MM.

Clinical features and outcomes of plasma cell leukemia: a single-institution experience in the era of novel agents

PubMed Central

Talamo, Giampaolo; Dolloff, Nathan G.; Sharma, Kamal; Zhu, Junjia; Malysz, Jozef

2012-01-01

Plasma cell leukemia (PCL) is a rare hematologic malignancy with aggressive clinical and biologic features. Data regarding its prognosis with the use of the novel agents, i.e., the immunomodulatory drugs thalidomide and lenalidomide, and the proteasome inhibitor bortezomib, are limited. We retrospectively reviewed clinical outcomes, response to therapy, and survival of 17 patients seen at the Penn State Hershey Cancer Institute since the availability of novel agents (2006–2011). Twelve patients had primary PCL (pPCL), and 5 secondary PCL (sPCL). PCL was associated with aggressive clinicobiological features, such as high-risk cytogenetics, elevated serum beta-2-microglobulin and lactate dehydrogenase, International Staging System stage III, and rapid relapse after therapy. With the use of thalidomide, lenalidomide, and bortezomib in 53%, 53%, and 88% patients, respectively, median overall survival (OS) was 18 months in the whole group (95% confidence interval, 11–21 months), and 21 and 4 months in pPCL and sPCL, respectively (P=0.015). OS was inferior to that of 313 consecutive patients with multiple myeloma (MM) treated in the same period, even when compared with a subset of 47 MM with high-risk cytogenetics. Although our data are limited by the small sample size, we conclude that novel agents may modestly improve survival in patients with PCL, when compared to historical controls. Novel therapies do not seem to overcome the negative prognosis of PCL as compared with MM. PMID:23087795

Real-world Outcomes of Multiple Myeloma: Retrospective Analysis of the Czech Registry of Monoclonal Gammopathies.

PubMed

Hájek, Roman; Jarkovsky, Jiri; Maisnar, Vladimír; Pour, Ludek; Špička, Ivan; Minařík, Jiri; Gregora, Evžen; Kessler, Petr; Sýkora, Michal; Fraňková, Hana; Campioni, Marco; DeCosta, Lucy; Treur, Maarten; Gonzalez-McQuire, Sebastian; Bouwmeester, Walter

2018-06-01

Real-world data on patient outcomes and treatment patterns in multiple myeloma (MM) are limited. The present noninterventional, observational, retrospective analysis of prospectively collected Czech patient medical record data from the Registry of Monoclonal Gammopathies estimated real-world outcomes in adults with a diagnosis of symptomatic MM made between May 2007 and June 2014. In total, 2446 patients had initiated first-line treatment. The median overall survival since the diagnosis (primary endpoint) was 50.3 months (95% confidence interval, 46.1-54.5 months) and decreased with each successive treatment line. A similar trend was observed for progression-free survival and the depth of response. In line with European guidelines and clinical practice, bortezomib-, thalidomide-, and lenalidomide-based regimens were most commonly used across all treatment lines (42.3%, 28.9%, and 18.4%, respectively). In the first line, bortezomib and thalidomide were used most often, with lenalidomide the most commonly used agent in the relapse setting (second to fourth lines). Exploratory analyses revealed that younger age (≤ 65 years), lower international staging system stage, and previous stem cell transplantation were associated with significant improvements in overall and progression-free survival, especially in the early treatment lines. The present study is the first analysis of Czech data from the Registry of Monoclonal Gammopathies, and it provides important insights into the real-world management of MM for physicians and healthcare providers. Copyright © 2018 Elsevier Inc. All rights reserved.

An old drug with a new future: bendamustine in multiple myeloma.

PubMed

Gentile, Massimo; Recchia, Anna Grazia; Mazzone, Carla; Vigna, Ernesto; Martino, Massimo; Morabito, Lucio; Lucia, Eugenio; Bossio, Sabrina; De Stefano, Laura; Granata, Teresa; Palummo, Angela; Morabito, Fortunato

2013-11-01

Bendamustine is a unique bifunctional alkylating agent with promising activity in multiple myeloma (MM). It is currently licensed in Europe for use as frontline treatment with prednisolone for patients with MM who are unsuitable for transplantation and who are contraindicated for thalidomide and bortezomib therapy. Studies evaluating the safety and efficacy of bendamustine administered alone or in combination in both the upfront and relapse settings of MM patients, including those with renal insufficiency, were reviewed. The use of bendamustine as conditioning for autologous stem-cell transplantation and the possibility of stem-cell mobilization after bendamustine therapy are discussed. Bendamustine seems to be efficacious either in monotherapy or in combination with other drugs in previously treated or untreated patients. This is due to its unique mechanism of action including its ability to activate apoptosis and inhibit mitotic checkpoints, making it potentially more effective than other alkylating agents. Moreover, it has an acceptable toxicity profile and is suitable for patients with renal impairment. Finally, this drug does not seem to compromise the possibility of achieving a stem-cell mobilization. Nonetheless, data from Phase III studies demonstrating its effectiveness in terms of overall survival are not yet available.

IgD multiple myeloma a descriptive report of 17 cases: survival and response to therapy

PubMed Central

2012-01-01

Background Immunoglobulin D multiple myeloma (MM) is rare and has a poorer prognosis than other MM isotypes. Design and methods Seventeen patients (pts) diagnosed from 1993 to 2009 with IgD MM were selected from six institutions of Multiple Myeloma Latium-Region GIMEMA Working Group. Results Median age was 55 years, 14 patients had bone lesions, eight had renal impairment with estimated glomerular filtration rate (eGFR) < 50 ml/min, one serum calcium ≥ 12 mg/dl, 11 had lambda light chains, five stage III of ISS, six with chromosomal abnormalities. Six pts received conventional chemotherapy (CT): five melphalan + steroids based regimens. Eleven underwent high-doses of chemotherapy with autologous stem cell transplantation (HDT/ASCT), five single and six tandem ASCT: six received bortezomib and/or thalidomide as induction therapy and five VAD. Thalidomide maintenance was used in two pts: one in HDT/ASCT and one in CT group; bortezomib was used in one patient after HDT/ASCT. At a median follow up of 38 (range 19-60) and 50 months (range 17-148) for pts treated with CT and HDT/ASCT, respectively, the overall response rate (ORR) was 83% and 90%. In the group of patients treated with CT, median overall survival (OS) was 34 months (95% CI 15- 54 months), median progression free survival (PFS) was 18 months (95% CI 3-33 months) and median duration of response (DOR) was 7 months (95% CI 5-9 months). Median OS, PFS and DOR were not reached at the time of this analysis in the HDT/ASCT group of patients. Death was observed in 27.3% of pts treated with HDT/ASCT and in 66.7% undergone CT. Conclusions Despite the retrospective analysis and the small number of pts our study showed that the use of HDT/ASCT seems to improve also the prognosis of IgD MM patients. Treatment options including new drugs, before and after stem cell transplantation, may further improve the outcomes of these patients. PMID:22381082

Left thigh phlegmon caused by Nocardia farcinica identified by 16S rRNA sequencing in a patient with leprosy: a case report.

PubMed

De Nardo, Pasquale; Giancola, Maria Letizia; Noto, Salvatore; Gentilotti, Elisa; Ghirga, Piero; Tommasi, Chiara; Bellagamba, Rita; Paglia, Maria Grazia; Nicastri, Emanuele; Antinori, Andrea; Corpolongo, Angela

2013-04-04

In recent years, Nocardia farcinica has been reported to be an increasingly frequent cause of localized and disseminated infections in the immunocompromised patient. However, recent literature is limited. We report a case of left thigh phlegmon caused by N. farcinica that occurred in a patient with leprosy undergoing treatment with prednisone for leprosy reaction. We describe the case of left thigh phlegmon caused by Nocardia farcinica in a 54-year-old Italian man affected by multi-bacillary leprosy. The patient had worked in South America for 11 years. Seven months after his return to Italy, he was diagnosed with leprosy and started multi-drug antibiotic therapy plus thalidomide and steroids. Then, during therapy with rifampicin monthly, minocycline 100 mg daily, moxifloxacin 400 mg daily, and prednisone (the latter to treat type 2 leprosy reaction), the patient complained of high fever associated with erythema, swelling, and pain in the left thigh. Therefore, he was admitted to our hospital with the clinical suspicion of cellulitis. Ultrasound examination and Magnetic Resonance Imaging showed left thigh phlegmon. He was treated with drainage and antibiotic therapy (meropenem and vancomycin replaced by daptomycin). The responsible organism, Nocardia farcinica, was identified by 16S rRNA sequencing in the purulent fluid taken out by aspiration. The patient continued treatment with intravenous trimethoprim/sulfamethoxazole and imipenem followed by oral trimethoprim/sulfamethoxazole and moxifloxacin. A whole-body computed tomography did not reveal dissemination to other organs like the lung or brain.The patient was discharged after complete remission. Oral therapy with trimethoprim/sulfamethoxazole, moxifloxacin, rifampicin monthly, clofazimine and thalidomide was prescribed to be taken at home. One month after discharge from the hospital the patient is in good clinical condition with complete resolution of the phlegmon. N. farcinica is a rare infectious agent that mainly affects immunocompromised patients. Presentation of phlegmon only without disseminated infection is unusual, even in these kinds of patients. In any case, a higher index of suspicion is needed, as diagnosis can easily be missed due to the absence of characteristic symptoms and the several difficulties usually encountered in identifying the pathogen.

[Wilson's principles--a base of modern teratology].

PubMed

Burdan, Franciszek; Bełzek, Artur; Szumiło, Justyna; Dudka, Jarosław; Korobowicz, Agnieszka; Tokarska, Edyta; Klepacz, Lidia; Bełzek, Marta; Klepacz, Robert

2006-03-01

Wilson's principles were formulated after thalidomide tragedy. They become a fundamental for teratological studies with drugs and other factors that may disturb fetal development. It is postulated that susceptibility to teratogen depends on the genotype and developmental stage of the conceptus. Teratogenic agents act in specific manner on developing cells and tissues. The exposition depends on the agent's nature and availability. Manifestations of deviant development depends on the dosage and exposure frequency. In case of abnormal development the final manifestations include death of embryo or fetus, malformation, growth retardation and functional disorder.

Trichuris suis ova, lecithin and other fancy molecules.

PubMed

Schölmerich, Jürgen

2014-01-01

During the last 20 years, treatment paradigms as well as drugs used for IBD have changed significantly. However, there are still many unmet needs and a significant number of patients needing better therapy. It is obvious from this situation that many attempts have been made to implement new drugs and treatment algorithms including biologicals, new formulations of old drugs and 'fancy molecules or approaches'. For about 10 years, the application of Trichuris suis ova has been promoted and used in quite a number of patients. Two early studies suggested positive effects in ulcerative colitis as well as in Crohn's disease. These studies were based on experimental data in animal models as well as in vitro experiments. However, two large randomized controlled trials were not able to provide significant clinical effects in active Crohn's disease as compared to placebo, although a biological reaction (eosinophilia) was found. Another approach is the use of locally released phosphatidylcholine in ulcerative colitis. This approach is based on decreased phosphatidylcholine concentrations in the colonic mucus in patients, and showed positive effects in a number of monocentric trials in steroid-refractory and chronic active ulcerative colitis. A dose-finding study gave a positive signal in the highest-dose group and this approach is being tested further in controlled trials. Many other 'fancy molecules' including cannabis, vitamin D, thalidomide, hyaluronic acid, lidocaine, clonidine, chondroitin sulfate, naltrexone and melatonin have been tested in patients with claims of success. For most of those, however, controlled data in appropriate studies are lacking. Many more substances have been used in animal models and are probably applied in individual patients. Results of preliminary studies on some of the molecules mentioned are presented. © 2014 S. Karger AG, Basel.

Caspase-1 from Human Myeloid-Derived Suppressor Cells Can Promote T Cell-Independent Tumor Proliferation.

PubMed

Zeng, Qi; Fu, Juan; Korrer, Michael; Gorbounov, Mikhail; Murray, Peter J; Pardoll, Drew; Masica, David L; Kim, Young J

2018-05-01

Immunosuppressive myeloid-derived suppressive cells (MDSCs) are characterized by their phenotypic and functional heterogeneity. To better define their T cell-independent functions within the tumor, sorted monocytic CD14 + CD11b + HLA-DR low/- MDSCs (mMDSC) from squamous cell carcinoma patients showed upregulated caspase-1 activity, which was associated with increased IL1β and IL18 expression. In vitro studies demonstrated that mMDSCs promoted caspase-1-dependent proliferation of multiple squamous carcinoma cell lines in both human and murine systems. In vivo , growth rates of B16, MOC1, and Panc02 were significantly blunted in chimeric mice adoptively transferred with caspase-1 null bone marrow cells under T cell-depleted conditions. Adoptive transfer of wild-type Gr-1 + CD11b + MDSCs from tumor-bearing mice reversed this antitumor response, whereas caspase-1 inhibiting thalidomide-treated MDSCs phenocopied the antitumor response found in caspase-1 null mice. We further hypothesized that MDSC caspase-1 activity could promote tumor-intrinsic MyD88-dependent carcinogenesis. In mice with wild-type caspase-1, MyD88-silenced tumors displayed reduced growth rate, but in chimeric mice with caspase-1 null bone marrow cells, MyD88-silenced tumors did not display differential tumor growth rate. When we queried the TCGA database, we found that caspase-1 expression is correlated with overall survival in squamous cell carcinoma patients. Taken together, our findings demonstrated that caspase-1 in MDSCs is a direct T cell-independent mediator of tumor proliferation. Cancer Immunol Res; 6(5); 566-77. ©2018 AACR . ©2018 American Association for Cancer Research.

Multicenter, Phase I, Dose-Escalation Trial of Lenalidomide Plus Bortezomib for Relapsed and Relapsed/Refractory Multiple Myeloma

PubMed Central

Richardson, Paul G.; Weller, Edie; Jagannath, Sundar; Avigan, David E.; Alsina, Melissa; Schlossman, Robert L.; Mazumder, Amitabha; Munshi, Nikhil C.; Ghobrial, Irene M.; Doss, Deborah; Warren, Diane L.; Lunde, Laura E.; McKenney, Mary; Delaney, Carol; Mitsiades, Constantine S.; Hideshima, Teru; Dalton, William; Knight, Robert; Esseltine, Dixie-Lee; Anderson, Kenneth C.

2009-01-01

Purpose Lenalidomide and bortezomib are active in relapsed and relapsed/refractory multiple myeloma (MM). In preclinical studies, lenalidomide sensitized MM cells to bortezomib and dexamethasone. This phase I, dose-escalation study (ie, NCT00153933) evaluated safety and determined the maximum-tolerated dose (MTD) of lenalidomide plus bortezomib in patients with relapsed or with relapsed and refractory MM. Patients and Methods Patients received lenalidomide 5, 10, or 15 mg/d on days 1 through 14 and received bortezomib 1.0 or 1.3 mg/m2 on days 1, 4, 8, and 11 of 21-day cycles. Dexamethasone (20mg or 40 mg on days 1, 2, 4, 5, 8, 9, 11, and 12) was added for progressive disease after two cycles. Primary end points were safety and MTD determination. Results Thirty-eight patients were enrolled across six dose cohorts. The MTD was lenalidomide 15 mg/d plus bortezomib 1.0 mg/m2. Dose-limiting toxicities (n = 1 for each) were grade 3 hyponatremia and herpes zoster reactivation and grade 4 neutropenia. The most common treatment-related, grades 3 to 4 toxicities included reversible neutropenia, thrombocytopenia, anemia, and leukopenia. Among 36 response-evaluable patients, 61% (90% CI, 46% to 75%) achieved minimal response or better. Among 18 patients who had dexamethasone added, 83% (90% CI, 62% to 95%) achieved stable disease or better. Median overall survival was 37 months. Conclusion Lenalidomide plus bortezomib was well tolerated and showed promising activity with durable responses in patients with relapsed and relapsed/refractory MM, including patients previously treated with lenalidomide, bortezomib, and/or thalidomide. The combination of lenalidomide, bortezomib, and dexamethasone is being investigated in a phase II study in this setting and in newly diagnosed MM. PMID:19786667

IgG1 antimycobacterial antibodies can reverse the inhibitory effect of pentoxifylline on tumour necrosis factor alpha (TNF-alpha) secreted by mycobacterial antigen-stimulated adherent cells.

PubMed

Thakurdas, S M; Hasan, Z; Hussain, R

2004-05-01

Chronic inflammation associated with cachexia, weight loss, fever and arthralgia is the hallmark of advanced mycobacterial diseases. These symptoms are attributed to the chronic stimulation of tumour necrosis factor (TNF)-alpha. Mycobacterial components directly stimulate adherent cells to secrete TNF-alpha. We have shown recently that IgG1 antimycobacterial antibodies play a role in augmenting TNF-alpha in purified protein derivative (PPD)-stimulated adherent cells from non-BCG-vaccinated donors. We now show that IgG1 antibodies can also augment TNF-alpha expression in stimulated adherent cells obtained from BCG-vaccinated donors and this augmentation is not linked to interleukin (IL)-10 secretion. In addition IgG1 antimycobacterial antibodies can reverse the effect of TNF-alpha blockers such as pentoxifylline and thalidomide. These studies therefore have clinical implications for anti-inflammatory drug treatments which are used increasingly to alleviate symptoms associated with chronic inflammation.

A physical control interface with proprioceptive feedback and multiple degrees of freedom

NASA Technical Reports Server (NTRS)

Creasey, G. H.; Gow, D.; Sloan, Y.; Meadows, B.

1991-01-01

The use of the drug thalidomide by pregnant mothers in Britain resulted in a variety of deformities including the birth of children having no arms. Such children were provided with powered artificial arms with up to five degrees of freedom simultaneously controlled in real time by shoulder movement. The physiological sense of proprioception was extended from the user into the device, reducing the need for visual feedback and conscious control. With the banning of thalidomide, this technique fell into disuse but it is now being re-examined as a control mechanism for other artificial limbs and it may have other medical applications to allow patients to control formerly paralyzed limbs moved by electrical stimulation. It may also have commercial applications in robotic manipulation or physical interaction with virtual environments. To allow it to be investigated further, the original pneumatic control system has recently been converted to an electrical analogue to allow interfacing to electronic and computer-assisted systems. A harness incorporates force-sensitive resistors and linear potentiomenters for sensing position and force at the interface with the skin, and miniature electric motors and lead screws for feeding back to the user the position of the robotic arm and the forces applied to it. In the present system, control is applied to four degrees of freedom using elevation/depression and protraction/reaction of each shoulder so that each collar bone emulates a joystick. However, both electrical and mechanical components have been built in modular form to allow rapid replication and testing of a variety of force and position control strategies.

Thromboembolism and congenital malformations: from Duane syndrome to thalidomide embryopathy.

PubMed

Parsa, Cameron F; Robert, Matthieu P

2013-04-01

To propose a pathophysiologic mechanism to unify a variety of disparate sporadic congenital malformations. Inductive and deductive analyses to correlate malformation laterality with asymmetries in thoracic anatomy, critical analysis of malformations with female predominance, and concepts of hydrodynamic pressure gradients in vascular growth were applied to the ensuing development of guiding tissue scaffolds for cellular proliferation, differentiation, and apoptosis. Duane syndrome may develop following a focal vascular insult to the sixth nerve trunk with axonal degeneration, allowing for substitutive innervation from third nerve axons to the lateral rectus muscle. Causative fibrin clots may originate from the venous system and paradoxically migrate through physiological right-to left shunts, or they may arise directly from the heart. Hence, the unilateral, left-sided, and female predominance of Duane syndrome results from the asymmetry in the thoracic anatomy and from thrombosis risk factors. Embolic occlusions may also alter local hemodynamic pressure gradients, leading to the compensatory enlargement and persistence of the fetal vasculature and may dysregulate tissue growth. Within the eye, this results in forms of Peters anomaly, unilateral congenital cataracts, and the morning glory disc anomaly, all in the vascular territory of the carotid arteries that also share a propensity for left-sided involvement in girls. Most aberrant misinnervation phenomena (eg, jaw-winking syndrome, crocodile tear syndrome, Brown syndrome, and congenital fibrosis syndrome) and, by extrapolation, the hypoplasia or dysgenesis of noncephalic anatomical structures (including limbs) may be similarly explained. Such malformations will occur more frequently under thrombogenic conditions, such as those induced by thalidomide. Fibrin emboli and focal hypoperfusion may explain the development of many sporadic congenital malformations.

Reverse translation of adverse event reports paves the way for de-risking preclinical off-targets.

PubMed

Maciejewski, Mateusz; Lounkine, Eugen; Whitebread, Steven; Farmer, Pierre; DuMouchel, William; Shoichet, Brian K; Urban, Laszlo

2017-08-08

The Food and Drug Administration Adverse Event Reporting System (FAERS) remains the primary source for post-marketing pharmacovigilance. The system is largely un-curated, unstandardized, and lacks a method for linking drugs to the chemical structures of their active ingredients, increasing noise and artefactual trends. To address these problems, we mapped drugs to their ingredients and used natural language processing to classify and correlate drug events. Our analysis exposed key idiosyncrasies in FAERS, for example reports of thalidomide causing a deadly ADR when used against myeloma, a likely result of the disease itself; multiplications of the same report, unjustifiably increasing its importance; correlation of reported ADRs with public events, regulatory announcements, and with publications. Comparing the pharmacological, pharmacokinetic, and clinical ADR profiles of methylphenidate, aripiprazole, and risperidone, and of kinase drugs targeting the VEGF receptor, demonstrates how underlying molecular mechanisms can emerge from ADR co-analysis. The precautions and methods we describe may enable investigators to avoid confounding chemistry-based associations and reporting biases in FAERS, and illustrate how comparative analysis of ADRs can reveal underlying mechanisms.

Current approaches for the treatment of multiple myeloma.

PubMed

Watanabe, Reiko; Tokuhira, Michihide; Kizaki, Masahiro

2013-03-01

The development of novel therapeutic agents over the past decade, including the proteasome inhibitor, bortezomib, and the immunomodulatory drugs, lenalidomide and thalidomide, has resulted in improved outcomes for patients with multiple myeloma. However, there is still considerable controversy as to which regimen should be used as first-line therapy, which patients should be considered for autologous or allogeneic transplantation, and how consolidation or maintenance therapy is used in patients that have a good response to first-line therapy. The present paper will review clinical evidence from previous and ongoing studies to explore issues related to these questions.

The hydrolysis of polyimides

NASA Technical Reports Server (NTRS)

Hoagland, P. D.; Fox, S. W.

1973-01-01

Thermal polymerization of aspartic acid produces a polysuccinimide (I), a chain of aspartoyl residues. An investigation was made of the alkaline hydrolysis of the imide rings of (I) which converts the polyimide to a polypeptide. The alkaline hydrolysis of polyimides can be expected to be kinetically complex due to increasing negative charge generated by carboxylate groups. For this reason, a diimide, phthaloyl-DL-aspartoyl-beta-alanine (IIA) was synthesized for a progressive study of the hydrolysis of polyimides. In addition, this diimide (IIA) can be related to thalidomide and might be expected to exhibit similar reactivity during hydrolysis of the phthalimide ring.

Effects of exercise on fatigue, sleep, and performance: a randomized trial.

PubMed

Coleman, Elizabeth Ann; Goodwin, Julia A; Kennedy, Robert; Coon, Sharon K; Richards, Kathy; Enderlin, Carol; Stewart, Carol B; McNatt, Paula; Lockhart, Kim; Anaissie, Elias J

2012-09-01

To compare usual care with a home-based individualized exercise program (HBIEP) in patients receiving intensive treatment for multiple myeloma (MM)and epoetin alfa therapy. Randomized trial with repeated measures of two groups (one experimental and one control) and an approximate 15-week experimental period. Outpatient setting of the Myeloma Institute for Research and Therapy at the Rockfellow Cancer Center at the University of Arkansas for Medical Sciences. 187 patients with newly diagnosed MM enrolled in a separate study evaluating effectiveness of the Total Therapy regimen, with or without thalidomide. Measurements included the Profile of Mood States fatigue scale, Functional Assessment of Cancer Therapy-Fatigue, ActiGraph® recordings, 6-Minute Walk Test, and hemoglobin levels at baseline and before and after stem cell collection. Descriptive statistics were used to compare demographics and treatment effects, and repeated measures analysis of variance was used to determine effects of HBIEP. Fatigue, nighttime sleep, performance (aerobic capacity) as dependent or outcome measures, and HBIEP combining strength building and aerobic exercise as the independent variable. Both groups were equivalent for age, gender, race, receipt of thalidomide, hemoglobin levels, and type of treatment regimen for MM. No statistically significant differences existed among the experimental and control groups for fatigue, sleep, or performance (aerobic capacity). Statistically significant differences (p < 0.05) were found in each of the study outcomes for all patients as treatment progressed and patients experienced more fatigue and poorer nighttime sleep and performance (aerobic capacity). The effect of exercise seemed to be minimal on decreasing fatigue, improving sleep, and improving performance (aerobic capacity). Exercise is safe and has physiologic benefits for patients undergoing MM treatment; exercise combined with epoetin alfa helped alleviate anemia.

Comparison of cyclophosphamide-thalidomide-dexamethasone to bortezomib-cyclophosphamide-dexamethasone as induction therapy for multiple myeloma patients in Brazil.

PubMed

Vigolo, Suelen; Zuckermann, Joice; Bittencourt, Rosane Isabel; Silla, Lúcia; Pilger, Diogo André

2017-09-01

Chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT) remains the standard treatment for multiple myeloma (MM). Thalidomide or bortezomib may be combined with cyclophosphamide and dexamethasone, in what are known as the CTD and VCD protocols, respectively. The objective of this study was to evaluate the clinical characteristics and response rates obtained with CTD and VCD, observing whether the inclusion of bortezomib to treat MM patients in Brazil increases therapeutic efficiency. Forty-three MM patients treated with induction protocols CTD and VCD between January 2010 and March 2015 were included. The parameters analyzed were staging, frequency of comorbidities prior to treatment, response rates obtained at each induction cycle, progression-free survival, and overall survival of patients. Very good partial response and complete response obtained with the VCD protocol were superior, compared with the CTD treatment. The presence of comorbidities was similar in the two groups, except kidney failure, which prevailed in the VCD group. Also, 78.3% and 48.3% of patients treated with the VCD and CTD protocols underwent autologous HSCT, respectively. In patients given the VCD protocol, 45.5% had complete response before autologous HSCT. Among those given CTD, this number was only 7.1% (p=0.023). Disease progression after autologous HSCT did not differ between the two groups. VCD afforded better responses than the CTD protocol, and improved patient condition before autologous HSCT. However, more studies are necessary including more patients and addressing various clinical conditions, besides the analysis of cost-effectiveness of these treatments. Copyright © 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier B.V. All rights reserved.

Lenalidomide enhances the function of chimeric antigen receptor T cells against the epidermal growth factor receptor variant III by enhancing immune synapses.

PubMed

Kuramitsu, S; Ohno, M; Ohka, F; Shiina, S; Yamamichi, A; Kato, A; Tanahashi, K; Motomura, K; Kondo, G; Kurimoto, M; Senga, T; Wakabayashi, T; Natsume, A

2015-10-01

The epidermal growth factor receptor variant III (EGFRvIII) is exclusively expressed on the cell surface in ~50% of glioblastoma multiforme (GBM). This variant strongly and persistently activates the phosphatidylinositol 3-kinase-Akt signaling pathway in a ligand-independent manner resulting in enhanced tumorigenicity, cellular motility and resistance to chemoradiotherapy. Our group generated a recombinant single-chain variable fragment (scFv) antibody specific to the EGFRvIII, referred to as 3C10-scFv. In the current study, we constructed a lentiviral vector transducing the chimeric antigen receptor (CAR) that consisted of 3C10-scFv, CD3ζ, CD28 and 4-1BB (3C10-CAR). The 3C10-CAR-transduced peripheral blood mononuclear cells (PBMCs) and CD3(+) T cells specifically lysed the glioma cells that express EGFRvIII. Moreover, we demonstrated that CAR CD3(+) T cells migrated to the intracranial xenograft of GBM in the mice treated with 3C10-CAR PBMCs. An important and novel finding of our study was that a thalidomide derivative lenalidomide induced 3C10-CAR PBMC proliferation and enhanced the persistent antitumor effect of the cells in vivo. Lenalidomide also exhibited enhanced immunological synapses between the effector cells and the target cells as determined by CD11a and F-actin polymerization. Collectively, lentiviral-mediated transduction of CAR effectors targeting the EGFRvIII showed specific efficacy, and lenalidomide even intensified CAR cell therapy by enhanced formation of immunological synapses.

Environmental Impact on Vascular Development Predicted by High-Throughput Screening

PubMed Central

Judson, Richard S.; Reif, David M.; Sipes, Nisha S.; Singh, Amar V.; Chandler, Kelly J.; DeWoskin, Rob; Dix, David J.; Kavlock, Robert J.; Knudsen, Thomas B.

2011-01-01

Background: Understanding health risks to embryonic development from exposure to environmental chemicals is a significant challenge given the diverse chemical landscape and paucity of data for most of these compounds. High-throughput screening (HTS) in the U.S. Environmental Protection Agency (EPA) ToxCast™ project provides vast data on an expanding chemical library currently consisting of > 1,000 unique compounds across > 500 in vitro assays in phase I (complete) and Phase II (under way). This public data set can be used to evaluate concentration-dependent effects on many diverse biological targets and build predictive models of prototypical toxicity pathways that can aid decision making for assessments of human developmental health and disease. Objective: We mined the ToxCast phase I data set to identify signatures for potential chemical disruption of blood vessel formation and remodeling. Methods: ToxCast phase I screened 309 chemicals using 467 HTS assays across nine assay technology platforms. The assays measured direct interactions between chemicals and molecular targets (receptors, enzymes), as well as downstream effects on reporter gene activity or cellular consequences. We ranked the chemicals according to individual vascular bioactivity score and visualized the ranking using ToxPi (Toxicological Priority Index) profiles. Results: Targets in inflammatory chemokine signaling, the vascular endothelial growth factor pathway, and the plasminogen-activating system were strongly perturbed by some chemicals, and we found positive correlations with developmental effects from the U.S. EPA ToxRefDB (Toxicological Reference Database) in vivo database containing prenatal rat and rabbit guideline studies. We observed distinctly different correlative patterns for chemicals with effects in rabbits versus rats, despite derivation of in vitro signatures based on human cells and cell-free biochemical targets, implying conservation but potentially differential contributions of developmental pathways among species. Follow-up analysis with antiangiogenic thalidomide analogs and additional in vitro vascular targets showed in vitro activity consistent with the most active environmental chemicals tested here. Conclusions: We predicted that blood vessel development is a target for environmental chemicals acting as putative vascular disruptor compounds (pVDCs) and identified potential species differences in sensitive vascular developmental pathways. PMID:21788198

Identification of a novel compound (β-sesquiphellandrene) from turmeric (Curcuma longa) with anticancer potential: comparison with curcumin.

PubMed

Tyagi, Amit Kumar; Prasad, Sahdeo; Yuan, Wei; Li, Shiyou; Aggarwal, Bharat B

2015-12-01

Considering that as many as 80% of the anticancer drugs have their roots in natural products derived from traditional medicine, we examined compounds other than curcumin from turmeric (Curcuma longa) that could exhibit anticancer potential. Present study describes the isolation and characterization of another turmeric-derived compound, β-sesquiphellandrene (SQP) that exhibits anticancer potential comparable to that of curcumin. We isolated several compounds from turmeric, including SQP, α-curcumene, ar-turmerone, α-turmerone, β-turmerone, and γ-turmerone, only SQP was found to have antiproliferative effects comparable to those of curcumin in human leukemia, multiple myeloma, and colorectal cancer cells. While lack of the NF-κB-p65 protein had no effect on the activity of SQP, lung cancer cells that expressed p53 were more susceptible to the cytotoxic effect of SQP than were cells that lacked p53 expression. SQP was also found to be highly effective in suppressing cancer cell colony formation and inducing apoptosis, as shown by assays of intracellular esterase activity, plasma membrane integrity, and cell-cycle phase. SQP was found to induce cytochrome c release and activate caspases that lead to poly ADP ribose polymerase cleavage. SQP exposure was associated with downregulation of cell survival proteins such cFLIP, Bcl-xL, Bcl-2, c-IAP1, and survivin. Furthermore, SQP was found to be synergistic with the chemotherapeutic agents velcade, thalidomide and capecitabine. Overall, our results indicate that SQP has anticancer potential comparable to that of curcumin.

Prognostic Significance of Blood Transfusion in Newly Diagnosed Multiple Myeloma Patients without Autologous Hematopoietic Stem Cell Transplantation

PubMed Central

Fan, Liping; Fu, Danhui; Zhang, Jinping; Wang, Qingqing; Ye, Yamei; Xie, Qianling

2017-01-01

The aim of this study was to evaluate whether blood transfusions affect overall survival (OS) and progression-free survival (PFS) in newly diagnosed multiple myeloma (MM) patients without hematopoietic stem cell transplantation. A total of 181 patients were enrolled and divided into two groups: 68 patients in the transfused group and 113 patients in the nontransfused group. Statistical analyses showed that there were significant differences in ECOG scoring, Ig isotype, platelet (Plt) counts, hemoglobin (Hb) level, serum creatinine (Scr) level, and β2-microglobulin (β2-MG) level between the two groups. Univariate analyses showed that higher International Staging System staging, Plt counts < 100 × 109/L, Scr level ≥ 177 μmol/L, serum β2-MG ≥ 5.5 μmol/L, serum calcium (Ca) ≥ 2.75 mmol/L, and thalidomide use were associated with both OS and PFS in MM patients. Age ≥ 60 was associated with OS and Ig isotype was associated with PFS in MM patients. Moreover, blood transfusion was associated with PFS but not OS in MM patients. Multivariate analyses showed that blood transfusion was not an independent factor for PFS in MM patients. Our preliminary results suggested that newly diagnosed MM patients may benefit from a liberal blood transfusion strategy, since blood transfusion is not an independent impact factor for survival. PMID:28567420

The effect of proton pump inhibitors on the CYP2C19 enzyme activity evaluated by the pantoprazole-13C breath test in GERD patients: clinical relevance for personalized medicine.

PubMed

Modak, Anil S; Klyarytska, Iryna; Kriviy, Valerij; Tsapyak, Tatjana; Rabotyagova, Yliya

2016-12-17

Patients with gastroesophageal reflux disease (GERD) are routinely prescribed one of the six FDA approved proton pump inhibitors (PPI). All of these PPI are inhibitors of CYP2C19 enzyme to varying degrees. The phenotype pantoprazole- 13 C breath test (Ptz-BT) was used to identify patients who are poor metabolizers (PM) and the extent of phenoconversion of CYP2C19 enzyme activity caused by four PPI (omeprazole, esomprazole pantoprazole and rabeprazole) in 54 newly diagnosed GERD patients prior to initiating randomly selected PPI therapy and 30 d after PPI therapy. The phenoconversion after 30 d of PPI therapy in GERD patients was statistically significant (p  =0.001) with omeprazole/esomeprazole (n  =  27) strong CYP2C19 inhibitors, while there was no change in CYP2C19 enzyme activity (p  =  0.8) with pantoprazole/ rabeprazole (n  =  27), weak CYP2C19 inhibitors. The concommitant use of omeprazole/esomeprazole, therefore, could have critical clinical relevance in individualizing medications metabolized primarily by CYP2C19 such as PPI, clopidogrel, phenytoin, cyclophosphamide, thalidomide, citalopram, clonazepam, diazepam, proguanil, tivantinib etc. The rapid (30 min), in vivo, and non-invasive phenotype Ptz-BT can evaluate CYP2C19 enzyme activity. More importantly, it can identify GERD patients with low CYP2C19 enzyme activity (PM), caused by PPI or other concomitant medications, who would benefit from dose adjustments to maintain efficacy and avoid toxicity. The existing CYP2C19 genotype tests cannot predict the phenotype nor can it detect phenoconversion due to non genetic factors.

Reverse translation of adverse event reports paves the way for de-risking preclinical off-targets

PubMed Central

Maciejewski, Mateusz; Lounkine, Eugen; Whitebread, Steven; Farmer, Pierre; DuMouchel, William; Shoichet, Brian K; Urban, Laszlo

2017-01-01

The Food and Drug Administration Adverse Event Reporting System (FAERS) remains the primary source for post-marketing pharmacovigilance. The system is largely un-curated, unstandardized, and lacks a method for linking drugs to the chemical structures of their active ingredients, increasing noise and artefactual trends. To address these problems, we mapped drugs to their ingredients and used natural language processing to classify and correlate drug events. Our analysis exposed key idiosyncrasies in FAERS, for example reports of thalidomide causing a deadly ADR when used against myeloma, a likely result of the disease itself; multiplications of the same report, unjustifiably increasing its importance; correlation of reported ADRs with public events, regulatory announcements, and with publications. Comparing the pharmacological, pharmacokinetic, and clinical ADR profiles of methylphenidate, aripiprazole, and risperidone, and of kinase drugs targeting the VEGF receptor, demonstrates how underlying molecular mechanisms can emerge from ADR co-analysis. The precautions and methods we describe may enable investigators to avoid confounding chemistry-based associations and reporting biases in FAERS, and illustrate how comparative analysis of ADRs can reveal underlying mechanisms. DOI: http://dx.doi.org/10.7554/eLife.25818.001 PMID:28786378

5-hydroxy-2-methyl-1,4-naphthoquinone, a vitamin K3 analogue, suppresses STAT3 activation pathway through induction of protein tyrosine phosphatase, SHP-1: potential role in chemosensitization.

PubMed

Sandur, Santosh K; Pandey, Manoj K; Sung, Bokyung; Aggarwal, Bharat B

2010-01-01

The activation of signal transducers and activators of transcription 3 (STAT3) has been linked with carcinogenesis through survival, proliferation, and angiogenesis of tumor cells. Agents that can suppress STAT3 activation have potential not only for prevention but also for treatment of cancer. In the present report, we investigated whether 5-hydroxy-2-methyl-1,4-naphthoquinone (plumbagin), an analogue of vitamin K, and isolated from chitrak (Plumbago zeylanica), an Ayurvedic medicinal plant, can modulate the STAT3 pathway. We found that plumbagin inhibited both constitutive and interleukin 6-inducible STAT3 phosphorylation in multiple myeloma (MM) cells and this correlated with the inhibition of c-Src, Janus-activated kinase (JAK)1, and JAK2 activation. Vanadate, however, reversed the plumbagin-induced downregulation of STAT3 activation, suggesting the involvement of a protein tyrosine phosphatase. Indeed, we found that plumbagin induced the expression of the protein tyrosine phosphatase, SHP-1, and silencing of the SHP-1 abolished the effect of plumbagin. This agent also downregulated the expression of STAT3-regulated cyclin D1, Bcl-xL, and vascular endothelial growth factor; activated caspase-3; induced poly (ADP ribose) polymerase cleavage; and increased the sub-G(1) population of MM cells. Consistent with these results, overexpression of constitutive active STAT3 significantly reduced the plumbagin-induced apoptosis. When compared with AG490, a rationally designed STAT3/JAK2 inhibitor, plumbagin was found more potent in suppressing the proliferation of cells. Plumbagin also significantly potentiated the apoptotic effects of thalidomide and bortezomib in MM cells. Overall, these results suggest that the plumbagin inhibits STAT3 activation pathway through the induction of SHP-1 and this may mediate the sensitization of STAT3 overexpressing cancers to chemotherapeutic agents.

[Therapy of multiple myeloma: indications and options].

PubMed

Peest, D; Ganser, A

2007-12-01

The multiple myeloma (MM) has an incidence of 3-4/100,000 in the Caucasian population. MM has to be distinguished from smouldering MM and monoclonal gammopathy of uncertain significance (MGUS). In younger patients (<65 years) a good long-term remission is the aim of therapy, while in the elderly patients with comorbidities the aim is a good partial remission with good quality of life. In the elderly this can be achieved with a combination of melphalan and prednisone. High-dose chemotherapy, often as a tandem transplantation, is part of standard therapy of MM patients <65 years. However, allogeneic stem cell transplantation is the only curative approach. New substances approved for treatment of relapsed MM include bortezomib, thalidomide, and lenalidomide.

Real-World Use of 3rd Line Therapy for Multiple Myeloma in Austria: An Austrian Myeloma Registry (AMR) Analysis of the Therapeutic Landscape and Clinical Outcomes prior to the Use of Next Generation Myeloma Therapeutics.

PubMed

Willenbacher, Ella; Weger, Roman; Rochau, Ursula; Siebert, Uwe; Willenbacher, Wolfgang

2016-01-01

Clinical trials demonstrate improving survival in patients with multiple myeloma (MM) after treatment. However, it is unclear whether increased survival translates to a similar benefit in a real world setting. We analyzed the overall survival of 347 multiple myeloma patients in Austria by means of a national registry (AMR), focused on results from 3rd and later lines of therapy. This benchmark was chosen to define a baseline prior to the broad application of upcoming 2nd generation drugs (carfilzomib, pomalidomide). Projected 10 years survival for patients with MM in Austria is estimated to be 56% in patients diagnosed in between the years 2011-2014, 21% in patients with a diagnosis made between 2000-2005, and 39% in those with a diagnosis made between 2006-2010). For the same intervals a significant increase in the use of both bortezomib, lenalidomide and thalidomide-so called IMiDs (from 2005 onwards) and their simultaneous use in combination therapies (from 2010 onwards) could be shown. The use of autologous transplantation (ASCT) remained more or less constant at ~ 35% of patients in the 1st line setting over the whole period, comparing well to international practice patterns, while the use of 2nd line ASCT increased from 5.5% to 18.7% of patients. Patients in 3rd or later line treatment (n = 105), showed that even in relapsed and refractory disease median survival was 27 months with a considerable proportion of long-term survivors (~20%). With the expected emergence of additional active anti-myeloma compounds, we aim to assess survival in patients with relapsed and refractory MM.

Second primary malignancies after autologous hematopoietic cell transplantation for multiple myeloma.

PubMed

Krishnan, Amrita Y; Mei, Matthew; Sun, Can-Lan; Thomas, Sandra H; Teh, Jennifer Berano; Kang, Tongjun; Htut, Myo; Somlo, George; Sahebi, Firoozeh; Forman, Stephen J; Bhatia, Smita

2013-02-01

Recent studies demonstrate an increased risk of second primary malignancies (SPMs) in patients with multiple myeloma (MM) receiving maintenance lenalidomide after autologous stem cell transplantation (ASCT). We explored the possibility of other risk factors driving post-ASCT SPMs in patients with MM through analysis of our large transplantation database in conjunction with our Long-Term Follow-Up Program. We conducted a retrospective cohort study of 841 consecutive patients with MM who underwent ASCT at City of Hope between 1989 and 2009, as well as a nested case-control analysis evaluating the role of all therapeutic exposures before, during, and after ASCT. Median duration of follow-up for the entire cohort was 3.4 years (range, 0.3-19.9 years). Sixty cases with a total of 70 SPMs were identified. The overall cumulative incidence of SPMs was 7.4% at 5 years and 15.9% at 10 years when nonmelanoma skin cancers (NMSCs) were included and 5.3% at 5 years and 11.2% at 10 years when NMSCs were excluded. Multivariate analysis of the entire cohort revealed associations of both older age (≥55 years; relative risk, 2.3; P < .004) and race (non-Hispanic white; relative risk, 2.4; P = .01) with an increased risk of SPM. Furthermore, thalidomide exposure demonstrated a trend toward increased risk (odds ratio, 3.5; P = .15); however, an insufficient number of patients were treated with lenalidomide to allow us to accurately assess the risk of this agent. Exclusion of NMSCs retained the association with these variables but was accompanied by loss of statistical significance. This large single-institution analysis identified associations between race and older age and increased risk of developing SPM. The trend toward increased risk with thalidomide exposure suggests a class effect from immunomodulatory drugs that might not be restricted to lenalidomide. Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

The modulation of tumor vessel permeability by thalidomide and its impacts on different types of targeted drug delivery systems in a sarcoma mouse model.

PubMed

Wang, Dan; Fu, Jijun; Shi, Yujie; Peng, Dong; Yuan, Lan; He, Bing; Dai, Wenbing; Zhang, Hua; Wang, Xueqing; Tian, Jie; Zhang, Qiang

2016-09-28

The transport of nanocarriers is supposed to be based on EPR effect which is affected by diverse factors, so the modulation of EPR effect seems very significant for nanocarriers including targeted drug delivery systems (TDDSs). Besides, it is extremely unclear how the EPR effect impacts the fate of different types of TDDSs. To make the most advantage of EPR effect for TDDSs, it is definitely necessary to clarify these key issues. Here, we construct and characterize various TDDSs, including sterically-stabilized liposomes (SSL), RGD functionalized SSL (RGD-SSL) and novel 7PEP functionalized SSL (7PEP-SSL), loaded with doxorubicin (DOX), DIR or DID. Here, we modulate the permeability of tumor vessels by thalidomide (THD) in a sarcoma-bearing EPR mouse model via monitoring endogenous deoxygenated hemoglobin in circulation, and then we confirm the effect of THD on tumor vessel permeability by vessel density, vessel maturity, VEGF expression and so on. Importantly, we investigate and find the impacts of EPR effect on the antitumor efficacy, in vivo distribution and intratumoral microdistribution of the three TDDSs. Interestingly, the EPR effects affect different TDDSs differently. The elevated EPR effect enhances the tumor accumulation of SSL and RGD-SSL but fails to increase their efficacy. The RGD-SSL exhibits the best efficacy with the least fluctuation, demonstrating the advantage of angiogenesis targeted systems. 7PEP-SSL seems the biggest beneficiary of EPR effect, suggesting the significance of EPR modulation for cells targeted systems. Generally, this study demonstrates the feasibility of modulating EPR effect bidirectionally by THD as well as the impacts of EPR effect on different type of testing TDDSs based on this animal model. It certainly provides novel insight into the design and potential use of TDDSs. Copyright © 2016 Elsevier B.V. All rights reserved.

Adjusted comparison of daratumumab monotherapy versus real-world historical control data from the Czech Republic in heavily pretreated and highly refractory multiple myeloma patients.

PubMed

Jelínek, Tomáš; Maisnar, Vladimír; Pour, Luděk; Špička, Ivan; Minařík, Jiří; Gregora, Evžen; Kessler, Petr; Sýkora, Michal; Fraňková, Hana; Adamová, Dagmar; Wróbel, Marek; Mikula, Peter; Jarkovský, Jiří; Diels, Joris; Gatopoulou, Xenia; Veselá, Šárka; Besson, Hervé; Brožová, Lucie; Ito, Tetsuro; Hájek, Roman

2018-05-01

We conducted an adjusted comparison of progression-free survival (PFS) and overall survival (OS) for daratumumab monotherapy versus standard of care, as observed in a real-world historical cohort of heavily pretreated multiple myeloma patients from Czech Republic. Using longitudinal chart data from the Registry of Monoclonal Gammopathies (RMG) of the Czech Myeloma Group, patient-level data from the RMG was pooled with pivotal daratumumab monotherapy studies (GEN501 and SIRIUS; 16 mg/kg). From the RMG database, we identified 972 treatment lines in 463 patients previously treated with both a proteasome inhibitor and an immunomodulatory drug. Treatment initiation dates for RMG patients were between March 2006 and March 2015. The most frequently used treatment regimens were lenalidomide-based regimens (33.4%), chemotherapy (18.1%), bortezomib-based regimens (13.6%), thalidomide-based regimens (8.0%), and bortezomib plus thalidomide (5.3%). Few patients were treated with carfilzomib-based regimens (2.5%) and pomalidomide-based regimens (2.4%). Median observed PFS for daratumumab and the RMG cohort was 4.0 and 5.8 months (unadjusted hazard ratio [HR], 1.14; 95% confidence interval [CI], 0.94-1.39), respectively, and unadjusted median OS was 20.1 and 11.9 months (unadjusted HR, 0.61; 95% CI, 0.48-0.78), respectively. Statistical adjustments for differences in baseline characteristics were made using patient-level data. The adjusted HRs (95% CI) for PFS and OS for daratumumab versus the RMG cohort were 0.79 (0.56-1.12; p = .192) and 0.33 (0.21-0.52; p < .001), respectively. Adjusted comparisons between trial data and historical cohorts can provide useful insights to clinicians and reimbursement decision makers on relative treatment efficacies in the absence of head-to-head comparison studies for daratumumab monotherapy.

The usage of a three-compartment model to investigate the metabolic differences between hepatic reductase null and wild-type mice.

PubMed

Hill, Lydia; Chaplain, Mark A J; Wolf, Roland; Kapelyukh, Yury

2017-03-01

The Cytochrome P450 (CYP) system is involved in 90% of the human body's interactions with xenobiotics and due to this, it has become an area of avid research including the creation of transgenic mice. This paper proposes a three-compartment model which is used to explain the drug metabolism in the Hepatic Reductase Null (HRN) mouse developed by the University of Dundee (Henderson, C. J., Otto, D. M. E., Carrie, D., Magnuson, M. A., McLaren, A. W., Rosewell, I. and Wolf, C. R. (2003) Inactivation of the hepatic cytochrome p450 system by conditional deletion of hepatic cytochrome p450 reductase. J. Biol. Chem. , 13480-13486). The model is compared with a two-compartment model using experimental data from studies using wild-type and HRN mice. This comparison allowed for metabolic differences between the two types of mice to be isolated. The three sets of drug data (Gefitinib, Midazolam and Thalidomide) showed that the transgenic mouse has a decreased rate of metabolism. © The authors 2015. Published by Oxford University Press on behalf of the Institute of Mathematics and its Applications. All rights reserved.

Erythema Nodosum Leprosum: Update and challenges on the treatment of a neglected condition.

PubMed

Costa, Perpétua do Socorro Silva; Fraga, Lucas Rosa; Kowalski, Thayne Woycinck; Daxbacher, Egon Luiz Rodrigues; Schuler-Faccini, Lavínia; Vianna, Fernanda Sales Luiz

2018-07-01

Erythema Nodosum Leprosum (ENL) occurs due to the immunological complication of multibacillary leprosy and is characterized by painful nodules and systemic compromising. It is usually recurrent and/or chronic and has both physical and economic impact on the patient, being a very important cause of disability. In addition, ENL is a major health problem in countries where leprosy is endemic. Therefore, adequate control of this condition is important. The management of ENL aims to control acute inflammation and neuritis and prevent the onset of new episodes. However, all currently available treatment modalities have one or two drawbacks and are not effective for all patients. Corticosteroid is the anti-inflammatory of choice in ENL but may cause dependence, especially for chronic patients. Thalidomide has a rapid action but its use is limited due the teratogenicity and neurotoxicity. Clofazimine and pentoxifylline have slow action and have important adverse effects. Finally, there is no pattern or guidelines for treating these patients, becoming more difficult to evaluate and to control this condition. This review aims to show the main drugs used in the treatment of ENL and the challenges in the management of the reaction. Copyright © 2018 Elsevier B.V. All rights reserved.

Inhibition of Inflammation Mediated Through the Tumor Necrosis Factor α Biochemical Pathway Can Lead to Favorable Outcomes in Alzheimer Disease

PubMed Central

Shamim, Daniah; Laskowski, Michael

2017-01-01

Tumor necrosis factor α (TNF-α) inhibitors have long been used as disease-modifying agents in immune disorders. Recently, research has shown a role of chronic neuroinflammation in the pathophysiology of neurodegenerative diseases such as Alzheimer disease, and interest has been generated in the use of anti-TNF agents and TNF-modulating agents for prevention and treatment. This article extensively reviewed literature on animal studies testing these agents. The results showed a role for direct and indirect TNF-α inhibition through agents such as thalidomide, 3,6-dithiothalidomide, etanercept, infliximab, exendin-4, sodium hydrosulfide, minocycline, imipramine, and atorvastatin. Studies were performed on mice, rats, and monkeys, with induction of neurodegenerative physiology either through the use of chemical agents or through the use of transgenic animals. Most of these agents showed an improvement in cognitive function as tested with the Morris water maze, and immunohistochemical and histopathological staining studies consistently showed better outcomes with these agents. Brains of treated animals showed significant reduction in pro-inflammatory TNF-α and reduced the burden of neurofibrillary tangles, amyloid precursor protein, and β-amyloid plaques. Also, recruitment of microglial cells in the central nervous system was significantly reduced through these drugs. These studies provide a clearer mechanistic understanding of the role of TNF-α modulation in Alzheimer disease. All studies in this review explored the use of these drugs as prophylactic agents to prevent Alzheimer disease through immune modulation of the TNF inflammatory pathway, and their success highlights the need for further research of these drugs as therapeutic agents. PMID:28811745

Inhibition of Inflammation Mediated Through the Tumor Necrosis Factor α Biochemical Pathway Can Lead to Favorable Outcomes in Alzheimer Disease.

PubMed

Shamim, Daniah; Laskowski, Michael

2017-01-01

Tumor necrosis factor α (TNF-α) inhibitors have long been used as disease-modifying agents in immune disorders. Recently, research has shown a role of chronic neuroinflammation in the pathophysiology of neurodegenerative diseases such as Alzheimer disease, and interest has been generated in the use of anti-TNF agents and TNF-modulating agents for prevention and treatment. This article extensively reviewed literature on animal studies testing these agents. The results showed a role for direct and indirect TNF-α inhibition through agents such as thalidomide, 3,6-dithiothalidomide, etanercept, infliximab, exendin-4, sodium hydrosulfide, minocycline, imipramine, and atorvastatin. Studies were performed on mice, rats, and monkeys, with induction of neurodegenerative physiology either through the use of chemical agents or through the use of transgenic animals. Most of these agents showed an improvement in cognitive function as tested with the Morris water maze, and immunohistochemical and histopathological staining studies consistently showed better outcomes with these agents. Brains of treated animals showed significant reduction in pro-inflammatory TNF-α and reduced the burden of neurofibrillary tangles, amyloid precursor protein, and β-amyloid plaques. Also, recruitment of microglial cells in the central nervous system was significantly reduced through these drugs. These studies provide a clearer mechanistic understanding of the role of TNF-α modulation in Alzheimer disease. All studies in this review explored the use of these drugs as prophylactic agents to prevent Alzheimer disease through immune modulation of the TNF inflammatory pathway, and their success highlights the need for further research of these drugs as therapeutic agents.

940 nm diode laser therapy in management of recurrent apthous ulcer

PubMed Central

Misra, Neeta; Maiti, Debasmita; Misra, Pradyumna; Singh, Ashish Kumar

2013-01-01

Recurrent apthous stomatitis (RAS) is one of the most common oral inflammatory diseases characterised by painful recurrent ulcerations of the orofacial region. The ulcers occur in three clinical forms: minor, major and herpetiform. Several therapies have been advocated to manage these lesions such as topical corticosteroids (triamcinolone acetonide, hydrocortisone acetate and clobetasol propionate), chlorhexidine mouth rinses, tetracycline oral rinses, thalidomide, fluocinonide, colchicines and the immune boosting agent levamosile, vitamin therapy and topical interferon α-2a. Laser therapy is used as an alternative method in treatment of RAS. In this paper one patient with RAS was treated using a 940 nm diode laser for symptomatic relief of pain and burning sensation and healing of ulcer. PMID:23598930

Phase II drugs that are currently in development for the treatment of cachexia.

PubMed

Dingemans, Anne-Marie C; de Vos-Geelen, Judith; Langen, Ramon; Schols, Annemie M W

2014-12-01

Cachexia is a syndrome presenting with progressive unintentional weight loss and wasting and weakness of skeletal muscle. Cachexia is prevalent in cancer and in chronic diseases including chronic obstructive pulmonary disease (COPD). The authors searched trial registers for current Phase II clinical trials on cachexia. Twelve studies were found with 11 compounds, including the anti-inflammatory drugs thalidomide, OHR/AVR118, celecoxib, VT-122, omega-3 supplements, and anabolic agents such as ghrelin analogues, MT-102, BYM338 and ruxolotinib. The authors note that one of the studies related to COPD while the others were related to different cancers. Herein, the authors describe the mechanisms of action and their Phase II study design. The compounds under study affect several pathways involved in cachexia by modulating inflammatory activity, anabolic potential, digestion and direct interaction with the muscle. Due to the multifactorial aspects of cachexia syndrome, combinations of these new drugs with nutritional intervention is probably the most promising approach. Furthermore, future studies should include interventions in pre-cachetic patients, as this stage might be more responsive to treatment. Future studies will benefit from well-defined end points and improved measures of cachexia, providing new insight into the disease. This insight, in combination with the elucidation of cachexia's underlying mechanism, will yield new treatment strategies in the near future.

The past, present and perhaps future of pharmacovigilance: homage to Folke Sjoqvist.

PubMed

Moore, Nicholas

2013-05-01

Over the years since 1961 and the identification of thalidomide as the common link in thousands of birth defects, daily pharmacovigilance activities and signal generation have evolved from the analysis of individual case reports and imputology, to case series and underreporting, to spontaneous report databases and disproportionality analyses, to data mining in population databases. Regulatory requirements have also changed from purely passive monitoring and reacting to alerts to a proactive approach that includes risk management plans and risk minimization, and from reporting only by healthcare professionals to patient reporting and exploration of social media. The emphasis only on risk assessment is changing towards assessment of the risk/benefit ratio and the exploration of real-life efficacy studies to complement the measure of real-life risk. The interactions between industry and regulators have been amplified and strengthened. However, most adverse reactions, including severe ones, are related to well-known and often pharmacological effects of the older drugs, possibly with genetic predispositions. Prevention is the next frontier for pharmacovigilance, beyond simply generating alerts, and it involves not only the removal of drugs from the market, but also promotion of proper drug prescribing by better trained physicians and the proper use of drugs by better informed patients.

Preclinical studies in support of defibrotide for the treatment of multiple myeloma and other neoplasias.

PubMed

Mitsiades, Constantine S; Rouleau, Cecile; Echart, Cinara; Menon, Krishna; Teicher, Beverly; Distaso, Maria; Palumbo, Antonio; Boccadoro, Mario; Anderson, Kenneth C; Iacobelli, Massimo; Richardson, Paul G

2009-02-15

Defibrotide, an orally bioavailable polydisperse oligonucleotide, has promising activity in hepatic veno-occlusive disease, a stem cell transplantation-related toxicity characterized by microangiopathy. The antithrombotic properties of defibrotide and its minimal hemorrhagic risk could serve for treatment of cancer-associated thrombotic complications. Given its cytoprotective effect on endothelium, we investigated whether defibrotide protects tumor cells from cytotoxic antitumor agents. Further, given its antiadhesive properties, we evaluated whether defibrotide modulates the protection conferred to multiple myeloma cells by bone marrow stromal cells. Defibrotide lacks significant single-agent in vitro cytotoxicity on multiple myeloma or solid tumor cells and does not attenuate their in vitro response to dexamethasone, bortezomib, immunomodulatory thalidomide derivatives, and conventional chemotherapeutics, including melphalan and cyclophosphamide. Importantly, defibrotide enhances in vivo chemosensitivity of multiple myeloma and mammary carcinoma xenografts in animal models. In cocultures of multiple myeloma cells with bone marrow stromal cells in vitro, defibrotide enhances the multiple myeloma cell sensitivity to melphalan and dexamethasone, and decreases multiple myeloma-bone marrow stromal cell adhesion and its sequelae, including nuclear factor-kappaB activation in multiple myeloma and bone marrow stromal cells, and associated cytokine production. Moreover, defibrotide inhibits expression and/or function of key mediators of multiple myeloma interaction with bone marrow stromal cell and endothelium, including heparanase, angiogenic cytokines, and adhesion molecules. Defibrotide's in vivo chemosensitizing properties and lack of direct in vitro activity against tumor cells suggest that it favorably modulates antitumor interactions between bone marrow stromal cells and endothelia in the tumor microenvironment. These data support clinical studies of defibrotide in combination with conventional and novel therapies to potentially improve patient outcome in multiple myeloma and other malignancies.

Preclinical Studies in Support of Defibrotide for the Treatment of Multiple Myeloma and Other Neoplasias

PubMed Central

Mitsiades, Constantine S.; Rouleau, Cecile; Echart, Cinara; Menon, Krishna; Teicher, Beverly; Distaso, Maria; Palumbo, Antonio; Boccadoro, Mario; Anderson, Kenneth C.; Iacobelli, Massimo; Richardson, Paul G.

2015-01-01

Purpose of the study Defibrotide (DF), an orally bioavailable polydisperse oligonucleotide has promising activity in hepatic veno-occlusive disease (VOD), a stem cell transplantation-related toxicity, characterized by microangiopathy. The anti-thrombotic properties of DF and its minimal hemorrhagic risk could serve for treatment of cancer-associated thrombotic complications. Given its cytoprotective effect on endothelium, we investigated whether DF protects tumor cells from cytotoxic anti-tumor agents. Further, given its anti-adhesive properties, we evaluated whether DF modulates the protection conferred to multiple myeloma (MM) cells by bone marrow stromal cells (BMSCs). Methods-Results DF lacks significant single-agent in vitro cytotoxicity on MM or solid tumor cells and does not attenuate their in vitro response to dexamethasone, bortezomib, immunomodulatory thalidomide derivatives, and conventional chemotherapeutics, including melphalan and cyclophosphamide. Importantly, DF enhances in vivo chemosensitivity of MM and mammary carcinoma xenografts in animal models. In co-cultures of MM cells with BMSCs in vitro, DF enhances the MM cell sensitivity to melphalan and dexamethasone, decreases MM-BMSC adhesion and its sequelae, including NF-κB activation in MM and BMSCs, and associated cytokine production. Moreover, DF inhibits expression and/or function of key mediators of MM interaction with BMSC and endothelium, including heparanase, angiogenic cytokines and adhesion molecules. Conclusion Defibrotide’s in vivo chemosensitizing properties and lack of direct in vitro activity against tumor cells suggest that it favorably modulates antitumor interactions between BMSC and endothelia in the tumor microenvironment. These data support clinical studies of DF in combination with conventional and novel therapies to potentially improve patient outcome in MM and other malignancies. PMID:19228727

Lipopolysaccharide mitagates methamphetamine-induced striatal dopamine depletion via modulating local TNF-alpha and dopamine transporter expression.

PubMed

Lai, Yu-Ting; Tsai, Yen-Ping N; Cherng, Chianfang G; Ke, Jing-Jer; Ho, Ming-Che; Tsai, Chia-Wen; Yu, Lung

2009-04-01

Systemic lipopolysaccharide (LPS) treatment may affect methamphetamine (MA)-induced nigrostriatal dopamine (DA) depletion. This study was undertaken to determine the critical time window for the protective effects of LPS treatment and the underlying mechanisms. An LPS injection (1 mg/kg) 72 h before or 2 h after MA treatment [three consecutive, subcutaneous injections of MA (10 mg/kg each) at 2-h intervals] diminished the MA-induced DA depletion in mouse striatum. Such an LPS-associated effect was independent of MA-produced hyperthermia. TNF-alpha, IL-1beta, IL-6 expressions were all elevated in striatal tissues following a systemic injection with LPS, indicating that peripheral LPS treatment affected striatal pro-inflammatory cytokine expression. Striatal TNF-alpha expression was dramatically increased at 72 and 96 h after the MA treatment, while such TNF-alpha elevation was abolished by the LPS pretreatment protocol. Moreover, MA-produced activation of nuclear NFkappaB, a transcription factor following TNF-alpha activation, in striatum was abolished by the LPS (1 mg/kg) pretreatment. Furthermore, thalidomide, a TNF-alpha antagonist, treatment abolished the LPS pretreatment-associated protective effects. Pretreatment with mouse recombinant TNF-alpha in striatum diminished the MA-produced DA depletion. Finally, single LPS treatment caused a rapid down-regulation of dopamine transporter (DAT) in striatum. Taken together, we conclude that peripheral LPS treatment protects nigrostriatal DA neurons against MA-induced toxicity, in part, by reversing elevated TNF-alpha expression and subsequent signaling cascade and causing a rapid DAT down-regulation in striatum.

Limb/pelvis hypoplasia/aplasia with skull defect (Schinzel phocomelia): distinctive features and prenatal detection.

PubMed

Olney, R S; Hoyme, H E; Roche, F; Ferguson, K; Hintz, S; Madan, A

2001-11-01

Schinzel phocomelia syndrome is characterized by limb/pelvis hypoplasia/aplasia: specifically, intercalary limb deficiencies and absent or hypoplastic pelvic bones. The phenotype is similar to that described in a related multiple malformation syndrome known as Al-Awadi/Raas-Rothschild syndrome. The additional important feature of large parietooccipital skull defects without meningocele, encephalocele, or other brain malformation has thus far been reported only in children with Schinzel phocomelia syndrome. We recently evaluated a boy affected with Schinzel phocomelia born to nonconsanguineous healthy parents of Mexican origin. A third-trimester fetal ultrasound scan showed severe limb deficiencies and an absent pelvis. The infant died shortly after birth. Dysmorphology examination, radiographs, and autopsy revealed quadrilateral intercalary limb deficiencies with preaxial toe polydactyly; an absent pelvis and a 7 x 3-cm skull defect; and extraskeletal anomalies including microtia, telecanthus, micropenis with cryptorchidism, renal cysts, stenosis of the colon, and a cleft alveolar ridge. A normal 46,XY karyotype was demonstrated, and autosomal recessive inheritance was presumed on the basis of previously reported families. This case report emphasizes the importance of recognizing severe pelvic and skull deficiencies (either post- or prenatally) in differentiating infants with Schinzel phocomelia from other multiple malformation syndromes that feature intercalary limb defects, including thalidomide embryopathy and Roberts-SC phocomelia. Copyright 2001 Wiley-Liss, Inc.

Artificial sweetener saccharin disrupts intestinal epithelial cells' barrier function in vitro.

PubMed

Santos, P S; Caria, C R P; Gotardo, E M F; Ribeiro, M L; Pedrazzoli, J; Gambero, A

2018-06-25

Consumption of non-nutritive sweeteners (NNS) is a dietary practice used by those who wish to lose weight or by patients on a sugar-restricted diet such as those with DM2. Although these substances are safe, possible biological interactions with the digestive tract, particularly in relation to intestinal permeability, have not been studied. Thus, the current work sought to investigate the action of different NNS on intestinal permeability using an in vitro Caco-2 cell model. Caco-2 cells were incubated with acesulfame K, aspartame, saccharin, or sucralose at equimolar concentrations. Acesulfame K, aspartame, and sucralose did not disrupt monolayer integrity in the cells. However, saccharin increased paracellular permeability and decreased transepithelial electrical resistance (TEER) via a non-cytotoxic mechanism. The levels of the tight junction protein claudin-1 were reduced in Caco-2 cells that had previously been exposed to saccharin. The inhibition of nuclear factor-κB (NF-κB) was able to prevent the reduction in TEER induced by saccharin treatment. Thalidomide, as an inhibitor of ubiquitin ligase, was able to prevent the decrease in claudin-1 protein expression and the TEER reduction in Caco-2 cells. Saccharin disrupts monolayer integrity and alters paracellular permeability in a Caco-2 cell monolayer model, via a mechanism involving NF-κB activation, resulting in the ubiquitination of the tight junction protein claudin-1. Saccharin consumption may potentially alter the intestinal integrity in humans.

A Canadian Electric-Arm Prosthesis for Children

PubMed Central

Nicholls, Peter B.; Stevenson, David A.; Sherman, E. David; Lippay, Andrew L.; Gingras, Gustave

1967-01-01

The thalidomide tragedy in Canada initiated new efforts to produce functional prosthetic appliances for very young amputees. In 1962, the Rehabilitation Institute of Montreal began to fit 36 babies with adapted conventional and gas-operated devices. Practical experience with the Soviet prosthesis proved the feasibility of myoelectric control, and indicated the possibility of using skin electrodes over an active muscle for control purposes in children. We obtained assistance from the Northern Electric Company, whose research laboratories produced the prototype arms described in this report. An all-electric prosthetic system was developed which carries out four different movements driven by a single motor. Function is effected by switches, but a myoelectric control system could be readily adapted without major changes. In the description of our needs for the proposed arm, we asked for modular construction and a minimum service life of one year between major repairs. Details of design and performance are outlined in this report. Initial clinical experience indicates that the prosthesis is completely accepted by the young patient, in spite of its excessive weight and inconvenient control. Four powered joints give the child greater functional freedom. In future we plan to fit an older child and will study more bilateral installations in the next 14 months. After further use, study and improvement, this device will become a useful prosthesis. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5 PMID:6021562

Effects of medicinal compounds on the differentiation of the eukaryotic microorganism dictyostelium discoideum: can this model be used as a screening test for reproductive toxicity in humans?

PubMed

Dannat, K; Tillner, J; Winckler, T; Weiss, M; Eger, K; Dingermann, T

2003-03-01

Dictyostelium discoideum is a single-cell, eukaryotic microorganism that can undergo multicellular development in order to produce dormant spores. We investigated the capacity of D. discoideum to be used as a rapid screening system for potential developmental toxicity of compounds under development as pharmaceuticals. We used a set of four transgenic D. discoideum strains that expressed a reporter gene under the control of promoters that are active at certain time periods and in distinct cell types during D. discoideum development. We found that teratogens such as valproic acid, tretinoin, or thalidomide interfered to various extents with D. discoideum development, and had different effects on prestalk and prespore cell-specific reporter gene expression. Phenytoin was inactive in this assay, which may point to limitations in metabolization of the compound in Dictyostelium required to exert developmental toxicity. D. discoideum cell culture is cheap and easy to handle compared to mammalian cell cultures or animal teratogenicity models. Although the Dictyostelium-based assay described in this report may not securely predict the teratogenic potential of these drugs in humans, this organism may be qualified for rapid large-scale screenings of synthetic compounds under development as new pharmaceuticals for their potential to interfere with developmental processes and thus help to reduce the amount of teratogenicity tests in animal models.

[Pharmacokinetic alterations in pregnancy and use of therapeutic drug monitoring].

PubMed

Panchaud, Alice; Weisskopf, Etienne; Winterfeld, Ursula; Baud, David; Guidi, Monia; Eap, Chin B; Csajka, Chantal; Widmer, Nicolas

2014-01-01

Following the thalidomide tragedy, pharmacological research in pregnant women focused primarily on drug safety for the unborn child and remains only limited regarding the efficacy and safety of treatment for the mother. Significant physiological changes during pregnancy may yet affect the pharmacokinetics of drugs and thus compromise its efficacy and/or safety. Therapeutic drug monitoring (TDM) would maximize the potential effectiveness of treatments, while minimizing the potential risk of toxicity for the mother and the fetus. At present, because of the lack of concentration-response relationship studies in pregnant women, TDM can rely only on individual assessment (based on an effective concentration before pregnancy) and remains reserved only to unexpected situations such as signs of toxicity or unexplained inefficiency. © 2014 Société Française de Pharmacologie et de Thérapeutique.

Randomized Phase III Clinical Trial of Five Different Arms of Treatment in 332 Patients with Cancer Cachexia

PubMed Central

Macciò, Antonio; Madeddu, Clelia; Serpe, Roberto; Massa, Elena; Dessì, Mariele; Panzone, Filomena; Contu, Paolo

2010-01-01

Purpose. A phase III, randomized study was carried out to establish the most effective and safest treatment to improve the primary endpoints of cancer cachexia—lean body mass (LBM), resting energy expenditure (REE), and fatigue—and relevant secondary endpoints: appetite, quality of life, grip strength, Glasgow Prognostic Score (GPS) and proinflammatory cytokines. Patients and Methods. Three hundred thirty-two assessable patients with cancer-related anorexia/cachexia syndrome were randomly assigned to one of five treatment arms: arm 1, medroxyprogesterone (500 mg/day) or megestrol acetate (320 mg/day); arm 2, oral supplementation with eicosapentaenoic acid; arm 3, L-carnitine (4 g/day); arm 4, thalidomide (200 mg/day); and arm 5, a combination of the above. Treatment duration was 4 months. Results. Analysis of variance showed a significant difference between treatment arms. A post hoc analysis showed the superiority of arm 5 over the others for all primary endpoints. An analysis of changes from baseline showed that LBM (by dual-energy X-ray absorptiometry and by L3 computed tomography) significantly increased in arm 5. REE decreased significantly and fatigue improved significantly in arm 5. Appetite increased significantly in arm 5; interleukin (IL)-6 decreased significantly in arm 5 and arm 4; GPS and Eastern Cooperative Oncology Group performance status (ECOG PS) score decreased significantly in arm 5, arm 4, and arm 3. Toxicity was quite negligible, and was comparable between arms. Conclusion. The most effective treatment in terms of all three primary efficacy endpoints and the secondary endpoints appetite, IL-6, GPS, and ECOG PS score was the combination regimen that included all selected agents. PMID:20156909

Tumour necrosis factor-α inhibition with lenalidomide alleviates tissue oxidative injury and apoptosis in ob/ob obese mice.

PubMed

Zhu, Xiaoling; Jiang, Shasha; Hu, Nan; Luo, Fuling; Dong, Hailong; Kang, Yu-Ming; Jones, Kyla R; Zou, Yunzeng; Xiong, Lize; Ren, Jun

2014-07-01

Lenalidomide (Revlimid; Selleck Chemicals, Houston, TX, USA), an analogue of thalidomide, possesses potent cytokine modulatory capacity through inhibition of cytokines such as tumour necrosis factor (TNF)-α, a cytokine pivotal for the onset and development of complications in obesity and diabetes mellitus. The present study was designed to evaluate the effect of lenalidomide on oxidative stress, protein and DNA damage in multiple organs in an ob/ob murine model of obesity. To this end, C57BL/6 lean and ob/ob obese mice were administered lenalidomide (50 mg/kg per day, p.o.) for 5 days. Oxidative stress, protein and DNA damage were assessed using the conversion of reduced glutathione (GSH) to oxidized glutathione (GSSG), carbonyl formation and Comet assay, respectively. Apoptosis was evaluated using caspase 3 activity, and levels of Bax, Bcl-2, Bip, caspase 8, caspase 9 and TNF-α were assessed using western blot analysis. Lenalidomide treatment did not affect glucose clearance in lean or ob/ob mice. Obese mice exhibited a reduced GSH/GSSG ratio in the liver, gastrocnemius skeletal muscle and small intestine, as well as enhanced protein carbonyl formation, DNA damage and caspase 3 activity in the liver, kidney, skeletal muscle and intestine; these effects were alleviated by lenalidomide, with the exception of obesity-associated DNA damage in the liver and kidney. Western blot analysis revealed elevated TNF-α, Bax, Bcl-2, Bip, caspase 8 and caspase 9 in ob/ob mice with various degrees of reversal by lenalidomide treatment. Together, these data indicate that lenalidomide protects against obesity-induced tissue injury and protein damage, possibly in association with antagonism of cytokine production and cytokine-induced apoptosis and oxidative stress. © 2014 Wiley Publishing Asia Pty Ltd.

Flow Cytometry in Diagnosis of Myelomatous Pleural Effusion: A Case Report.

PubMed

Arora, Parul; Gupta, Sanjeev Kumar; Mallik, Nabhajit; Mittal, Reena; Sharma, Om Dutt; Kumar, Lalit

2016-06-01

Plasma cell myeloma is a multifocal plasma cell neoplasm associated with increased monoclonal protein in serum and/or urine. Pleural effusions in patients with myeloma are uncommon (6 %). However, effusions due to direct infiltration of the pleura by plasma cells (myelomatous pleural effusion) are extremely rare (<1 %) and usually seen with IgA myeloma. The diagnosis of such cases requires pleural fluid cytology, electrophoresis or pleural biopsy. We present a case of myelomatous pleural effusion diagnosed using flow cytometry immunophenotyping in addition to the pleural fluid cytology. A 45 year old female was diagnosed as plasma cell myeloma (IgG kappa) in 2007. She received multiple lines of therapy during the course of her treatment including thalidomide, dexamethasone, lenalidomide, bortezomib, and doxorubicin based regimens. However, the patient had progressive extramedullary disease and developed pleural effusion in 2014. Cytological examination of the pleural fluid showed degenerative changes. Few preserved areas showed mononuclear cells including morphologically abnormal plasma cells. Immunophenotyping of these cells by flow cytometry revealed a pattern indicating neoplastic plasma cells. There was expression of CD38, CD138, and CD56, with absence of CD19, CD10 and CD45. This confirmed the diagnosis of myelomatous pleural effusion. Subsequently, the patient was offered a dexamethasone, cyclophosphamide, etoposide and cisplatin based regimen but, she declined further treatment and succumbed to her disease 3 months later. Myelomatous pleural effusion is a rare complication of plasma cell myeloma. Flow cytometry can be used as an adjunctive technique in its diagnosis particularly in cases with equivocal cytology and electrophoresis findings.

Unilateral terminal aphalangia in father and daughter--exogenous or genetic cause?

PubMed

Neumann, L; Pelz, J; Kunze, J

1998-07-24

Published cases of familial unilateral terminal transverse defects are scarce. We report on a morphologically similar defect of the hand in a father and his daughter. The hand anomaly is similar in both, but on the opposite side. Thalidomide was taken in the sensitive period of the pregnancy by the father's mother. To our knowledge this is the second description of unilateral terminal aphalangia in successive generations. In order to evaluate the possible genetic basis we analyze epidemiological studies in respect to the recurrence risk of cases with isolated limb reduction defects. We compare reports of familial occurrence concerning the degree of relationship as well as the pattern of malformation. The latter seems to be an important aspect from an evolutionary and a developmental viewpoint. For our observation an autosomal dominant transmission is the most likely although multifactorial determination cannot be excluded.

Recent advances in multiple myeloma.

PubMed

Sjak-Shie, N N; Vescio, R A; Berenson, J R

2000-07-01

Multiple myeloma is the second most common hematologic malignancy, with approximately 15,000 new cases each year in the United States. Our understanding of the pathophysiology underlying myeloma continues to expand, but the cause of this plasma cell dyscrasia remains unclear. Though controversy remains regarding a possible viral cause of myeloma, evidence suggesting a role for the human herpesvirus-8 is mounting. The roles of cytogenetic abnormalities as well as aberrant angiogenesis and cytokine expression in the etiology of myeloma continue to be explored and may lead to future therapeutic strategies. Transplantation in myeloma is rarely curative but offers clinical benefit not only for young but possibly for older myeloma patients as well. Newer bisphosphonates may offer greater ease of administration, improved efficacy, and possibly even enhanced antitumor effect. Finally, thalidomide offers significant clinical benefit to patients with myeloma previously refractory to multiple agents, and its role in early stages of the disease is under investigation.

Histological variability and the importance of clinicopathological correlation in cutaneous Rosai-Dorfman disease.

PubMed

Gameiro, Ana; Gouveia, Miguel; Cardoso, José Carlos; Tellechea, Oscar

2016-01-01

Rosai-Dorfman disease is a benign histiocytic proliferative disorder of unknown etiology. The disease mainly affects lymph node tissue, although it is rarely confined to the skin. Here, we describe a 53-year-old woman with purely cutaneous Rosai-Dorfman disease. The patient presented with a large pigmented plaque on her left leg, and sparse erythematous papules on her face and arms. A complete clinical response was achieved with thalidomide, followed by recurrence at the initial site one year later. The histological examination displayed the typical features of Rosai-Dorfman disease in the recent lesions but not in the older lesions. In the setting of no lymphadenopathy, the histopathological features of Rosai-Dorfman disease are commonly misinterpreted. Therefore, awareness of the histological aspects present at different stages, not always featuring the hallmark microscopic signs of Rosai-Dorfman disease, is particularly important for a correct diagnosis of this rare disorder.

Management of paraproteinaemia

PubMed Central

Cook, Lucy; Macdonald, Donald H C

2007-01-01

A paraprotein is a monoclonal immunoglobulin or light chain present in the blood or urine; it is produced by a clonal population of mature B cells, most commonly plasma cells. In individuals aged >50 years the incidence of a paraprotein is 3.2%. Plasma cell disorders can be considered as a spectrum of conditions ranging from monoclonal gammopathy of undetermined significance (MGUS), through asymptomatic, to symptomatic myeloma. MGUS is defined by a low level of paraprotein <30 g/l, bone marrow plasma cells <10% and the absence of myeloma related organ or tissue damage (predominantly renal, skeletal or bone marrow impairment.) MGUS requires no therapy and the overall risk of progression to myeloma is 1% per year. Myeloma remains incurable with a median survival of 3–4 years; autologous stem cell transplant can prolong survival, if appropriate. Thalidomide in combination with dexamethasone has an emerging role in the treatment of myeloma. PMID:17403946

Mechanism of auditory hypersensitivity in human autism using autism model rats.

PubMed

Ida-Eto, Michiru; Hara, Nao; Ohkawara, Takeshi; Narita, Masaaki

2017-04-01

Auditory hypersensitivity is one of the major complications in autism spectrum disorder. The aim of this study was to investigate whether the auditory brain center is affected in autism model rats. Autism model rats were prepared by prenatal exposure to thalidomide on embryonic day 9 and 10 in pregnant rats. The superior olivary complex (SOC), a complex of auditory nuclei, was immunostained with anti-calbindin d28k antibody at postnatal day 50. In autism model rats, SOC immunoreactivity was markedly decreased. Strength of immunostaining of SOC auditory fibers was also weak in autism model rats. Surprisingly, the size of the medial nucleus of trapezoid body, a nucleus exerting inhibitory function in SOC, was significantly decreased in autism model rats. Auditory hypersensitivity may be, in part, due to impairment of inhibitory processing by the auditory brain center. © 2016 Japan Pediatric Society.

Risk, statistical inference, and the law of evidence: the use of epidemiological data in toxic tort cases.

PubMed

Brannigan, V M; Bier, V M; Berg, C

1992-09-01

Toxic torts are product liability cases dealing with alleged injuries due to chemical or biological hazards such as radiation, thalidomide, or Agent Orange. Toxic tort cases typically rely more heavily than other product liability cases on indirect or statistical proof of injury. There have been numerous theoretical analyses of statistical proof of injury in toxic tort cases. However, there have been only a handful of actual legal decisions regarding the use of such statistical evidence, and most of those decisions have been inconclusive. Recently, a major case from the Fifth Circuit, involving allegations that Benedectin (a morning sickness drug) caused birth defects, was decided entirely on the basis of statistical inference. This paper examines both the conceptual basis of that decision, and also the relationships among statistical inference, scientific evidence, and the rules of product liability in general.

A cybernetic theory of morality and moral autonomy.

PubMed

Chambers, J

2001-04-01

Human morality may be thought of as a negative feedback control system in which moral rules are reference values, and moral disapproval, blame, and punishment are forms of negative feedback given for violations of the moral rules. In such a system, if moral agents held each other accountable, moral norms would be enforced effectively. However, even a properly functioning social negative feedback system could not explain acts in which individual agents uphold moral rules in the face of contrary social pressure. Dr. Frances Kelsey, who withheld FDA approval for thalidomide against intense social pressure, is an example of the degree of individual moral autonomy possible in a hostile environment. Such extreme moral autonomy is possible only if there is internal, psychological negative feedback, in addition to external, social feedback. Such a cybernetic model of morality and moral autonomy is consistent with certain aspects of classical ethical theories.

Serum free light chains in myeloma patients with an intact M-protein by immunofixation: potential roles for response assessment and prognosis during induction therapy with novel agents

PubMed Central

Mori, Sherry; Crawford, Brooke S; Roddy, Julianna VF; Phillips, Gary; Elder, Pat; Hofmeister, Craig C; Efebera, Yvonne; Benson, Don M

2013-01-01

The ascertainment of serum free light chain levels (sFLC) has been shown to be valuable in screening for the presence of plasma cell dyscrasia as well as for baseline prognosis in newly diagnosed patients. For patients with amyloidosis and those with oligo- or non-secretory multiple myeloma (MM), serial measurement of sFLC has also been shown to be valuable in monitoring disease status. However, in patients with a measureable, intact monoclonal protein by immunofixation (M protein), the serial measurement of sFLC remains undefined and is currently not recommended in professional guidelines. Herein, we provide data comparing sFLC to M protein as biomarkers of response in newly-diagnosed patients with MM undergoing induction therapy with the novel agents thalidomide, lenalidomide and/or bortezomib. We show that while M protein appears to outperform sFLC comparatively over the course of induction therapy, the addition of FLC to M-protein further informs the characterization of residual disease status post-induction. Moreover, sFLC at the time of stem cell mobilization appears to hold prognostic power for survival endpoints following HDC/SCT. These findings suggest potentially novel roles for sFLC in patients with MM with an intact M-protein receiving novel agent-based induction strategies followed by HDC/SCT. PMID:22028144

A phase 2 trial of lenalidomide, bortezomib, and dexamethasone in patients with relapsed and relapsed/refractory myeloma

PubMed Central

Xie, Wanling; Jagannath, Sundar; Jakubowiak, Andrzej; Lonial, Sagar; Raje, Noopur S.; Alsina, Melissa; Ghobrial, Irene M.; Schlossman, Robert L.; Munshi, Nikhil C.; Mazumder, Amitabha; Vesole, David H.; Kaufman, Jonathan L.; Colson, Kathleen; McKenney, Mary; Lunde, Laura E.; Feather, John; Maglio, Michelle E.; Warren, Diane; Francis, Dixil; Hideshima, Teru; Knight, Robert; Esseltine, Dixie-Lee; Mitsiades, Constantine S.; Weller, Edie; Anderson, Kenneth C.

2014-01-01

In this prospective, multicenter, phase 2 study, 64 patients with relapsed or relapsed and refractory multiple myeloma (MM) received up to 8 21-day cycles of bortezomib 1.0 mg/m2 (days 1, 4, 8, and 11), lenalidomide 15 mg/day (days 1-14), and dexamethasone 40/20 mg/day (cycles 1-4) and 20/10 mg/day (cycles 5-8) (days of/after bortezomib dosing). Responding patients could receive maintenance therapy. Median age was 65 years; 66% were male, 58% had relapsed and 42% had relapsed and refractory MM, and 53%, 75%, and 6% had received prior bortezomib, thalidomide, and lenalidomide, respectively. Forty-eight of 64 patients (75%; 90% confidence interval, 65-84) were alive without progressive disease at 6 months (primary end point). The rate of partial response or better was 64%; median duration of response was 8.7 months. Median progression-free and overall survivals were 9.5 and 30 months, respectively (median follow-up: 44 months). Common treatment-related toxicities included sensory neuropathy (53%), fatigue (50%), and neutropenia (42%); common grade 3/4 treatment-related toxicities included neutropenia (30%), thrombocytopenia (22%), and lymphopenia (11%). Grade 3 motor neuropathy was reported in 2 patients. Lenalidomide-bortezomib-dexamethasone appears effective and tolerable in patients with relapsed or relapsed and refractory MM, demonstrating substantial activity among patients with diverse prior therapies and adverse prognostic characteristics. This trial is registered with www.clinicaltrials.gov as #NCT00378209. PMID:24429336

Lenalidomide for refractory cutaneous manifestations of pediatric systemic lupus erythematosus.

PubMed

Wu, E Y; Schanberg, L E; Wershba, E C; Rabinovich, C E

2017-05-01

Objective Cutaneous manifestations of pediatric systemic lupus erythematosus cause significant morbidity. Lenalidomide, a thalidomide analogue, has shown promise treating cutaneous lupus erythematosus in adults. Our objective was to evaluate lenalidomide's efficacy and safety in treating refractory cutaneous manifestations of pediatric systemic lupus erythematosus. Methods We performed a retrospective chart review of 10 adolescents who received lenalidomide for recalcitrant cutaneous lupus erythematosus. Information was gathered at drug initiation and 6-month follow-up. The Wilcoxon matched-pairs signed-rank test was used to assess change in quantitative parameters of disease activity. Results Nine subjects were girls and six were African-American. Indications for lenalidomide treatment included alopecia, nasal and oral ulcers, extensive malar rash, discoid lesions, bullous lesions, panniculitis, cutaneous vasculitis, and Raynaud's phenomenon with digital ulcerations. Within 6 months, all patients demonstrated complete or near resolution based on physician report. Prednisone dose decreased from a mean 23.5 mg (SD± 13.3) to 12.25 mg (SD± 9.2) ( P= 0.008). Sedimentation rate decreased from a mean 29 mm/hour (SD± 31.5) to 17 mm/hour (SD± 18.1) ( P= 0.004). Lenalidomide was well tolerated. Conclusion Lenalidomide is an effective and safe treatment for a spectrum of dermatological conditions in pediatric systemic lupus erythematosus. Its use may allow a reduction in prednisone dose and decreased disfigurement. Prospective study is needed to clarify lenalidomide's role in treating cutaneous manifestations of systemic lupus erythematosus.

A missense mutation in the CRBN gene that segregates with intellectual disability and self-mutilating behaviour in a consanguineous Saudi family

PubMed Central

Sheereen, Atia; Alaamery, Manal; Bawazeer, Shahad; Al Yafee, Yusra; Massadeh, Salam; Eyaid, Wafaa

2017-01-01

Background Autosomal-recessive non-syndromic intellectual disability (ARNS-ID) is an aetiologically heterogeneous disorder. Although little is known about the function of human cereblon (CRBN), its relationship to mild cognitive deficits suggests that it is involved in the basic processes of human memory and learning. Objectives We aim to identify the genetic cause of intellectual disability and self-mutilation in a consanguineous Saudi family with five affected members. Methods Clinical whole-exome sequencing was performed on the proband patient, and Sanger sequencing was done to validate and confirm segregation in other family members. Results A missense variant (c. 1171T>C) in the CRBN gene was identified in five individuals with severe intellectual disability (ID) in a consanguineous Saudi family. The homozygous variant was co-segregating in the family with the phenotype of severe ID, seizures and self-mutilating behaviour. The missense mutation (p.C391R) reported here results in the replacement of a conserved cysteine residue by an arginine in the CULT (cereblon domain of unknown activity, binding cellular ligands and thalidomide) domain of CRBN, which contains a zinc-binding site. Conclusions These findings thus contribute to a growing list of ID disorders caused by CRBN mutations, broaden the spectrum of phenotypes attributable to ARNS-ID and provide new insight into genotype–phenotype correlations between CRBN mutations and the aetiology of ARNS-ID. PMID:28143899

[Influence of inflammatory bowel disease on pregnancy and fertility - optimal treatment and management].

PubMed

Kierkuś, Jarosław; Szymańska, Edyta; Szymańska, Sylwia; Kamińska, Ewa

2013-01-01

Inflammatory bowel diseases (IBD) affect mainly the young population and therefore fertility and pregnancy-related issues are important clinical considerations. Generally, men and women with IBD do not have decreased fertility compared to the general population. Drugs used for IBD do not affect significantly fertility in humans, except sulfasalazine, which causes a temporary reduction in spermatogenesis, but does not reduce fertility itself. The disease course during pregnancy and the risk of pregnancy-related complications depend mainly on the disease activity at the time of conception, therefore, pregnancy should be planned during a phase of remission. Except for methotrexate, mycophenolate mofetil and thalidomide, which are strongly contraindicated, drugs used for IBD appear safe in pregnancy, if they are administered carefully. The highest degree of safety was proved for 5-ASA- -containing agents, thiopurines and corticosteroids. The use of TNFα agents remains disputable, especially in the third trimester of pregnancy, due to their high concentration in the infant`s blood and the lack of data concerning its long-term safety. Surgery, if necessary, should be delayed if possible, although pregnancy is not a contraindication for surgical procedures. The management of IBD in reproductive age and pregnant women remains still controversial, because literature data comes mostly from retrospective studies. The aim of this paper was to summarize and to present proper management of patients with IBD prior to conception, as well as pregnant women and breast-feeding mothers with IBD, based on current European Crohn's and Colitis Organisation (ECCO) guidelines and available literature.

[Response and prognosis of patients with multiple myeloma induced by PAD/TAD].

PubMed

Zeng, Tianmei; He, Haiyan; Shi, Haotian; Xi, Hao; Du, Juan; Zhang, Chunyang; Jiang, Hua; Fu, Weijun; Zhou, Fan; Hou, Jian

2015-03-17

To evaluate the impact of cytogenetic grouping and autologous stem cell transplantation on the prognosis of patients with multiple myeloma (MM) induced by PAD (velcade+epirubicin+dexamethasone) and TAD (thalidomide+epirubicin+dexamethasone). A total of 191 patients with a definite diagnosis of MM were enrolled from May 2008 to December 2013 into this prospective study. They were non-randomly induced by PAD (n = 132) or TAD (n = 59) plus autologous stem cell transplantation or chemotherapy. Response and survival rates were also analyzed between two groups. The overall response rates of PAD and TAD groups were 84.4% (108/128) and 69.5% (41/59) (P = 0.011) respectively. The very good partial remission (VGPR) rates were 70.3% (90/128) and 32.2% (19/59) (P < 0.001) and near complete remission/complete remission (nCR/CR) rates 68.0% (87/128) and 25.4% (15/59) respectively (P < 0.001). Both progression-free survival (PFS) and overall survival (OS) showed no significant inter-group difference (P = 0.223, 0.989). The survival analysis of PAD group showed that FISH high-risk group had shorter PFS and OS than FISH low-risk group (15.2 vs 19.1 months for PFS, P = 0.098; 41.2 months vs non-attaining for OS, P = 0.017). In FISH high-risk group, patients consolidated with autologous stem cell transplantation showed longer PFS than those with chemotherapy (17.8 vs 14.6 months, P = 0.029) while the OS showed no difference (P = 0.840). In FISH low-risk group, no difference were observed in PFS and OS between patients with consolidation therapies alone (P = 0.131, 0.294). The response rates are higher in patients induced by PAD than by TAD. After PAD induction, cytogenetic grouping may further distinguish the prognosis of MM patients. For FISH high-risk patients, their PFS is prolonged by autologous stem cell transplantation.

Novel therapy in multiple myeloma.

PubMed

Avilés, Agustin; Neri, Natividad; Nambo, M Jesús; Cleto, Sergio; Castañeda, Claudia; González, Martha; Talavera, Alejandra; Huerta-Guzmán, Judith

2005-10-01

Treatment in patients with multiple myeloma remain to be defined. Younger patients (defined as a cut-off level < 65 years old) will be treated with chemotherapy and transplant procedures. However, most patients > 65 years old are not candidates for this therapeutic approach and the use of intensive chemotherapy could be associated to severe toxicity. We developed an new, not-cytotoxic regimen with dexamethasone 30 mg/m(2), iv, days 1 to 4, all trans retinoic acid 45 mg/m(2), po, days 5 to 14 and interferon alfa 2a 4.5 MU, sc, daily, days 5 to 14 (DAI regimen) administered every 28 days in number of 6 cycles, at this point patients were restaging, if they showed complete response, objective response or partial response they were conducted to received thalidomide 100-200 mg po, daily and dexamethasone 10 mg/2, po days 1 to 4 at monthly intervals, for 18 months. Forty one patients were enrolled in an Phase II study. In an intent to treat analysis all patients were evaluable. Complete response was observed in 18 cases (43%), objective response in 10 patients (24%) and partial response in 5 patients (12%), overall response rate was 80%. Eight patients were considered failures. At an median of 36 months, no relapse of progression disease has been observed, thus actuarial curves at 3-years showed that event free survival is 100% and overall survival is 91%. Toxicity was mild, all patients received the planned dose in time. This regimen appear to be useful in older patients with multiple myeloma, the response rate is higher and toxicity was mild. Controlled clinical trials comparing with conventional chemotherapy will be conducted to define the role of this therapeutic approach.

LDH is an adverse prognostic factor independent of ISS in transplant-eligible myeloma patients receiving bortezomib-based induction regimens.

PubMed

Chim, Chor Sang; Sim, Joycelyn; Tam, Sidney; Tse, Eric; Lie, Albert Kwok Wai; Kwong, Yok Lam

2015-04-01

Serum lactate dehydrogenase (LDH) has been an adverse prognostic factor for myeloma but does not feature in the International Staging System (ISS). We examined whether elevated serum LDH at diagnosis remains an adverse risk factor independent of ISS for survivals transplant-eligible myeloma patients receiving early/frontline bortezomib-based induction, followed by autologous stem cell transplantation (ASCT). Seventy-seven transplant-eligible Chinese patients received three induction regimens [staged approach (N = 25), PAD (N = 19), VTD (N = 33)], followed by ASCT and thalidomide maintenance. Five-year overall (OS) and event-free (EFS) survivals were 66.4% and 36.2%. There was no difference in demographics, complete remission/near complete remission (CR/nCR rates postinduction or ASCT, and survivals among patients induced by the three induction regimens. Elevated LDH was associated with male gender (P = 0.006), ISS III (P = 0.042) and serum β2-microglobulin (P = 0.040). Univariate analysis showed that elevated LDH, ISS III, high β2-microglobulin, and failure to attain CR/nCR post-ACST were risk factors adversely impacting both OS and EFS. Multivariate analysis showed that elevated LDH was the only factor impacting both OS (P = 0.007) and EFS (P = 0.008). In this uniformly treated cohort of transplant-eligible myeloma patients, elevated serum LDH is an adverse risk factor independent of ISS for both OS and EFS. Bortezomib-based induction/ASCT regimen had not abolished the adverse impact of elevated LDH. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chromothripsis and epigenomics complete causality criteria for cannabis- and addiction-connected carcinogenicity, congenital toxicity and heritable genotoxicity.

PubMed

Reece, Albert Stuart; Hulse, Gary Kenneth

2016-07-01

The recent demonstration that massive scale chromosomal shattering or pulverization can occur abruptly due to errors induced by interference with the microtubule machinery of the mitotic spindle followed by haphazard chromosomal annealing, together with sophisticated insights from epigenetics, provide profound mechanistic insights into some of the most perplexing classical observations of addiction medicine, including cancerogenesis, the younger and aggressive onset of addiction-related carcinogenesis, the heritability of addictive neurocircuitry and cancers, and foetal malformations. Tetrahydrocannabinol (THC) and other addictive agents have been shown to inhibit tubulin polymerization which perturbs the formation and function of the microtubules of the mitotic spindle. This disruption of the mitotic machinery perturbs proper chromosomal segregation during anaphase and causes micronucleus formation which is the primary locus and cause of the chromosomal pulverization of chromothripsis and downstream genotoxic events including oncogene induction and tumour suppressor silencing. Moreover the complementation of multiple positive cannabis-cancer epidemiological studies, and replicated dose-response relationships with established mechanisms fulfils causal criteria. This information is also consistent with data showing acceleration of the aging process by drugs of addiction including alcohol, tobacco, cannabis, stimulants and opioids. THC shows a non-linear sigmoidal dose-response relationship in multiple pertinent in vitro and preclinical genotoxicity assays, and in this respect is similar to the serious major human mutagen thalidomide. Rising community exposure, tissue storage of cannabinoids, and increasingly potent phytocannabinoid sources, suggests that the threshold mutagenic dose for cancerogenesis will increasingly be crossed beyond the developing world, and raise transgenerational transmission of teratogenicity as an increasing concern. Copyright © 2016 Elsevier B.V. All rights reserved.

A review of supernumerary and absent limbs and digits of the upper limb.

PubMed

Klaassen, Zachary; Choi, Monica; Musselman, Ruth; Eapen, Deborah; Tubbs, R Shane; Loukas, Marios

2012-03-01

For years people have been enamored by anomalies of the human limbs, particularly supernumerary and absent limbs and digits. Historically, there are a number of examples of such anomalies, including royal families of ancient Chaldea, tribes from Arabia, and examples from across nineteenth century Europe. The development of the upper limbs in a growing embryo is still being elucidated with the recent advent of homeobox genes, but researchers agree that upper limbs develop between stages 12-23 through a complex embryological process. Maternal thalidomide intake during limb development is known to cause limb reduction and subsequent amelia or phocomelia. Additionally, a number of clinical reports have illustrated different limb anomaly cases, with each situation unique in phenotype and developmental abnormality. Supernumerary and absent limbs and digits are not unique to humans, and a number of animal cases have also been reported. This review of the literature illustrates the historical, anatomical, and clinical aspects of supernumerary and absent limbs and digits for the upper limb.

Drug safety: withdrawn medications are only part of the picture.

PubMed

Rawson, Nigel S B

2016-02-13

In a research article published in BMC Medicine, Onakpoya and colleagues provide a historical review of withdrawals of medications for safety reasons. However, withdrawn medications are only one part of the picture about how regulatory agencies manage drug risks. Moreover, medications introduced before the increased pre-marketing regulations and post-marketing monitoring systems instituted after the thalidomide tragedy have little relevance when considering the present drug safety picture because the circumstances under which they were introduced were completely different. To more fully understand drug safety management and regulatory agency actions, withdrawals should be evaluated within the setting and timeframe in which the medications are approved, which requires information about approvals and safety warnings. Studies are needed that provide a more comprehensive current picture of the identification and evaluation of drug safety risks as well as how regulatory agencies deal with them. Please see related research article: http://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0553-2.

The impact of HIV infection on society's perception of clinical trials.

PubMed

Levine, R J

1994-06-01

All international codes of research ethics and virtually all national legislation and regulation in the field of research involving human subjects project an attitude of protectionism. Written with the aim of avoiding a repetition of atrocities like those committed by the Nazi physician-researchers, calamities like the thalidomide experience, or ethical violations like those of the Tuskegee syphilis study, their dominant concerns are the protection of individuals from injury and from exploitation. In recent years, however, society's perception of clinical research has shifted dramatically. Now, largely as a consequence of the efforts of the AIDS activists, clinical research is widely perceived as benign and beneficial. Although this shift in attitude has resulted in some important improvements in research policies and practices, this new perception is just as wrong-headed as was the earlier excessive protectionism. It is necessary to maintain a balanced perspective; our policies should encourage the conduct of ethical research while maintaining the vigilance necessary to safeguard the rights and welfare of the subjects.

From the bench to the bedside: emerging new treatments in multiple myeloma

PubMed Central

Mitsiades, Constantine S.; Hayden, Patrick J.; Anderson, Kenneth C.; Richardson, Paul G.

2012-01-01

Within the last decade, several novel classes of anti-myeloma therapeutics have become available. The clinical successes achieved by thalidomide, lenalidomide, and the proteasome inhibitor bortezomib, and in particular the ability of these agents to lead to major clinical responses in patients resistant to conventional or high-dose chemotherapy, have highlighted the importance of expanding even further the spectrum of classes of agents utilized for the treatment of myeloma. Herein, we review the current state of the field of development of novel anti-myeloma agents, with emphasis on classes of therapeutics which have already translated into clinical trials or those in advanced stages of preclinical development. These include second-generation proteasome inhibitors (NPI-0052 and PR-171), heat shock protein 90 (hsp90) inhibitors, 2-methoxyestradiol, histone deacetylase (HDAC) inhibitors (e.g. SAHA, tubacin and LBH589), fibroblast growth factor receptor 3 (FGF-R3) inhibitors, insulin-like growth factor 1 receptor (IGF-1R) inhibitors, mTOR inhibitors, monoclonal antibodies, and agents targeting the tumor microenvironment, including defibrotide. PMID:18070720

Therapy of spondylarthropathy in inflammatory bowel disease.

PubMed

Generini, S; Fiori, G; Matucci Cerinic, M

2002-01-01

Musculoskeletal manifestations represent the most common extra-intestinal complication of inflammatory bowel diseases (IBD) and are usually included in the clinical spectrum of the spondyloarthropathies (SpA). Although control of intestinal inflammation often ameliorates articular symptoms, sometimes arthropathy is independent of the gut disease course and may require the same therapeutic options which apply to primary SpA diseases, but with caution so as not aggravate the IBD. At the moment, salicylates (sulphasalazine and mesalazine) and selective COX-2 inhibitors (which are preferable to traditional NSAIDs although they cannot be assumed to be safe for the gastrointestinal tract) are the first choice treatment. Several immunosuppressive and biological agents including methotrexate, thalidomide and TNFalpha antagonists have efficacy for both articular and intestinal inflammation and are currently in use for the induction of remission and for maintenance in more severe cases. New combination therapies and novel biologically-driven treatments, targeted to specific pathophysiological processes, might offer less toxicity and the potential for better treatment outcomes.

Profiles in drug metabolism and toxicology: Richard Tecwyn Williams (1909-1979).

PubMed

Jones, Alan Wayne

2015-01-01

This article pays homage to the life and work of a veritable pioneer in toxicology and drug metabolism, namely a Welshman, Richard Tecwyn Williams, FRS. Professor Williams, or RT as he was known, made major contributions to knowledge about the metabolism and toxicology of drugs and xenobiotics during a scientific career spanning nearly 50 years. Author or coauthor of close to 400 research articles and reviews, including a classic book, entitled Detoxication Mechanisms, Williams and his research school investigated virtually all aspects of drug metabolism, especially conjugations. In particular, the concepts of phase 1 and phase II metabolic pathways were introduced by Williams; the biliary excretion of drugs was extensively studied as were species differences in drug metabolism and detoxication. Besides investigating the metabolism of many pharmaceutical drugs, such as sulfonamides and thalidomide, Williams and his group investigated the disposition and fate in the body of organic pesticides and recreational drugs of abuse, such as amphetamine, methamphetamine and lysergic acid diethylamide (LSD).

[Classification and etiology of hyperthyroidism].

PubMed

Łacka, Katarzyna; Fraczek, Magdalena Maria

2014-03-01

The prevalence of hyperthyroidism in women is between 0.5-2% and it is 10 times less common in men. The most common causes are Graves' disease, toxic multinodular goiter, and autonomously functioning thyroid adenoma. Rare causes of hyperthyroidisms are as follow: pituitary adenoma, autoimmune thyroiditis (Hashitoxicosis), levothyroxine overdose, inadequate iodine supplementation (including amiodaron induced hyperthyroidism, iodine-based contrast media), hCG excess (pregnancy, gestational trophoblastic disease, germ-cell tumors), drug induced hyperthyroidism, differentiated thyroid carcinomas and/or their metastases, struma ovarii, and familial nonautoimmune hyperthyroidism. This article focuses on the current data of etiopathogenesis of hyperthyroidisms. Genetic factors (like HLA-DR3,CD40, CTLA-4, PTPN22, FOXP3 CD25) and thyroid specific genes (thyroglobulin, TSHR, G(s)alpha) and environmental and endogenous factors (such as age, iodine, selenium, emotional stress, smoking, gender, pregnancy, sex hormones, fetal microchimerism, fetal growth, bacterial infections, viral infections, allergies, drugs (alemtuzumab, interferon alpha, iplimumab/tremelimumab, tyrosine kinase inhibitors, denileukindiftitox, thalidomide/lenalidomide, exposition to fallout and radiotherapy) have been described.

A Patient with Erythema Nodosus Leprosum and Chagas Cardiopathy: Challenges in Patient Management and Review of the Literature

PubMed Central

Trindade, Maria Ângela B.; Carvalho, Noemia B.; Belfort, Elaini C.; Pagliari, Carla; Gakiya, Erika; Sakai-Valente, Neusa Y.; Benard, Gil; Shikanai-Yasuda, Maria A.

2011-01-01

We report a patient with severe multi-bacillary leprosy complicated by recurrent episodes of erythema nodosum necrotisans that required thalidomide and/or corticosteroids during follow-up. Although the patient was from an area to which Chagas disease is endemic, this diagnosis was initially missed and was only investigated when heart failure developed in the patient. The difficulties of managing erythema nodosum necrotisans and heart failure concomitantly and those involved in excluding the diagnosis of acute myocarditis caused by reactivation of Chagas disease secondary to the immunosuppressive regimen are discussed. Other potential causes for the heart failure and possible interactions between the two diseases and their treatments are discussed. We also reviewed the literature for the association between leprosy and Chagas disease, both of which are highly endemic in Brazil. This case emphasizes the importance of searching for subclinical co-infections in leprosy patients because reactions frequently develop during specific treatment in these patients, and these reactions require prolonged therapy with immunosuppressive drugs. PMID:21633036

[Subcutaneous bortezomib as a new promising way to successful maintenance therapy in multiple myeloma].

PubMed

Grosicki, Sebastian

2012-01-01

Multiple myeloma (MM) despite the introduction to clinical practice of a new drugs in the last years, and still searching of new points of the handle for targeting treatment, remaining incurable disease. Even most intensive and most modern induction-consolidation regimens is not in the state to eradicate of the clone of myeloma, and even complete remission in immunofixation the most often after some time ends progression. Optimal way of maintenance treatment is still searching, which would be maximally effective near acceptable toxicity. Now hypothesis about possible successful maintenance therapy, which may prolong survival of MM patients became more actual in the face of the introduction to the studies with maintenance of a new drugs as: thalidomide, lenalidomide and bortesomib. The expectations on the essential progress to establish the optimal bortesomib-based regimen of the maintenance treatment in MM cause the results of the studies with its subcutaneous administration, which proved comparable efficacy with advantage in toxicity profile, especially neurological in comparison to classic intravenous way.

A missense mutation in the CRBN gene that segregates with intellectual disability and self-mutilating behaviour in a consanguineous Saudi family.

PubMed

Sheereen, Atia; Alaamery, Manal; Bawazeer, Shahad; Al Yafee, Yusra; Massadeh, Salam; Eyaid, Wafaa

2017-04-01

Autosomal-recessive non-syndromic intellectual disability (ARNS-ID) is an aetiologically heterogeneous disorder. Although little is known about the function of human cereblon (CRBN), its relationship to mild cognitive deficits suggests that it is involved in the basic processes of human memory and learning. We aim to identify the genetic cause of intellectual disability and self-mutilation in a consanguineous Saudi family with five affected members. Clinical whole-exome sequencing was performed on the proband patient, and Sanger sequencing was done to validate and confirm segregation in other family members. A missense variant (c. 1171T>C) in the CRBN gene was identified in five individuals with severe intellectual disability (ID) in a consanguineous Saudi family. The homozygous variant was co-segregating in the family with the phenotype of severe ID, seizures and self-mutilating behaviour. The missense mutation (p.C391R) reported here results in the replacement of a conserved cysteine residue by an arginine in the CULT (cereblon domain of unknown activity, binding cellular ligands and thalidomide) domain of CRBN, which contains a zinc-binding site. These findings thus contribute to a growing list of ID disorders caused by CRBN mutations, broaden the spectrum of phenotypes attributable to ARNS-ID and provide new insight into genotype-phenotype correlations between CRBN mutations and the aetiology of ARNS-ID. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

The Clinical Presentation and Management of Systemic Light-Chain Amyloidosis in China.

PubMed

Huang, Xiang-Hua; Liu, Zhi-Hong

2016-04-01

Amyloidosis includes a group of diseases characterized by the extracellular deposition of various fibrillary proteins that can autoaggregate in a highly abnormal fibrillary conformation. The amyloid precursor protein of systemic light-chain (AL) amyloidosis is comprised of monoclonal light chains that are due to plasma cell dyscrasia. The clinical presentation of patients with AL amyloidosis varies from patient to patient. Current treatment strategies target the clone in order to decrease the production of the pathologic light chains. Recent advances in therapy have helped many patients with AL amyloidosis achieve hematologic and organ responses. AL amyloidosis is the most common type of systemic amyloidosis in China with increasing morbidity and a high mortality rate. The clinical presentation of AL amyloidosis is variable, and the median overall survival was found to be 36.3 months. The disease prognosis and risk stratification are linked to serialized measurement of cardiac biomarkers and free light chains. The treatment of AL amyloidosis is mainly based on chemotherapy and autologous hematopoietic stem cell transplantation (ASCT). The use of novel agents (thalidomide, lenalidomide, and bortezomib) alone and in combination with steroids and alkylating agents has shown efficacy and continues to be explored. AL amyloidosis is the most common type of systemic amyloidosis in China with increasing morbidity and a high mortality rate. The lack of prospective clinical trials using the current therapies is a challenge for evidence-based decision making concerning the treatment of AL amyloidosis. (1) AL amyloidosis is the most prevalent type of amyloidosis accounting for 65% of the amyloidosis-diagnosed patients in the UK and for 93% of the amyloidosis-diagnosed patients in China. The predisposition of men over women to develop AL amyloidosis might be higher in China than in Western countries (2:1 vs. 1.3:1). Both in the East and West, incidence increases with age. At the time of diagnosis, edema is twice as frequent and the proportion of renal involvement is higher in Chinese compared to Western patients. (2) Melphalan followed by ASCT is the current standard therapy but is restricted to eligible patients. The efficacy and safety of bortezomib combined with dexamethasone were proven in Western patients and recently confirmed in a Chinese cohort. Recent studies in China and the US indicate that bortezomib induction prior to ASCT increases the response rate. Thalidomide and lenalidomide have shown benefit, but toxicity and lack of clinical evidence exclude these agents from first-line therapy. The green tea extract epigallocatechin-3-gallate is under investigation as an inhibitor of AL amyloid formation and a compound that might dissolve amyloid.

Optimization of the treatment with immunosuppressants and biologics in inflammatory bowel disease

PubMed Central

Renna, Sara; Cottone, Mario; Orlando, Ambrogio

2014-01-01

Many placebo controlled trials and meta-analyses evaluated the efficacy of different drugs for the treatment of inflammatory bowel disease (IBD), including immunosuppressants and biologics. Their use is indicated in moderate to severe disease in non responders to corticosteroids and in steroid-dependent patients, as induction and maintainance treatment. Infliximab, as well as cyclosporine, is considered a second line therapy in the case of severe ulcerative colitis, or non-responders to intravenous corticosteroids. An adequate dosage and duration of therapy with thiopurines should be reached before evaluating their efficacy. Methotrexate is a valid option in patients with Crohn’s disease but its use is confined to patients who are intolerant or non-responders to thiopurines. Evidence for the use of methotrexate in ulcerative colitis is insufficient. The use of thalidomide and mycophenolate mofetil is not recommended in patients with inflammatory bowel disease, these treatments could be considered in case of failure of all other therapeutic options. In patients with moderately active ulcerative colitis, refractory to thiopurines, the use of tacrolimus is considered an alternative to biologics. An increase of the dose or a decrease in the interval of administration of biological treatment could be useful in the presence of an incomplete clinical response. In the case of primary failure of an anti-tumor necrosis factor alpha a switch to another one should be considered. Data on the efficacy of combination therapy are up to now insufficient to consider this strategy in all IBD patients. The final outcome of the treatment should be considered the clinical remission, with mucosa healing, and not the clinical response. The evaluation of serum concentration of thiopurine methyl transferase activity, thiopurine metabolites, biologic serum levels and antibiologic antibodies could be useful for the management of the treatment but it has not been routinely applied in clinical practice. The evidence of high risk development of lymphoma and cutaneous malignancies should be considered in patients treated with immunosuppressants and biologics for a long period. PMID:25110407

Effective Drug Delivery in Diffuse Intrinsic Pontine Glioma: A Theoretical Model to Identify Potential Candidates

PubMed Central

El-Khouly, Fatma E.; van Vuurden, Dannis G.; Stroink, Thom; Hulleman, Esther; Kaspers, Gertjan J. L.; Hendrikse, N. Harry; Veldhuijzen van Zanten, Sophie E. M.

2017-01-01

Despite decades of clinical trials for diffuse intrinsic pontine glioma (DIPG), patient survival does not exceed 10% at two years post-diagnosis. Lack of benefit from systemic chemotherapy may be attributed to an intact bloodbrain barrier (BBB). We aim to develop a theoretical model including relevant physicochemical properties in order to review whether applied chemotherapeutics are suitable for passive diffusion through an intact BBB or whether local administration via convection-enhanced delivery (CED) may increase their therapeutic potential. Physicochemical properties (lipophilicity, molecular weight, and charge in physiological environment) of anticancer drugs historically and currently administered to DIPG patients, that affect passive diffusion over the BBB, were included in the model. Subsequently, the likelihood of BBB passage of these drugs was ascertained, as well as their potential for intratumoral administration via CED. As only non-molecularly charged, lipophilic, and relatively small sized drugs are likely to passively diffuse through the BBB, out of 51 drugs modeled, only 8 (15%)—carmustine, lomustine, erlotinib, vismodegib, lenalomide, thalidomide, vorinostat, and mebendazole—are theoretically qualified for systemic administration in DIPG. Local administration via CED might create more therapeutic options, excluding only positively charged drugs and drugs that are either prodrugs and/or only available as oral formulation. A wide variety of drugs have been administered systemically to DIPG patients. Our model shows that only few are likely to penetrate the BBB via passive diffusion, which may partly explain the lack of efficacy. Drug distribution via CED is less dependent on physicochemical properties and may increase the therapeutic options for DIPG. PMID:29164054

Lenalidomide in multiple myeloma: an evidence-based review of its role in therapy

PubMed Central

Richardson, Paul; Mitsiades, Constantine; Laubach, Jacob; Schlossman, Robert; Ghobrial, Irene; Hideshima, Teru; Munshi, Nikhil; Anderson, Kenneth

2010-01-01

Introduction: Multiple myeloma (MM) is a relatively common and incurable hematological malignancy. Currently, there is no single standard therapy, with choice of treatment dependent on individual patient factors. Lenalidomide is an immunomodulatory drug with potent antitumor, antiangiogenic, immunomodulatory, and proapoptotic activity in MM. Aims: To evaluate the evidence for the use of lenalidomide in its current indication in relapsed or refractory MM, and additionally its investigational use for the treatment of newly diagnosed MM. Evidence review: In patients with relapsed and refractory MM, adding lenalidomide to high-dose dexamethasone significantly improves response rates and time-to-progression, relative to high-dose dexamethasone alone. This translates into a significant extension of overall survival (with a median extension of 9.1 months in a pivotal phase III study). Outcome is independent of patient age, number of previous therapies, type of previous therapy (including thalidomide or autologous stem cell transplantation), renal impairment, and β2-microglobulin level. Evidence suggests that combining lenalidomide with low-dose dexamethasone improves outcomes in patients with newly diagnosed disease and is superior to lenalidomide combined with high-dose dexamethasone. Myelosuppression is the predominant toxicity observed, although some studies have shown high incidences of venous thromboembolism in the absence of prophylactic antithrombotic anticoagulation therapy. There is currently only limited evidence regarding the health economics of lenalidomide. Role in therapy: The encouraging results obtained with lenalidomide alone and in combination with dexamethasone in patients with relapsed or refractory MM have led to its adoption as a recommended therapy in patients who have received at least one prior treatment. Emerging evidence supports the ongoing investigation of lenalidomide in combination with low-dose dexamethasone, and in other combinations including bortezomib, for use both in relapsed, refractory, and newly diagnosed MM. PMID:20694078

VANTAGE 095: An International, Multicenter, Open-Label Study of Vorinostat (MK-0683) in Combination With Bortezomib in Patients With Relapsed and Refractory Multiple Myeloma.

PubMed

Siegel, David S; Dimopoulos, Meletios; Jagannath, Sundar; Goldschmidt, Hartmut; Durrant, Simon; Kaufman, Jonathan L; Leleu, Xavier; Nagler, Arnon; Offner, Fritz; Graef, Thorsten; Eid, Joseph E; Houp, Jennifer; Gause, Christine; Vuocolo, Scott; Anderson, Kenneth C

2016-06-01

The present global, open-label, single-arm, multicenter, phase IIb study was designed to determine the efficacy and tolerability of oral vorinostat combined with standard doses of bortezomib in patients with multiple myeloma considered refractory to novel myeloma agents. Eligible patients were age ≥ 18 years, had received ≥ 2 previous regimens, had disease refractory to ≥ 1 previous bortezomib-containing regimen, and had received ≥ 1 dose of an immunomodulatory drug (thalidomide or lenalidomide)-based regimen. The patients received 21-day cycles of bortezomib (1.3 mg/m(2) intravenously on days 1, 4, 8, and 11) plus oral vorinostat (400 mg/d on days 1-14). Oral dexamethasone, 20 mg, on the day of and the day after each dose of bortezomib could be added for patients with progressive disease after 2 cycles or no change after 4 cycles. The primary endpoint was the objective response rate. The objective response rate was 11.3% (95% confidence interval, 6.6%-17.7%), and the median duration of response was 211 days (range, 64-550 days). The median overall survival duration was 11.2 months (95% confidence interval, 8.5-14.4 months), with a 2-year survival rate of 32%. The frequently reported adverse events were thrombocytopenia (69.7%), nausea (57.0%), diarrhea (53.5%), anemia (52.1%), and fatigue (48.6%); the overall safety profile was consistent with that of bortezomib and vorinostat. The combination of vorinostat and bortezomib is active in patients with multiple myeloma refractory to novel treatment modalities and offers a new therapeutic option for this difficult-to-treat patient population (ClinicalTrials.gov identifier, NCT00773838). Copyright © 2016 Elsevier Inc. All rights reserved.

3,6'-Dithiothalidomide, a new TNF-α synthesis inhibitor, attenuates the effect of Aβ1-42 intracerebroventricular injection on hippocampal neurogenesis and memory deficit.

PubMed

Russo, Isabella; Caracciolo, Luca; Tweedie, David; Choi, Sang-Ho; Greig, Nigel H; Barlati, Sergio; Bosetti, Francesca

2012-09-01

Evidence indicates altered neurogenesis in neurodegenerative diseases associated with inflammation, including Alzheimer's disease (AD). Neuroinflammation and its propagation have a critical role in the degeneration of hippocampal neurons, cognitive impairment, and altered neurogenesis. Particularly, tumor necrosis factor (TNF)-α plays a central role in initiating and regulating the cytokine cascade during an inflammatory response and is up-regulated in brain of AD patients. In this study, we investigated the effects of a novel thalidomide-based TNF-α lowering drug, 3,6'-dithiothalidomide, on hippocampal progenitor cell proliferation, neurogenesis and, memory tasks after intracerebroventricular injection of β-amyloid (Aß)(1-42) peptide. Seven days after Aβ(1-42) injection, a significant proliferation of hippocampal progenitor cells and memory impairment were evident. Four weeks after Aβ(1-42) peptide injection, elevated numbers of surviving 5-bromo-2'-deoxyuridine cells and newly formed neurons were detected. Treatment with 3,6'-dithiothalidomide attenuated these Aβ(1-42) provoked effects. Our data indicate that although treatment with 3,6'-dithiothalidomide in part attenuated the increase in hippocampal neurogenesis caused by Aβ(1-42) -induced neuroinflammation, the drug prevented memory deficits associated with increased numbers of activated microglial cells and inflammatory response. Therefore, 3,6'-dithiothalidomide treatment likely reduced neuronal tissue damage induced by neuroinflammation following Aβ(1-42) injection. Understanding the modulation of neurogenesis, and its relationship with memory function could open new therapeutic interventions for AD and other neurodegenerative disorders with an inflammatory component. Published 2012. This article is a US Government work and is in the public domain in the USA.

A Computational Model Predicting Disruption of Blood Vessel Development

PubMed Central

Kleinstreuer, Nicole; Dix, David; Rountree, Michael; Baker, Nancy; Sipes, Nisha; Reif, David; Spencer, Richard; Knudsen, Thomas

2013-01-01

Vascular development is a complex process regulated by dynamic biological networks that vary in topology and state across different tissues and developmental stages. Signals regulating de novo blood vessel formation (vasculogenesis) and remodeling (angiogenesis) come from a variety of biological pathways linked to endothelial cell (EC) behavior, extracellular matrix (ECM) remodeling and the local generation of chemokines and growth factors. Simulating these interactions at a systems level requires sufficient biological detail about the relevant molecular pathways and associated cellular behaviors, and tractable computational models that offset mathematical and biological complexity. Here, we describe a novel multicellular agent-based model of vasculogenesis using the CompuCell3D (http://www.compucell3d.org/) modeling environment supplemented with semi-automatic knowledgebase creation. The model incorporates vascular endothelial growth factor signals, pro- and anti-angiogenic inflammatory chemokine signals, and the plasminogen activating system of enzymes and proteases linked to ECM interactions, to simulate nascent EC organization, growth and remodeling. The model was shown to recapitulate stereotypical capillary plexus formation and structural emergence of non-coded cellular behaviors, such as a heterologous bridging phenomenon linking endothelial tip cells together during formation of polygonal endothelial cords. Molecular targets in the computational model were mapped to signatures of vascular disruption derived from in vitro chemical profiling using the EPA's ToxCast high-throughput screening (HTS) dataset. Simulating the HTS data with the cell-agent based model of vascular development predicted adverse effects of a reference anti-angiogenic thalidomide analog, 5HPP-33, on in vitro angiogenesis with respect to both concentration-response and morphological consequences. These findings support the utility of cell agent-based models for simulating a morphogenetic series of events and for the first time demonstrate the applicability of these models for predictive toxicology. PMID:23592958

Development of multiple myeloma in a patient with chronic hepatitis C: A case report and review of the literature

PubMed Central

Lakatos, Peter Laszlo; Fekete, Sandor; Horanyi, Margit; Fischer, Simon; Abonyi, Margit E

2006-01-01

An association between chronic hepatitis C virus (HCV) infection and essential mixed cryoglobulinaemia and non-Hodgkin lymphoma (NHL) has been suggested. However, a causative role of HCV in these conditions has not been established. The authors report a case of a 50 year-old woman with chronic hepatitis C (CHC) who has been followed up since 1998 due to a high viral load, genotype 1b and moderately elevated liver function tests (LFTs). Laboratory data and liver biopsy revealed moderate activity (grade: 5/18, stage: 1/6). In April 1999, one-year interferon therapy was started. HCV-RNA became negative with normalization of LFTs. However, the patient relapsed during treatment. In September 2002, the patient was admitted for chronic back pain. A CT examination demonstrated degenerative changes. In March 2003, multiple myeloma was diagnosed (IgG-kappa, bone ma-rrow biopsy: 50% plasma cell infiltration). MRI revealed a compression fracture of the 5th lumbar vertebral body and an abdominal mass in the right lower quadrant, infiltrating the canalis spinalis. Treatment with vincristine, adriamycin and dexamethasone (VAD) was started and bisphosphonate was administered regularly. In January 2004, after six cycles of VAD therapy, the multiple myeloma regressed. Thalidomide, as a second line trea-tment of refractory multiple myeloma (MM) was initiated, and followed by peginterferon-α2b and ribavirin against the HCV infection in June. In June 2005, LFTs returned to normal, while HCV-RNA was negative, demonstrating an end of treatment response. Although a pathogenic role of HCV infection in malignant lymphoproliferative disorders has not been established, NHL and possibly MM may develop in CHC patients, supporting a role of a complex follow-up in these patients. PMID:16610042

New Therapeutic Approaches for Waldenstrom Macroglobulinemia

PubMed Central

Stedman, Jennifer; Roccaro, Aldo; Leleu, Xavier; Ghobrial, Irene M.

2011-01-01

Waldenstrom Macroglobulinemia (WM) is a B-cell disorder characterized by the infiltration of the bone marrow (BM) with lymphoplasmacytic cells, as well as detection of an IgM monoclonal gammopathy in the serum. WM is an incurable disease, with an overall medial survival of only 5-6 years. First-line therapy of WM has been based on single-agent or combination therapy with alkylator agents (e.g. chlorambucil or cyclophasphamide), nucleoside analogues (cladribine or fludarabine), and the monoclonal antibody rituximab. Novel therapeutic agents that have demonstrated efficacy in WM include thalidomide, lenalidomide, bortezomib, everolimus, Atacicept, and perifosine. The range of the ORR to these agents is between 25-80%. Ongoing and planned future clinical trials include those using PKC inhibitors such as enzastaurin, new proteasome inhibitors such as carfilzomib, histone deacetylase inhibitors such as panobinostat, humanized CD20 antibodies such as Ofatumumab, and additional alkylating agents such as bendamustine. These agents, when compared to traditional chemotherapeutic agents, may lead in the future to higher responses, longer remissions and better quality of life for patients with WM. PMID:21869855

Value of innovation in hematologic malignancies: a systematic review of published cost-effectiveness analyses.

PubMed

Saret, Cayla J; Winn, Aaron N; Shah, Gunjan; Parsons, Susan K; Lin, Pei-Jung; Cohen, Joshua T; Neumann, Peter J

2015-03-19

We analyzed cost-effectiveness studies related to hematologic malignancies from the Tufts Medical Center Cost-Effectiveness Analysis Registry (www.cearegistry.org), focusing on studies of innovative therapies. Studies that met inclusion criteria were categorized by 4 cancer types (chronic myeloid leukemia, chronic lymphocytic leukemia, non-Hodgkin lymphoma, and multiple myeloma) and 9 treatment agents (interferon-α, alemtuzumab, bendamustine, bortezomib, dasatinib, imatinib, lenalidomide, rituximab alone or in combination, and thalidomide). We examined study characteristics and stratified cost-effectiveness ratios by type of cancer, treatment, funder, and year of study publication. Twenty-nine studies published in the years 1996-2012 (including 44 cost-effectiveness ratios) met inclusion criteria, 22 (76%) of which were industry funded. Most ratios fell below $50,000 per quality-adjusted life-years (QALY) (73%) and $100,000/QALY (86%). Industry-funded studies (n = 22) reported a lower median ratio ($26,000/QALY) than others (n = 7; $33,000/QALY), although the difference was not statistically significant. Published data suggest that innovative treatments for hematologic malignancies may provide reasonable value for money. © 2015 by The American Society of Hematology.

Emerging therapies for multiple myeloma

PubMed Central

Podar, Klaus; Tai, Yu-Tzu; Hideshima, Teru; Vallet, Sonia; Richardson, Paul G; Anderson, Kenneth C

2011-01-01

Multiple myeloma (MM) is a clonal plasma cell malignancy clinically characterized by osteolytic lesions, immunodeficiency, and renal disease. There are an estimated 750,000 people diagnosed with MM worldwide, with a median overall survival of 3 – 5 years. Besides chromosomal aberrations, translocations, and mutations in essential growth and tumor-suppressor genes, accumulating data strongly highlight the pathophysiologic role of the bone marrow (BM) microenvironment in MM pathogenesis. Based on this knowledge, several novel agents have been identified, and treatment options in MM have fundamentally changed during the last decade. Thalidomide, bortezomib, and lenalidomide have been incorporated into conventional cytotoxic and transplantation regimens, first in relapsed and refractory and now also in newly diagnosed MM. Despite these significant advances, there remains an urgent need for more efficacious and tolerable drugs. Indeed, a plethora of preclinical agents awaits translation from the bench to the bedside. This article reviews the scientific rationale of new therapy regimens and newly identified therapeutic agents – small molecules as well as therapeutic antibodies – that hold promise to further improve outcome in MM. PMID:19249983

Incomplete ileus and hemafecia as the presenting features of multi-organ involved primary systemic AL amyloidosis: a rare case report.

PubMed

Tian, Li; Tang, Anliu; Zhang, Xian; Mei, Zhen; Liu, Fen; Li, Jingbo; Li, Xiayu; Ai, Feiyan; Wang, Xiaoyan; Shen, Shourong

2017-06-05

AL Amyloidosis is known to be a systemic disease affecting multiple organs and tissue while it's rare that patients present with gastrointestinal symptoms at first and later develop multiple-organ dysfuction. Clinical signs are not specific and the diagnosis is rarely given before performing immunofixation and endoscopy with multiple biopsies. We would like to emphasize the value of precise diagnostic process of AL amyloidosis. In this case report, we describe a 56-year-old man who presented with recurrent periumbilical pain for 4 months and gradually worsened over a month. After a series of tests, he was finally diagnosed with primary systemic AL amyloidosis. He was treated with a chemotherapy regimen (Melphalan, dexamethasone and thalidomide) achieving a good clinical response. On account of the high misdiagnosis rate, establishing the most precise diagnosis in first time with typing amyloidogenic protein becomes increasingly vital. Although the presenting feature is usually nonspecific, AL amyloidosis ought to be considered when multiple organs are involved in a short period.

Management of Myelofibrosis-Related Cytopenias.

PubMed

Bose, Prithviraj; Verstovsek, Srdan

2018-05-23

Cytopenias, particularly anemia, are frequently encountered in patients with myelofibrosis. Management of cytopenias in myelofibrosis can be very challenging because current therapeutic interventions are only of modest efficacy and ruxolitinib, the only approved drug for myelofibrosis, is myelosuppressive. Yet, dose optimization of ruxolitinib is important for its survival benefit in patients with advanced disease. We sought to summarize the data on treatments for cytopenias available at present and review promising agents in development and emerging strategies. The activin receptor ligand traps hold considerable promise for the treatment of anemia and could represent an attractive combination strategy with ruxolitinib. Low-dose thalidomide, which could offset both anemia and thrombocytopenia caused by ruxolitinib, represents another potential partner for ruxolitinib. The anti-fibrotic agent PRM-151 produced sustained improvements in cytopenias in some patients, and further data on this drug are eagerly awaited. Finally, several preclinical leads with translational potential are worthy of clinical investigation as strategies to halt/reverse bone marrow fibrosis and thereby improve cytopenias. Cytopenias remain a significant hurdle in myelofibrosis management, but several novel investigational agents hold considerable promise for the future.

[Xanthoma disseminatum with asymptomatic multisystem involvement].

PubMed

Zinoun, M; Hali, F; Marnissi, F; Lazaar, S; Benchikhi, H

2015-04-01

Xanthogranulomas belong to non-Langerhans histiocytosis of the second group in the Histiocyte Society classification. They comprise a heterogeneous group of rare entities frequently involving cutaneous tropism. Xanthoma disseminatum belongs to this group of non-Langerhans histiocytosis. We report a case of xanthoma disseminatum (XD) in which localized skin and mucous impairment revealed multisystem involvement. A 28-year-old man presented with a two-year history of progressive yellow-orange and infiltrated xanthomatous papulonodular lesions of the face. Lesions of the oral mucosa and genital region were seen, with no functional repercussions. No ophthalmic or other complications were found. Histopathology showed a dense histiocytic infiltrate within the dermis with Touton giant cells, foamy multinucleated giant cells and inflammatory cells, without necrobiosis. Histiocytes were positive for CD68 but negative for CD1a. Gastric and lung involvement was seen and was confirmed at histology. Bone scintigraphy showed suspicious left ulnar hyperfixation suggesting bone involvement. No monoclonal gammopathy or diabetes insipidus was seen. Our patient was treated with corticosteroids 1mg/kg/day and thalidomide 100 mg/day. The outcome was marked by regression and exfiltration of the cutaneous lesions from the second week of treatment, with subsidence continuing at 3 months. This case involves a very rare form of xanthoma disseminatum. The localized facial skin lesions revealed multifocal non-Langerhans histiocytosis that was in fact asymptomatic. The diagnosis of XD was based on clinical, histological and immunohistochemical criteria. Xanthoma disseminatum is a non-Langerhans histiocytic proliferation first described by Montgomery in 1938. This rare entity is characterized by skin and mucous membrane xanthomatosis in which the facial involvement is common, together with diabetes insipidus and normal lipid metabolism. The prognosis is determined by the presence of mucosal xanthomas and visceral involvement. Thus, all xanthogranulomas involving multiple lesions warrant screening for visceral involvement. Diagnosis of this entity can be difficult and is usually based on clinical and histopathological findings. In addition, treatment is complex and non-consensual. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Impact of prior treatment and depth of response on survival in MM-003, a randomized phase 3 study comparing pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone in relapsed/refractory multiple myeloma

PubMed Central

San Miguel, Jesus F.; Weisel, Katja C.; Song, Kevin W.; Delforge, Michel; Karlin, Lionel; Goldschmidt, Hartmut; Moreau, Philippe; Banos, Anne; Oriol, Albert; Garderet, Laurent; Cavo, Michele; Ivanova, Valentina; Alegre, Adrian; Martinez-Lopez, Joaquin; Chen, Christine; Renner, Christoph; Bahlis, Nizar Jacques; Yu, Xin; Teasdale, Terri; Sternas, Lars; Jacques, Christian; Zaki, Mohamed H.; Dimopoulos, Meletios A.

2015-01-01

Pomalidomide is a distinct oral IMiD® immunomodulatory agent with direct antimyeloma, stromal-support inhibitory, and immunomodulatory effects. The pivotal, multicenter, open-label, randomized phase 3 trial MM-003 compared pomalidomide + low-dose dexamethasone vs high-dose dexamethasone in 455 patients with refractory or relapsed and refractory multiple myeloma after failure of bortezomib and lenalidomide treatment. Initial results demonstrated significantly longer progression-free survival and overall survival with an acceptable tolerability profile for pomalidomide + low-dose dexamethasone vs high-dose dexamethasone. This secondary analysis describes patient outcomes by treatment history and depth of response. Pomalidomide + low-dose dexamethasone significantly prolonged progression-free survival and favored overall survival vs high-dose dexamethasone for all subgroups analyzed, regardless of prior treatments or refractory status. Both univariate and multivariate analyses showed that no variable relating to either the number (≤ or > 3) or type of prior treatment was a significant predictor of progression-free survival or overall survival. No cross-resistance with prior lenalidomide or thalidomide treatment was observed. Patients achieving a minimal response or better to pomalidomide + low-dose dexamethasone treatment experienced a survival benefit, which was even higher in those achieving at least a partial response (17.2 and 19.9 months, respectively, as compared with 7.5 months for patients with less than minimal response). These data suggest that pomalidomide + low-dose dexamethasone should be considered a standard of care in patients with refractory or relapsed and refractory multiple myeloma regardless of prior treatment. ClinicalTrials.gov: NCT01311687; EudraCT: 2010-019820-30. PMID:26160879

Long-Term Efficacy of Maintenance Therapy for Multiple Myeloma: A Quantitative Synthesis of 22 Randomized Controlled Trials.

PubMed

Li, Jie-Li; Fan, Guang-Yu; Liu, Yu-Jie; Zeng, Zi-Hang; Huang, Jing-Juan; Yang, Zong-Ming; Meng, Xiang-Yu

2018-01-01

We aimed to quantitatively synthesize data from randomized controlled trials (RCTs) concerning maintenance for multiple myeloma (MM). We searched electronic literature databases and conference proceedings to identify relevant RCTs. We selected eligible RCTs using predefined selection criteria. We conducted meta-analysis comparing maintenance containing new agents and conventional maintenance, and subgroup analysis by transplantation status and mainstay agent as well. We performed trial sequential analysis (TSA) to determine adequacy of sample size for overall and subgroup meta-analyses. We performed network meta-analysis (NMA) to compare and rank included regimens. A total of 22 RCTs involving 9,968 MM patients and 15 regimens were included, the overall quality of which was adequate. Significant heterogeneity was detected for progression-free survival (PFS) but not overall survival (OS). Meta-analyses showed that maintenance containing new agents significantly improved PFS but not OS [PFS: Hazard Ratio (HR) = 0.59, 95% Confidence Interval (CI) = 0.54 to 0.64; OS: HR = 0.93, 95% CI = 0.87 to 1.00], compared with controls. Subgroup analyses revealed lenalidomide (Len)-based therapies better than thalidomide-based ones (HR = 0.50 and 0.66, respectively; P = 0.001). NMA revealed that most of the maintenance regimens containing new agents were significantly better than simple observation in terms of PFS but not OS. Len single agent was the most effective, considering PFS and OS both. We concluded that conventional maintenance has very limited effect. Maintenance containing new agents is highly effective in improving PFS, but has very limited effect on OS. Maintenance with Len may have the largest survival benefits. Emerging strategies may further change the landscape of maintenance of MM.

Interferon-alpha in the treatment of multiple myeloma.

PubMed

Khoo, Teh Liane; Vangsted, Annette Juul; Joshua, Douglas; Gibson, John

2011-03-01

Interferons are soluble proteins produced naturally by cells in response to viruses. It has both anti-proliferative and immunomodulating properties and is one of the first examples of a biological response modifier use to treat the haematological malignancy multiple myeloma. Interferon has been used in this clinical practice for over thirty years. However, despite considerable efforts, numerous clinical trials and two large meta-analysis, its exact role in the management of multiple myeloma still remains unclear. Its role in the treatment of multiple myeloma has been as a single induction agent, a co-induction agent with other chemotherapy regimens, and as maintenance therapy after conventional chemotherapy or complete remission after autologous or allogeneic transplantation. Interferon as a single induction agent or co-induction agent with other chemotherapy agents appears only to have minimal benefit in myeloma. Its role as maintenance therapy in the plateau phase of myeloma also remains uncertain. More recently, the use of interferon must now compete with the "new drugs"--thalidomide, lenalidomide and bortezomib in myeloma treatment. Will there be a future role of interferon in the treatment of multiple myeloma or will interferon be resigned to the history books remains to be seen.

[Therapy of multiple myeloma. What is confirmed?].

PubMed

Peest, D; Ganser, A; Einsele, H

2013-12-01

Multiple myeloma (MM) is a malignant plasma cell disorder with clonal development. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are precursor stages of MM and both have to be differentiated from MM which is characterized by organ complications. High-dose chemotherapy combined with autologous stem cell support is the therapy of choice for most patients in order to achieve long-lasting complete remission with few symptoms, prevention of new organ complications and survival prolongation. Patients who cannot be intensively treated due to advanced age and comorbidities should be treated with low-dose chemotherapy, normally alkylating agents, for improved quality of life and also survival prolongation. Including thalidomide, lenalidomide, pomalidomide, bortezomib or carfilzomib in both high-dose and low-dose chemotherapy concepts results in a significantly higher remission rate and longer survival. Allogeneic stem cell transplantation is associated with a relatively high mortality during the first year after transplantation which will be refined with the aim of healing in various trials and is an alternative treatment approach for selected patients. A treatment concept for MM patients has to be individually complemented by local irradiation, administration of bisphosphonates and supportive infusions of immunoglobulins.

Vulvovaginal gingival lichen planus: report of two cases and review of literature.

PubMed

Lucchese, A; Dolci, A; Minervini, G; Salerno, C; DI Stasio, D; Minervini, G; Laino, L; Silvestre, F; Serpico, R

2016-01-01

Oral Lichen Planus (OLP) is a chronic inflammatory disease of skin and mucous membranes. Approximately 20% of women with oral lichen planus develops lesions in the genital mucosa. In 1982, Pelisse described a special form of lichen planus (LP), which consists of a triad of symptoms: vulval, vaginal and gingival (VVG)-LP lesions. Aim of the present report is to report two new cases and review the international literature. Two cases of VVG-LP are reported and a review of recent literature is performed. The onset of erosive or ulcerative mouth lesions may precede or follow by months or even years the onset of vulvovaginal lesions. Vaginal agglutination is associated with the postmenopausal state in conjunction with a dermatologic condition. Intra-lesional corticosteroids have a role in localized chronic ulceration, while systemic therapies such as corticosteroids, azathioprine, mycophenolate mofetil, hydroxychloroquine, ciclosporin, methotrexate, retinoids, thalidomide and photo chemotherapy have been used in more severe cases with varying success. VVG-LP is rather a rare condition and has been documented in the literature mainly in the form of case reports. Lack of a precise diagnostic criteria of VVG-LP depends on the specialists.

Update on treatment of light chain amyloidosis

PubMed Central

Mahmood, Shameem; Palladini, Giovanni; Sanchorawala, Vaishali; Wechalekar, Ashutosh

2014-01-01

Light chain amyloidosis is the most common type of amyloidosis as a consequence of protein misfolding of aggregates composed of amyloid fibrils. The clinical features are dependent on the organs involved, typically cardiac, renal, hepatic, peripheral and autonomic neuropathy and soft tissue. A tissue biopsy or fat aspirate is needed to confirm the presence/type of amyloid and prognostic tools are important in a risk stratified approach to treatment. Autologous stem cell transplant eligibility should be assessed at baseline, weighing the reversible or non-reversible contraindications, toxicity of treatment and chemotherapy alternatives available. Chemotherapy options include melphalan, thalidomide, bortezomib, lenalidomide, bendamustine in combination with dexamethasone. Many studies have explored these treatment modalities, with ongoing debate about the optimal first line and sequential treatment thereafter. Attaining a very good partial response or better is the treatment goal coupled with early assessment central to optimizing treatment. One major challenge remains increasing the awareness of this disease, frequently diagnosed late as the presenting symptoms mimic many other medical conditions. This review focuses on the treatments for light chain amyloidosis, how these treatments have evolved over the years, improved patient risk stratification, toxicities encountered and future directions. PMID:24497558

A Pilot Safety Study of Lenalidomide and Radiotherapy for Patients With Newly Diagnosed Glioblastoma Multiforme

DOE Office of Scientific and Technical Information (OSTI.GOV)

Drappatz, Jan; Division of Cancer Neurology, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Wong, Eric T.

2009-01-01

Purpose: To define the maximum tolerated dose (MTD) of lenalidomide, an analogue of thalidomide with enhanced immunomodulatory and antiangiogenic properties and a more favorable toxicity profile, in patients with newly diagnosed glioblastoma multiforme (GBM) when given concurrently with radiotherapy. Patients and Methods: Patients with newly diagnosed GBM received radiotherapy concurrently with lenalidomide given for 3 weeks followed by a 1-week rest period and continued lenalidomide until tumor progression or unacceptable toxicity. Dose escalation occurred in groups of 6. Determination of the MTD was based on toxicities during the first 12 weeks of therapy. The primary endpoint was toxicity. Results: Twenty-threemore » patients were enrolled, of whom 20 were treated and evaluable for both toxicity and tumor response and 2 were evaluable for toxicity only. Common toxicities included venous thromboembolic disease, fatigue, and nausea. Dose-limiting toxicities were eosinophilic pneumonitis and transaminase elevations. The MTD for lenalidomide was determined to be 15 mg/m{sup 2}/d. Conclusion: The recommended dose for lenalidomide with radiotherapy is 15 mg/m{sup 2}/d for 3 weeks followed by a 1-week rest period. Venous thromboembolic complications occurred in 4 patients, and prophylactic anticoagulation should be considered.« less

Perspectives on the use of the baboon in embryology and teratology research.

PubMed

Hendrickx, A G; Peterson, P E

1997-01-01

This paper summarizes the developmental stages of the baboon during the period of organ formation and provides comparative information for other primates, including the human. Special attention is directed to the early development of the nervous system, eye, ear and nose/palate. The similarity in development of these structures with humans indicates that the baboon is a suitable model for studies of normal and abnormal neurological development. Spontaneous prenatal loss rates in the baboon (2.4-11.2%) are slightly lower than those reported in rhesus and cynomologus monkeys. The baboon, in addition to the cynomologus monkey and macaque, has been used as a model in teratology research to assess the potential risk of thalidomide, sex steroids, Bendectin and rubella virus, as well as to study the pathogenesis of malformations associated with the corticosteroid triamcinolone acetonide. The rate of spontaneous malformations (<1%) in baboons, similar to that reported for other commonly used primates, supports their continued use as a teratological model. In this regard, a sample protocol is provided for the safety evaluation of biotechnology products using nonhuman primates, which are the most appropriate model for those compounds which are bioactive in species closely related to humans.

Drug safety in pregnancy: utopia or achievable prospect? Risk information, risk research and advocacy in Teratology Information Services.

PubMed

Schaefer, Christof

2011-03-01

Even though from preclinical testing to drug risk labeling, the situation with drugs in pregnancy has improved substantially since the thalidomide scandal, there is still an increasing need to provide healthcare professionals and patients with updated individualized risk information for clinical decision making. For the majority of drugs, clinical experience is still insufficient with respect to their safety in pregnancy. There is often uncertainty in how to interpret the available scientific data. Based on 20 years of experience with Teratology Information Services (TIS) cooperating in the European Network of Teratology Information Services (ENTIS) methods of risk interpretation, follow-up of exposed pregnancies through the consultation process and their evaluation is discussed. Vitamin K antagonists, isotretinoin and angiotensin (AT) II-receptor-antagonists are presented as examples of misinterpretation of drug risks and subjects of research based on observational clinical data recorded in TIS. As many TIS are poorly funded, advocacy is necessary by establishing contacts with decision makers in health politics and administration, informing them of the high return in terms of health outcomes and cost savings provided by TIS as reference institutions in clinical teratology. © 2011 The Author. Congenital Anomalies © 2011 Japanese Teratology Society.

What causes autism? Exploring the environmental contribution.

PubMed

Landrigan, Philip J

2010-04-01

Autism is a biologically based disorder of brain development. Genetic factors--mutations, deletions, and copy number variants--are clearly implicated in causation of autism. However, they account for only a small fraction of cases, and do not easily explain key clinical and epidemiological features. This suggests that early environmental exposures also contribute. This review explores this hypothesis. Indirect evidence for an environmental contribution to autism comes from studies demonstrating the sensitivity of the developing brain to external exposures such as lead, ethyl alcohol and methyl mercury. But the most powerful proof-of-concept evidence derives from studies specifically linking autism to exposures in early pregnancy - thalidomide, misoprostol, and valproic acid; maternal rubella infection; and the organophosphate insecticide, chlorpyrifos. There is no credible evidence that vaccines cause autism. Expanded research is needed into environmental causation of autism. Children today are surrounded by thousands of synthetic chemicals. Two hundred of them are neurotoxic in adult humans, and 1000 more in laboratory models. Yet fewer than 20% of high-volume chemicals have been tested for neurodevelopmental toxicity. I propose a targeted discovery strategy focused on suspect chemicals, which combines expanded toxicological screening, neurobiological research and prospective epidemiological studies.

A facile and efficient single-step approach for the fabrication of vancomycin functionalized polymer-based monolith as chiral stationary phase for nano-liquid chromatography.

PubMed

Xu, Dongsheng; Shao, Huikai; Luo, Rongying; Wang, Qiqin; Sánchez-López, Elena; Fanali, Salvatore; Marina, Maria Luisa; Jiang, Zhengjin

2018-07-06

A facile single-step preparation strategy for fabricating vancomycin functionalized organic polymer-based monolith within 100μm fused-silica capillary was developed. The synthetic chiral functional monomer, i.e 2-isocyanatoethyl methacrylate (ICNEML) derivative of vancomycin, was co-polymerized with the cross-linker ethylene dimethacrylate (EDMA) in the presence of methanol and dimethyl sulfoxide as the selected porogens. The co-polymerization conditions were systematically optimized in order to obtain satisfactory column performance. Adequate permeability, stability and column morphology were observed for the optimized poly(ICNEML-vancomycin-co-EDMA) monolith. A series of chiral drugs were evaluated on the monolith in either polar organic-phase or reversed-phase modes. After the optimization of separation conditions, baseline or partial enantioseparation were obtained for series of drugs including thalidomide, colchicine, carteolol, salbutamol, clenbuterol and several other β-blockers. The proposed single-step approach not only resulted in a vancomycin functionalized organic polymer-based monolith with acceptable performance, but also significantly simplified the preparation procedure by reducing time and labor. Copyright © 2018 Elsevier B.V. All rights reserved.

Asymmetry at the molecular level in biology

NASA Astrophysics Data System (ADS)

Johnson, Louise N.

2005-10-01

Naturally occurring biological molecules are made of homochiral building blocks. Proteins are composed of L-amino acids (and not D-amino acids); nucleic acids such as DNA have D-ribose sugars (and not L-ribose sugars). It is not clear why nature selected a particular chirality. Selection could have occurred by chance or as a consequence of basic physical chemistry. Possible proposals, including the contribution of the parity violating the weak nuclear force, are discussed together with the mechanisms by which this very small contribution might be amplified. Homochirality of the amino acids has consequences for protein structure. Helices are right handed and beta sheets have a left-hand twist. When incorporated into the tertiary structure of a protein these chiralities limit the topologies of connections between helices and sheets. Polypeptides comprised of D-amino acids can be synthesized chemically and have been shown to adopt stable structures that are the mirror image of the naturally occurring L-amino acid polypeptides. Chirality is important in drug design. Three examples are discussed: penicillin; the CD4 antagonistic peptides; and thalidomide. The absolute hand of a biological structure can only be established by X-ray crystallographic methods using the technique of anomalous scattering.

Drug safety in pregnancy--monitoring congenital anomalies.

PubMed

Morgan, Margery; De Jong-van den Berg, Lolkje T W; Jordan, Sue

2011-04-01

This paper outlines research into the causes of congenital anomalies, and introduces a pan-European study. The potential roles of nurses and midwives in this area are illustrated by a case report. Since the thalidomide disaster, use of drugs in pregnancy has been carefully monitored to prevent anything similar happening again. However, monitoring is incomplete and questions remain unanswered. Many medicines are essential for the health of pregnant women. However, drug use in pregnancy requires surveillance. Methods include spontaneous reporting of adverse events, cohort studies and case control studies. It is hoped that a Europe-wide study, combining data from several congenital anomaly registers, will provide a sufficiently large population to assess the impact of selected drugs on congenital anomalies. However, this work depends on the consistency of reporting by nurses and midwives. Drug safety in pregnancy remains undetermined. Collaboration across Europe has the potential to provide a framework for safety evaluation. Prescribers should consider the possibility of pregnancy in women of child-bearing age. Careful review of maternal drug use in early pregnancy is essential. Midwives and nurses should be aware of adverse event drug reporting systems, including congenital anomaly registers. © 2011 The Authors. Journal compilation © 2011 Blackwell Publishing Ltd.

Drug repurposing in malignant pleural mesothelioma: a breath of fresh air?

PubMed

Boyer, Arnaud; Pasquier, Eddy; Tomasini, Pascale; Ciccolini, Joseph; Greillier, Laurent; Andre, Nicolas; Barlesi, Fabrice; Mascaux, Celine

2018-03-31

Drug repurposing is the use of known drugs for new indications. Malignant pleural mesothelioma (MPM) is a rare cancer with a poor prognosis. So far, few treatments have been approved in this disease. However, its incidence is expected to increase significantly, particularly in developing countries. Consequently, drug repurposing appears as an attractive strategy for drug development in MPM, since the known pharmacology and safety profile based on previous approvals of repurposed drugs allows for faster time-to-market for patients and lower treatment cost. This is critical in low- and middle-income countries where access to expensive drugs is limited. This review assesses the published preclinical and clinical data about drug repurposing in MPM.In this review, we identified 11 therapeutic classes that could be repositioned in mesothelioma. Most of these treatments have been evaluated in vitro , half have been evaluated in vivo in animal models of MPM and only three ( i.e. valproate, thalidomide and zoledronic acid) have been investigated in clinical trials, with limited benefits so far. Efforts could be coordinated to pursue further investigations and test promising drugs identified in preclinical experiments in appropriately designed clinical trials. Copyright ©ERS 2018.

Anecdotal therapies.

PubMed

Millikan, L E

1999-01-01

Traditionally, many advances in medicine have been serendipitous. Are serendipitous and anecdotal synonymous? Many of our materia medica today relate to initial probes and anecdotal reports that matured to full investigation and therapeutic indications. The recent situation regarding Skin Cap is one that highlights the downside of this scenario. Several drugs in the US continue usage largely related to anecdotal indications, and anecdotal extension of legend indications is a standard for American Dermatology. The situation with systemic drugs, such as Trental, zinc preparations, imidazoles for extended indications, lysine and melatonin, all will be discussed. Topical preparations such as skin cap, cantharone, Vioform, all also are included in this category. It is important to place this topic in perspective in regards to geographic variation and therapeutic need. Many diseases lacking specific therapy are important targets for anecdotal therapy, and this will foster continued approaches in this area. The growing standardization of medicine and pharmaceutical regulation, threatens the anecdotal approach, but it provides still an important link to the future for some forms of therapy in diseases that are difficult to treat. Traditionally, the anecdote has been the first step in the therapeutic chain. Withering discovery of the benefits of the common fox glove in dropsy, was followed by many other anecdotes arriving via folk-medicine in the New World. This approach of utilizing folk medicine has now reached new heights, with very active searches by major pharmaceutical companies throughout the third world for remedies that may have potential. Couched with this is the history of anecdotal "snake-oil" remedies, that clearly had no benefit to anyone except the huckster marketing same. The excesses in this area of unproven and false therapies, led to the gradual organization of therapeutic trials and the Food and Drug Administration in the US as we know it today. The biggest shot in the arm for enhancing FDA protocols was the thalidomide situation, an outgrowth of an ethically studied and used medication that perhaps had been released too soon, prior to sufficient trials to determine the total patient risk. As in many situations, the pendulum swings in both directions, and after thalidomide, the acceptance of new treatments required more and more rigorous studies, and studies from other countries often were not acceptable unless a small part of a larger, whole proposal. The AIDS crisis has prompted a swing back, away from such expensive and rigorous pre-marketing review, to more expedited processes for the relief of patients with this fatal disease. This has streamlined the FDA, and hopefully the swing of the pendulum will not go too far, to result in problems in the future. Anecdotal therapies and medications are the first step in many parts of the world to therapeutic trials. The most widely used aspects of anecdotal therapies, again, remains in the situation with diseases without good therapies at the present time. The so-called orphan drugs and orphan diseases, while a serious medical problem, do not present a significant volume for effective drug screening in many instances, and the FDA has developed some new approaches to circumvent this very expensive development process for patients suffering from these rare and unusual disorders. The most recent example of anecdotal therapy catching the public fancy in dermatology was the Skin-Cap Spray. This product, over the period of twelve months, got rave reviews in the lay press in the non-peer reviewed dermatologic periodicals, and amassed impressive sales figures in this period of time. It was extremely effective, and most dermatologists who used it have patients who consider it the most effective therapy in the last year. The formulation of a low concentration of zinc pyrithione seemed unusual, and this truly was an anecdotal approach, using a homeopathic dosage of a commonly used p

Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma

PubMed Central

Arkenau, Hendrik-Tobias; Gimsing, Peter; Krejcik, Jakub; Lemech, Charlotte; Minnema, Monique C.; Lassen, Ulrik; Laubach, Jacob P.; Palumbo, Antonio; Lisby, Steen; Basse, Linda; Wang, Jianping; Sasser, A. Kate; Guckert, Mary E.; de Boer, Carla; Khokhar, Nushmia Z.; Yeh, Howard; Clemens, Pamela L.; Ahmadi, Tahamtan; Lokhorst, Henk M.; Richardson, Paul G.

2016-01-01

Daratumumab, a human CD38 immunoglobulin G1 kappa (IgG1κ) monoclonal antibody, has activity as monotherapy in multiple myeloma (MM). This phase 1/2 study investigated daratumumab plus lenalidomide/dexamethasone in refractory and relapsed/refractory MM. Part 1 (dose escalation) evaluated 4 daratumumab doses plus lenalidomide (25 mg/day orally on days 1-21 of each cycle) and dexamethasone (40 mg/week). Part 2 (dose expansion) evaluated daratumumab at the recommended phase 2 dose (RP2D) plus lenalidomide/dexamethasone. Safety, efficacy, pharmacokinetics, immunogenicity, and accelerated daratumumab infusions were studied. In part 1 (13 patients), no dose-limiting toxicities were observed, and 16 mg/kg was selected as the R2PD. In part 2 (32 patients), median time since diagnosis was 3.2 years, with a median of 2 prior therapies (range, 1-3 prior therapies), including proteasome inhibitors (91%), alkylating agents (91%), autologous stem cell transplantation (78%), thalidomide (44%), and lenalidomide (34%); 22% of patients were refractory to the last line of therapy. Grade 3 to 4 adverse events (≥5%) included neutropenia, thrombocytopenia, and anemia. In part 2, infusion-related reactions (IRRs) occurred in 18 patients (56%); most were grade ≤2 (grade 3, 6.3%). IRRs predominantly occurred during first infusions and were more common during accelerated infusions. In part 2 (median follow-up of 15.6 months), overall response rate was 81%, with 8 stringent complete responses (25%), 3 complete responses (9%), and 9 very good partial responses (28%). Eighteen-month progression-free and overall survival rates were 72% (95% confidence interval, 51.7-85.0) and 90% (95% confidence interval, 73.1-96.8), respectively. Daratumumab plus lenalidomide/dexamethasone resulted in rapid, deep, durable responses. The combination was well tolerated and consistent with the safety profiles observed with lenalidomide/dexamethasone or daratumumab monotherapy. This trial was registered at www.clinicaltrials.gov as #NCT01615029. PMID:27531679

Primary cutaneous follicular helper T-cell lymphoma: a new subtype of cutaneous T-cell lymphoma reported in a series of 5 cases.

PubMed

Battistella, Maxime; Beylot-Barry, Marie; Bachelez, Hervé; Rivet, Jacqueline; Vergier, Béatrice; Bagot, Martine

2012-07-01

Peripheral nodal follicular T-cell lymphomas expressing follicular helper T-cell (T(FH)) markers have recently been identified. Such lymphomas are characterized by a nodal neoplastic T-cell proliferation accompanied by numerous reactive B cells and demonstrate some overlap with nodal angioimmunoblastic T-cell lymphoma (AITL). We identified 5 cases of cutaneous T-cell lymphoma with a peculiar pathologic aspect and expression of T(FH) markers. The mean age of the patients was 61 years (range, 33-78 years). Four patients had multiple papules, plaques, and nodules predominating on the trunk and the head. One had a nodular plaque on the face. Lesional T-cell clonality was found in all 5 patients, and blood T-cell clonality in 4 of the 5. Nodal involvement was never found. Patients had no systemic symptoms and no biological signs of AITL. In 3 cases, findings from skin biopsy specimens were initially misdiagnosed as primary cutaneous follicle B-cell lymphoma due to major B-cell infiltrate and CD10 positivity. Rituximab-containing therapies were ineffective in these cases, and biopsy specimens after treatment with rituximab showed medium- to large-sized atypical T-cell skin infiltrate expressing T(FH) markers (CD10, Bcl-6, PD-1, CXCL13, and ICOS). The final diagnosis proposed for all patients was cutaneous T(FH) lymphoma. The patient with localized disease was successfully treated with radiotherapy. Patients with diffuse disease showed marked resistance to treatments, with only 1 case of complete remission after allogeneic hematopoietic stem cell transplantation followed by bortezomib and donor-lymphocyte infusion. Bexarotene, methotrexate, thalidomide, interferon alfa, gemcitabine, liposomal doxorubicin, or multiagent chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) were either ineffective or induced transitory partial remission. We describe an original clinicopathologic series of primary cutaneous lymphomas with T(FH) phenotype, suggesting the existence of a new entity among cutaneous T-cell lymphomas. Relations of these lymphomas with the provisional entity of primary cutaneous small to medium CD4 pleomorphic T-cell lymphoma need to be further addressed.

Waldenstrom macroglobulinemia: prognosis and management

PubMed Central

Oza, A; Rajkumar, S V

2015-01-01

Waldenstrom macroglobulinemia (WM) is a B-cell lymphoplasmacytic lymphoma characterized by monoclonal immunoglobulin M protein in the serum and infiltration of bone marrow with lymphoplasmacytic cells. Asymptomatic patients can be observed without therapy. First-line therapy should consist of the monoclonal anti-CD20 antibody, rituximab, given typically in combination with other agents. We prefer dexamethasone, rituximab, cyclophosphamide (DRC) as initial therapy for most patients with symptomatic WM. Other reasonable options are bortezomib, rituximab, dexamethasone (BoRD) or bendamustine plus rituximab (BR). All of these regimens are associated with excellent response and tolerability. Initial therapy is usually administered for 6 months, followed by observation. Response to therapy is assessed using the standard response criteria developed by the International Working Group on Waldenstrom macroglobulinemia. Relapse is almost inevitable in WM but may occur years after initial therapy. In symptomatic patients relapsing more than 1–2 years after initial therapy, the original treatment can be repeated. For relapse occurring sooner, an alternative regimen is used. In select patients, high-dose chemotherapy followed by autologous hematopoietic cell transplantation may be an option at relapse. Options for therapy of relapsed WM besides regimens used in the front-line setting include ibrutinib, purine nucleoside analogs (cladribine, fludarabine), carfilzomib and immunomodulatory agents (thalidomide, lenalidomide). PMID:25815903

Targeted therapy of multiple myeloma.

PubMed

Dolloff, Nathan G; Talamo, Giampaolo

2013-01-01

Multiple myeloma (MM) is a plasma cell malignancy and the second most common hematologic cancer. MM is characterized by the accumulation of malignant plasma cells within the bone marrow, and presents clinically with a broad range of symptoms, including hypercalcemia, renal insufficiency, anemia, and lytic bone lesions. MM is a heterogeneous disease associated with genomic instability, where patients may express multiple genetic abnormalities that affect several oncogenic pathways. Commonly detected genetic aberrations are translocations involving immunoglobulin heavy chain (IgH) switch regions (chromosome 14q32) and oncogenes such as c-maf [t(14:16)], cyclin D1 [t(11:14)], and FGFR3/MMSET [t(4:14)]. Advances in the basic understanding of MM and the development of novel agents, such as the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide and the proteasome inhibitor bortezomib, have increased therapeutic response rates and prolonged patient survival. Despite these advances MM remains incurable in the majority of patients, and it is therefore critical to identify additional therapeutic strategies and targets for its treatment. In this chapter, we review the underlying genetic components of MM and discuss the results of recent clinical trials that demonstrate the effectiveness of targeted agents in the management of MM. In addition, we discuss experimental therapies that are currently in clinical development along with their molecular rationale in the treatment of MM.

[Current approaches in multiple myeloma and other cancer-related bone diseases].

PubMed

Engelhardt, M; Kleber, M; Udi, J; Wäsch, R

2012-05-01

Multiple myeloma (MM) ranges second of all hematological malignancies and occurs most commonly in elderly patients. Almost all MM patients develop bone lesions in the course of their disease or have evidence of bone loss at initial diagnosis. Whole-body conventional radiography remains the gold standard in the diagnostic evaluation, albeit computed tomography (CT) and magnetic resonance imaging (MRI) are increasingly used as complementary techniques in the more sensitive detection of osteolytic processes. Bisphosphonates like zoledronate or pamidronate represent the cornerstone therapeutics in osteolytic disease, and are effective supportives to potent anti-myeloma therapies, including novel agents such as the proteasome inhibitor bortezomib or immunomodulatory drugs (IMIDs, e. g. thalidomide or lenalidomide). Several studies are ongoing to investigate the effects of alternative bone-seeking agents and their therapeutic potential for the management of myeloma bone disease, such as denosumab (RANKL-neutralizing antibody), anti-sclerostin (monoclonal antibody, generated against sclerostin) or sotatercept (potent activin-A inhibitor). This review summarizes the most prominent data on myeloma bone disease pathogenesis, the role of imaging techniques as well as therapy and prevention of lytic complications in myeloma which may similarly or equally be true for other bone metastases-inducing solid tumors. © Georg Thieme Verlag KG Stuttgart · New York.

Sensitization of TRPV1 receptors by TNF-α orchestrates the development of vincristine-induced pain.

PubMed

Wang, Ying; Feng, Chenyang; He, Haoying; He, Jinjin; Wang, Jun; Li, Xiaomin; Wang, Shasha; Li, Wei; Hou, Jiuzhou; Liu, Tong; Fang, Dong; Xie, Song-Qiang

2018-04-01

Vincristine is one of the most common anticancer drugs clinically employed in the treatment of various malignancies. A major side effect associated with vincristine is the development of neuropathic pain, which is not readily relieved by available analgesics. Although efforts have been made to identify the pathogenesis of vincristine-induced neuropathic pain, the mechanisms underlying its pathogenesis have not been fully elucidated. In the present study, a neuropathic pain model was established in Sprague-Dawley rats by intraperitoneal injection of vincristine sulfate. The results demonstrated that vincristine administration induced the upregulation of transient receptor potential cation channel subfamily V member 1 (TRPV1) protein expression and current density in dorsal root ganglion (DRG) nociceptive neurons. Consistently, inhibition of TRPV1 with capsazepine alleviated vincristine-induced mechanical allodynia and thermal hyperalgesia in rats. Furthermore, vincristine administration induced the upregulation of tumor necrosis factor (TNF)-α production in DRGs, and inhibition of TNF-α synthesis with thalidomide in vivo reversed TRPV1 protein expression, as well as pain hypersensitivity induced by vincristine in rats. The present results suggested that TNF-α could sensitize TRPV1 by promoting its expression, thus leading to mechanical allodynia and thermal hyperalgesia in vincristine-treated rats. Taken together, these findings may enhance our understanding of the pathophysiological mechanisms underlying vincristine-induced pain.

Congenital Anomalies of the Limbs

PubMed Central

Gingras, G.; Mongeau, M.; Moreault, P.; Dupuis, M.; Hebert, B.; Corriveau, C.

1964-01-01

As a preparatory step towards the development of a complete habilitation program for children with congenital limb anomalies associated with maternal ingestion of thalidomide, the medical records of all patients with congenital limb anomalies referred to the Rehabilitation Institute of Montreal in the past decade were studied, and an examination and a thorough reassessment were made of 41 patients (21 males and 20 females). The medical and prosthetic aspects were dealt with in Part I of this paper. Part II describes, in a joint report, the results of psychiatric, psychological and educational assessments. There was no evidence of major emotional disorder in any of the patients, although conflicts were intensified by the presence of the physical anomaly. No relation was found between intelligence, emotional adjustment and disability. The patient's attitude towards his disability and prosthesis is definitely influenced by the degree of parental acceptance of the handicap and by the character of the emotional undertones in the total environment. In order to favour the occurrence of the healthiest modes of development in these children, the authors believe that the medical profession should be made fully aware of the physical and emotional problems which may arise after the birth of a deformed child. It is considered very important that the mother should receive psychotherapeutic support as soon as possible after the child is born. PMID:14174527

In honor of the Teratology Society's 50th anniversary: The role of Teratology Society members in the development and evolution of in vivo developmental toxicity test guidelines.

PubMed

Tyl, Rochelle W

2010-06-01

Members of the Teratology Society (established in 1960) were involved in the first governmental developmental and reproductive toxicity testing guidelines (1966) by FDA following the thalidomide epidemic, followed by other national and international governmental testing guidelines. The Segment II (developmental toxicity) study design, described in rodents and rabbits, has evolved with additional enhanced endpoints and better descriptions, mechanistic insights, range-finding studies, and toxico/pharmacokinetic ADME information (especially for pharmaceuticals). Society members were also involved in the development of the current screening assays and tests for endocrine disruptors (beginning in 1996) and are now involved with developing new testing guidelines (e.g., the extended one-generation protocol), and evaluating the current test guidelines and new initiatives under ILSI/HESI sponsorship. New initiatives include ToxCast from the U.S. EPA to screen, prioritize, and predict toxic chemicals by high throughput and high-content in vitro assays, bioinformation, and modeling to reduce (or eliminate) in vivo whole animal studies. Our Society and its journal have played vital roles in the scientific and regulatory accomplishments in birth defects research over the past 50 years and will continue to do so in the future. Happy 50th anniversary! (c) 2010 Wiley-Liss, Inc.

Mini-Midi-Maxi? How to harness the graft-versus-myeloma effect and target molecular remission after allogeneic stem cell transplantation.

PubMed

Kröger, N

2007-09-01

Allogeneic stem cell transplantation in multiple myeloma after standard myeloablative conditioning induces a high rate of complete remissions, but long-term freedom from disease is achieved in 30-40% of the cases only. The therapeutic effect of allogeneic stem cell transplantation is due to cytotoxicity of high-dose chemotherapy and immune-mediated graft-versus-myeloma effect by donor T cells. Retrospective studies clearly suggest that both (a) reducing the intensity of high-dose chemotherapy by using reduced-intensity or non-myeloablative conditioning regimen or (b) reducing the immunotherapy of donor T cells by using T-cell depletion result in lower treatment-related morbidity and mortality, but also in higher rate of relapse. Therefore, this review will focus on potential strategies of how treatment-related morbidity and mortality might be kept low without an increased risk of relapse and how remission status after transplantation can be enhanced by using the newly established donor immunosystems after allografting as a platform for post-transplant treatment strategies with new drugs (thalidomide, lenalidomide, bortezomib) or immunotherapy (donor lymphocyte infusion, vaccination, tumor-specific T cells) in order to achieve remission on a molecular level, which seems to be a 'conditio sine qua non' to cure myeloma patients.

Aspects of Vitamin A

PubMed Central

Hedley-Whyte, John; Milamed, Debra R

2009-01-01

Musgrave Park Hospital in 1942 was the site of an Anglo-American Vitamin A caper. A threatened court-martial was pre-empted. Subsequently the Queen's lecturer in Anatomy, JW Millen, who was the other lecturer to the first editor of this journal, RH Hunter, did much distinguished work. The neurological effects of Vitamin A were elucidated. Further work on cerebrospinal fluid (CSF), placenta, thalidomide and poliomyelitis led to the pre-eminence in applied anatomy and teratology of now Reader James Wilson Millen and Professors JD Boyd and WJ Hamilton, all Queen's Medical School graduates. Training of RH Hunter, JH Biggart and JD Boyd at Johns Hopkins University profoundly influenced these seminal discoveries. The Garretts, a family of Lisburn, County Down origin, saved Johns Hopkins Hospital and Medical School from financial disaster. The Garretts founded a commercial and mercantile empire that took control of the Baltimore and Ohio (B and O) Railroad and enabled the Garretts to dictate that women should be admitted to the Hopkins Medical School and Hospital on exactly the same terms as men. All women and men should already be university honours graduates. Winston S Churchill on his progress up and down the B and O main line in March 1946, recounted to President Harry S Truman and Harry Hopkins his mother's tales of the Garrett boys' adventures. PMID:19907684

Development of acute pulmonary hypertension after bortezomib treatment in a patient with multiple myeloma: a case report and the review of the literature.

PubMed

Akosman, Cengiz; Ordu, Cetin; Eroglu, Elif; Oyan, Basak

2015-01-01

Bortezomib is widely used in treatment of multiple myeloma. In recent years, severe bortezomib-induced lung injury has been reported. The clinical course is generally characterized with fever and dyspnea, followed by respiratory failure with pulmonary infiltrates. Herein, we report a 57-year-old man with newly diagnosed multiple myeloma admitted with dyspnea, fever, and hypotension on the third day of the first dose of bortezomib therapy. He had bilateral jugular venous distention, crackles at the bases of the lungs and hepatomegaly. Transthoracic echocardiography revealed acute pulmonary hypertension (PH) with an estimated pressure of 70 mm Hg. The perfusion scintigraphy ruled out pulmonary embolism, and microbiological examination was negative. On his course, fever, dyspnea, hypoxia, and pulmonary vascular pressure subsided rapidly. The sudden onset of PH and its rapid decrement without any treatment suggests bortezomib as the underlying cause. Subsequently, the patient did not respond to vincristine-doxorubicin-dexamethasone regimen and thalidomide. Bortezomib treatment was repeated, and no pulmonary adverse reactions occurred. Follow-up echocardiographies revealed pulmonary arterial pressures to be maximally of 35 mm Hg. To our knowledge, this is the first case of acute PH after front-line bortezomib therapy. In this report, we review bortezomib-related pulmonary complications in the literature and possible underlying mechanisms.

Lenalidomide: a review of its use in patients with transfusion-dependent anaemia due to low- or intermediate-1-risk myelodysplastic syndrome associated with 5q chromosome deletion.

PubMed

Syed, Yahiya Y; Scott, Lesley J

2013-07-01

Lenalidomide (Revlimid(®)), a thalidomide analogue, is an orally administered second generation immunomodulator with anti-angiogenic, antineoplastic, anti-inflammatory and pro-erythropoietic properties. It is approved for the treatment of patients with transfusion-dependent anaemia due to International Prognostic Scoring System low- or intermediate-1-risk myelodysplastic syndrome (MDS) associated with either chromosome 5q deletion [del(5q)] with or without additional cytogenetic abnormalities (US, Japan and Switzerland etc.), or with an isolated del(5q) cytogenetic abnormality when other therapeutic options are insufficient or inadequate (EU) [featured indication]. In a randomized, double-blind, multicentre, registrational trial (MDS-004; n = 205) in this patient population, a significantly higher proportion of lenalidomide recipients than placebo recipients achieved red blood cell transfusion independence for ≥26 consecutive weeks (primary endpoint for efficacy) and cytogenetic responses. The erythroid response to lenalidomide was accompanied by an increase in the haemoglobin levels. These efficacy outcomes are generally consistent with those seen in an earlier noncomparative registrational trial (MDS-003; n = 148). In MDS-004, lenalidomide also significantly improved health-related quality of life compared with placebo at 12 weeks. Retrospective analyses that compared outcomes between lenalidomide-treated patients with low- or intermediate-1-risk del(5q) MDS and multicentre registry cohorts showed that lenalidomide treatment did not appear to increase the risk of progression to acute myeloid leukaemia. Lenalidomide had a manageable safety profile in the registrational trials, with ≤20 % of patients discontinuing treatment because of adverse events. The most common adverse events (incidence ≥20 %) occurring in lenalidomide recipients were thrombocytopenia and neutropenia, which were generally managed by dosage reductions and/or interruptions, and/or pharmacotherapy. Thus, lenalidomide is a useful option for the treatment of patients with transfusion-dependent anaemia due to low- or intermediate-1-risk del(5q) MDS, with or without additional cytogenetic abnormalities.

Chronic myeloproliferative disorders.

PubMed

Spivak, Jerry L; Barosi, Giovanni; Tognoni, Gianni; Barbui, Tiziano; Finazzi, Guido; Marchioli, Roberto; Marchetti, Monia

2003-01-01

The Philadelphia chromosome-negative chronic myeloproliferative disorders (CMPD), polycythemia vera (PV), essential thrombocythemia (ET) and chronic idiopathic myelofibrosis (IMF), have overlapping clinical features but exhibit different natural histories and different therapeutic requirements. Phenotypic mimicry amongst these disorders and between them and nonclonal hematopoietic disorders, lack of clonal diagnostic markers, lack of understanding of their molecular basis and paucity of controlled, prospective therapeutic trials have made the diagnosis and management of PV, ET and IMF difficult. In Section I, Dr. Jerry Spivak introduces current clinical controversies involving the CMPD, in particular the diagnostic challenges. Two new molecular assays may prove useful in the diagnosis and classification of CMPD. In 2000, the overexpression in PV granulocytes of the mRNA for the neutrophil antigen NBI/CD177, a member of the uPAR/Ly6/CD59 family of plasma membrane proteins, was documented. Overexpression of PRV-1 mRNA appeared to be specific for PV since it was not observed in secondary erythrocytosis. At this time, it appears that overexpression of granulocyte PRV-1 in the presence of an elevated red cell mass supports a diagnosis of PV; absence of PRV-1 expression, however, should not be grounds for excluding PV as a diagnostic possibility. Impaired expression of Mpl, the receptor for thrombopoietin, in platelets and megakaryocytes has been first described in PV, but it has also been observed in some patients with ET and IMF. The biologic basis appears to be either alternative splicing of Mpl mRNA or a single nucleotide polymorphism, both of which involve Mpl exon 2 and both of which lead to impaired posttranslational glycosylation and a dominant negative effect on normal Mpl expression. To date, no Mpl DNA structural abnormality or mutation has been identified in PV, ET or IMF. In Section II, Dr. Tiziano Barbui reviews the best clinical evidence for treatment strategy design in PV and ET. Current recommendations for cytoreductive therapy in PV are still largely similar to those at the end of the PVSG era. Phlebotomy to reduce the red cell mass and keep it at a safe level (hematocrit < 45%) remains the cornerstone of treatment. Venesection is an effective and safe therapy and previous concerns about potential side effects, including severe iron deficiency and an increased tendency to thrombosis or myelofibrosis, were erroneous. Many patients require no other therapy for many years. For others, however, poor compliance to phlebotomy or progressive myeloproliferation, as indicated by increasing splenomegaly or very high leukocyte or platelet counts, may call for the introduction of cytoreductive drugs. In ET, the therapeutic trade-off between reducing thrombotic events and increasing the risk of leukemia with the use of cytoreductive drugs should be approached by patient risk stratification. Thrombotic deaths seem very rare in low-risk ET subjects and there are no data indicating that fatalities can be prevented by starting cytoreductive drugs early. Therefore, withholding chemotherapy might be justifiable in young, asymptomatic ET patients with a platelet count below 1500000/mm(3) and with no additional risk factors for thrombosis. If cardiovascular risk factors together with ET are identified (smoking, obesity, hypertension, hyperlipidemia) it is wise to consider platelet-lowering agents on an individual basis. In Section III, Dr. Gianni Tognoni discusses the role of aspirin therapy in PV based on the recently completed European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) Study, a multi-country, multicenter project aimed at describing the natural history of PV as well as the efficacy of low-dose aspirin. Aspirin treatment lowered the risk of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke (relative risk 0.41 [95% CI 0.15-1.15], P =.0912). Total and cardiovascular mortality were also reduced by 46% and 59%, respectively. Major bleedings were slightly increased nonsignificnsignificantly by aspirin (relative risk 1.62, 95% CI 0.27-9.71). In Section IV, Dr. Giovanni Barosi reviews our current understanding of the pathophysiology of IMF and, in particular, the contributions of anomalous megakaryocyte proliferation, neoangiogenesis and abnormal CD34(+) stem cell trafficking to disease pathogenesis. The role of newer therapies, such as low-conditioning stem cell transplantation and thalidomide, is discussed in the context of a general treatment strategy for IMF. The results of a Phase II trial of low-dose thalidomide as a single agent in 63 patients with myelofibrosis with meloid metaplasia (MMM) using a dose-escalation design and an overall low dose of the drug (The European Collaboration on MMM) will be presented. Considering only patients who completed 4 weeks of treatment, 31% had a response: this was mostly due to a beneficial effect of thalidomide on patients with transfusion dependent anemia, 39% of whom abolished transfusions, patients with moderate to severe thrombocytopenia, 28% of whom increased their platelet count by more than 50 x 10(9)/L, and patients with the largest splenomegalies, 42% of whom reduced spleen size of more than 2 cm.

Teratogens: a public health issue – a Brazilian overview

PubMed Central

Mazzu-Nascimento, Thiago; Melo, Débora Gusmão; Morbioli, Giorgio Gianini; Carrilho, Emanuel; Vianna, Fernanda Sales Luiz; da Silva, André Anjos; Schuler-Faccini, Lavinia

2017-01-01

Abstract Congenital anomalies are already the second cause of infant mortality in Brazil, as in many other middle-income countries in Latin America. Birth defects are a result of both genetic and environmental factors, but a multifactorial etiology has been more frequently observed. Here, we address the environmental causes of birth defects – or teratogens – as a public health issue and present their mechanisms of action, categories and their respective maternal-fetal deleterious effects. We also present a survey from 2008 to 2013 of Brazilian cases involving congenital anomalies (annual average of 20,205), fetal deaths (annual average of 1,530), infant hospitalizations (annual average of 82,452), number of deaths of hospitalized infants (annual average of 2,175), and the average cost of hospitalizations (annual cost of $7,758). Moreover, we report on Brazilian cases of teratogenesis due to the recent Zika virus infection, and to the use of misoprostol, thalidomide, alcohol and illicit drugs. Special attention has been given to the Zika virus infection, now proven to be responsible for the microcephaly outbreak in Brazil, with 8,039 cases under investigation (from October 2015 to June 2016). From those cases, 1,616 were confirmed and 324 deaths occurred due to microcephaly complications or alterations on the central nervous system. Congenital anomalies impact life quality and raise costs in specialized care, justifying the classification of teratogens as a public health issue. PMID:28534929

CONGENITAL ANOMALIES OF THE LIMBS: II. PSYCHOLOGICAL AND EDUCATIONAL ASPECTS.

PubMed

GINGRAS, G; MONGEAU, M; MOREAULT, P; DUPUIS, M; HEBERT, B; CORRIVEAU, C

1964-07-18

As a preparatory step towards the development of a complete habilitation program for children with congenital limb anomalies associated with maternal ingestion of thalidomide, the medical records of all patients with congenital limb anomalies referred to the Rehabilitation Institute of Montreal in the past decade were studied, and an examination and a thorough reassessment were made of 41 patients (21 males and 20 females). The medical and prosthetic aspects were dealt with in Part I of this paper. Part II describes, in a joint report, the results of psychiatric, psychological and educational assessments.There was no evidence of major emotional disorder in any of the patients, although conflicts were intensified by the presence of the physical anomaly. No relation was found between intelligence, emotional adjustment and disability. The patient's attitude towards his disability and prosthesis is definitely influenced by the degree of parental acceptance of the handicap and by the character of the emotional undertones in the total environment. In order to favour the occurrence of the healthiest modes of development in these children, the authors believe that the medical profession should be made fully aware of the physical and emotional problems which may arise after the birth of a deformed child. It is considered very important that the mother should receive psychotherapeutic support as soon as possible after the child is born.

Medical treatment of epistaxis in hereditary hemorrhagic telangiectasia: an evidence-based review.

PubMed

Halderman, Ashleigh A; Ryan, Matthew W; Clark, Christopher; Sindwani, Raj; Reh, Douglas D; Poetker, David M; Invernizzi, Rosangela; Marple, Bradley F

2018-06-01

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant hereditary disorder resulting in vascular dysplasia and formation of arteriovenous malformations. Recurrent epistaxis is a hallmark of the disease. An array of medical therapies are used in this patient population, but robust evidence-based recommendations regarding the medical treatment of epistaxis are lacking. This systematic review was performed to look at the current literature and make meaningful evidence-based recommendations. A search of the Ovid MEDLINE, Embase, and Cochrane databases was conducted by a research librarian. Abstracts in the English language and published in a peer-review journal were reviewed for relevance and inclusion. PRISMA guidelines were followed. Eighteen studies met the inclusion criteria. In a few small studies, thalidomide was shown to consistently improve severity and frequency of epistaxis and improve hemoglobin concentrations while decreasing the need for transfusion. Tranexamic acid appeared to only impact the epistaxis severity score and not other clinical outcomes. Selective estrogen modulators (SERMs), propranolol, rose geranium oil, and N-acetylcysteine, have demonstrated promising efficacy in small trials. Appropriate medical therapies for epistaxis outcomes in HHT remain undefined, and there is no "gold standard." Many of the studies are small and the data reported are heterogeneous, and therefore the ability to make strong evidence-based recommendations is limited. However, many different medications appear to be promising options. © 2018 ARS-AAOA, LLC.

Management of mantle cell lymphoma in the elderly: current and potential strategies.

PubMed

Vignon, Marguerite; Venon, Marie-Dominique; Hermine, Olivier; Delarue, Richard

2013-12-01

Mantle cell lymphoma is a distinct subtype of B-cell non-Hodgkin lymphoma, accounting for 3-10 % of all non-Hodgkin lymphoma cases. The median age at diagnosis is nearly 70 years. The prognosis of patients is based on the Mantle Cell Lymphoma International Prognostic Index, which is calculated on the basis of four independent prognostic factors (age, performance status, serum lactate dehydrogenase and leukocyte count). Treatment of elderly patients with de novo untreated mantle cell lymphoma is based on rituximab combined with chemotherapy. The most commonly used regimen is the classical CHOP21 (cyclophosphamide, doxorubicin, vincristine and prednisone) regimen. Bendamustine is also an option, especially for patients with cardiac comorbidities. In elderly patients who are relatively young and fit, an approach based on treatment usually used for younger patients, with cytarabine-based induction followed by autologous stem cell transplantation, should be discussed. Treatment of relapsing patients is based on the use of newer effective drugs, including bortezomib, lenalidomide and thalidomide, and mammalian target of rapamycin (mTOR) inhibitors, such as temsirolimus. These drugs are often combined with rituximab and can be prescribed in combination with chemotherapy. Promising new drugs are Bruton tyrosine kinase inhibitors and other inhibitors of the phosphoinositide 3-kinase (PI3K)-mTOR-protein kinase B (AKT) pathway. Despite these new advances, mantle cell lymphoma remains an incurable disease, and further basic and clinical research is warranted.

VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial.

PubMed

Moreau, Philippe; Hulin, Cyrille; Macro, Margaret; Caillot, Denis; Chaleteix, Carine; Roussel, Murielle; Garderet, Laurent; Royer, Bruno; Brechignac, Sabine; Tiab, Mourad; Puyade, Mathieu; Escoffre, Martine; Stoppa, Anne-Marie; Facon, Thierry; Pegourie, Brigitte; Chaoui, Driss; Jaccard, Arnaud; Slama, Borhane; Marit, Gerald; Laribi, Karim; Godmer, Pascal; Luycx, Odile; Eisenmann, Jean-Claude; Allangba, Olivier; Dib, Mamoun; Araujo, Carla; Fontan, Jean; Belhadj, Karim; Wetterwald, Marc; Dorvaux, Véronique; Fermand, Jean-Paul; Rodon, Philippe; Kolb, Brigitte; Glaisner, Sylvie; Malfuson, Jean-Valere; Lenain, Pascal; Biron, Laetitia; Planche, Lucie; Caillon, Helene; Avet-Loiseau, Herve; Dejoie, Thomas; Attal, Michel

2016-05-26

The Intergroupe Francophone du Myélome conducted a randomized trial to compare bortezomib-thalidomide-dexamethasone (VTD) with bortezomib-cyclophosphamide-dexamethasone (VCD) as induction before high-dose therapy and autologous stem cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma. Overall, a total of 340 patients were centrally randomly assigned to receive VTD or VCD. After 4 cycles, on an intent-to-treat basis, 66.3% of the patients in the VTD arm achieved at least a very good partial response (primary end point) vs 56.2% in the VCD arm (P = .05). In addition, the overall response rate was significantly higher in the VTD arm (92.3% vs 83.4% in the VCD arm; P = .01). Hematologic toxicity was higher in the VCD arm, with significantly increased rates of grade 3 and 4 anemia, thrombocytopenia, and neutropenia. On the other hand, the rate of peripheral neuropathy (PN) was significantly higher in the VTD arm. With the exception of hematologic adverse events and PN, other grade 3 or 4 toxicities were rare, with no significant differences between the VTD and VCD arms. Our data support the preferential use of VTD rather than VCD in preparation for ASCT. This trial was registered at www.clinicaltrials.gov as #NCT01564537 and at EudraCT as #2013-003174-27. © 2016 by The American Society of Hematology.

Immunomodulatory drugs and the risk of serious infection in multiple myeloma: systematic review and meta-analysis of randomized and observational studies.

PubMed

Chen, Min; Zhao, Yongfeng; Xu, Chuanxin; Wang, Xian; Zhang, Xianping; Mao, Benyu

2018-06-01

The effect of immunomodulatory drugs (IMiDs) on serious infection remains uncertain. We therefore conducted a systematic review and meta-analysis to assess the possible impact of IMiDs on serious infection in patients with multiple myeloma (MM). We searched randomized controlled trials (RCTs) and observational studies from databases that addressed the effect of IMiDs on serious infection in patients with MM. We pooled data from RCTs and observational studies separately and used the GRADE approach to rate the quality of evidence. Rates in patients with individual IMiDs at different treatment status ranged from 7.00 to 23.00%. The use of thalidomide- or lenalidomide-based regimen induction therapy for autologous stem cell transplantation (ASCT)-ineligible patients suggests increase in serious infection (RR = 1.59, 95% CI 1.31-1.93, p < 0.01). Compared to conventional therapy, IMiDs' induction in ASCT-eligible patients significantly decreases the risk of serious infection (RR = 0.82, 95% CI 0.72-0.94, p < 0.01). Lenalidomide-based therapy was associated with a significant increase in risk of serious infection in patients treated compared with conventional therapy (RR = 2.45, 95% CI 1.57-3.83, p < 0.01). The current evidence suggests that patients with MM treated with IMiDs are at a high risk of serious infection.

The up-regulation of IL-6 in DRG and spinal dorsal horn contributes to neuropathic pain following L5 ventral root transection.

PubMed

Wei, Xu-Hong; Na, Xiao-Dong; Liao, Guang-Jie; Chen, Qiu-Ying; Cui, Yu; Chen, Feng-Ying; Li, Yong-Yong; Zang, Ying; Liu, Xian-Guo

2013-03-01

Our previous works have shown that pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) plays an important role in neuropathic pain produced by lumber 5 ventral root transection (L5-VRT). In the present work we evaluate the role of interleukin-6 (IL-6), another key inflammatory cytokine, in the L5-VRT model. We found that IL-6 was up-regulated in the ipsilateral L4 and L5 dorsal root ganglian (DRG) neurons and in bilateral lumbar spinal cord following L5-VRT. Double immunofluorescence stainings revealed that in DRGs the increased immunoreactivity (IR) of IL-6 was almost restricted in neuronal cells, while in the spinal dorsal horn IL-6-IR up-regulated in both glial cells (astrocyte and microglia) and neurons. Intrathecal administration of IL-6 neutralizing antibody significantly delayed the induction of mechanical allodynia in bilateral hindpaws after L5-VRT. Furthermore, inhibition of TNF-α synthesis by intraperitoneal thalidomide prevented both mechanical allodynia and the up-regulation of IL-6 in DRGs following L5-VRT. These data suggested that the increased IL-6 in afferent neurons and spinal cord contribute to the development of neuropathic pain following motor fiber injury, and that TNF-α is responsible for the up-regulation of IL-6. Copyright © 2012 Elsevier Inc. All rights reserved.

Behcet's disease.

PubMed

Suzuki Kurokawa, M; Suzuki, N

2004-09-01

Behcet's disease (BD) is a systemic disorder of recurrent acute inflammation, characterized by major symptoms of oral aphthous ulcers, uveitis, skin lesions and genital ulcers. Involvement of intestines, vessels, and central nervous system (CNS) sometimes leads to a poor prognosis. Patients with BD are known to distribute along the ancient Silk Road. The incidence is relatively higher from eastern Asia to the Mediterranean area as roughly 1-10 patients in 10,000 people, whereas only 1-2 patients in 1,000,000 people in UK and North America. Although etiology of the disease is still unknown, high prevalence of HLA-B51, increased expression of heat shock protein 60 and Th1 dominant immune responses in the patients are considered important in its pathogenesis. Non-infectious neutrophil activation and infection with Streptococcus sanguis and herpes simplex virus would also be associated. Because BD lacks any pathognomonic symptoms and laboratory findings, the diagnosis relies largely upon the criteria proposed by the International Study Group for Behcet's disease in 1990. In Japan, the diagnosis was also made according to the Japanese criteria revised in 1987. Recently, the Behcet's Disease Research Committee of Japan again revised the Japanese criteria in 2003 to avoid overdiagnosis. The new Japanese criteria are introduced in this review. Differential diagnosis excluding Sweet's disease, pemphigus, erythema nodosum and Crohn's disease is important, and positive laboratory data for pathergy test, prick test for dead Streptococci and HLA-B51 are emphasized to make appropriate diagnosis in these criteria. Pathological findings of the disease-affected site such as erythematous nodosum is also stressed. Treatment for the disease has been chosen according to the clinical symptoms. Non-steroidal anti-inflammatory drugs, immunosuppressants, corticosteroids and colchicine are basically introduced. Recently, effects of interferon-alpha/beta, anti-tumor necrosis factor antibody and thalidomide are encouraging, specifically in treatment for the cases with poor prognosis including eye, intestine, vessel and CNS involvement. Low dose weekly administration of methotraxate looks effective for the cases with CNS involvement. Further studies for elucidation of the etiology, improvement of the diagnostic criteria and development of new therapy are needed to conquer the disease.

A Drug Safety Rating System Based on Postmarketing Costs Associated with Adverse Events and Patient Outcomes.

PubMed

Hoffman, Keith B; Dimbil, Mo; Kyle, Robert F; Tatonetti, Nicholas P; Erdman, Colin B; Demakas, Andrea; Chen, Dingguo; Overstreet, Brian M

2015-12-01

Given the multiple limitations associated with relatively homogeneous preapproval clinical trials, inadequate data disclosures, slow reaction times from regulatory bodies, and deep-rooted bias against disclosing and publishing negative results, there is an acute need for the development of analytics that reflect drug safety in heterogeneous, real-world populations. To develop a drug safety statistic that estimates downstream medical costs associated with serious adverse events (AEs) and unfavorable patient outcomes associated with the use of 706 FDA-approved drugs. All primary suspect case reports for each drug were collected from the FDA's Adverse Event Reporting System database (FAERS) from 2010-2014. The Medical Dictionary for Regulatory Activities (MedDRA) was used to code serious AEs and outcomes, which were tallied for each case report. Medical costs associated with AEs and poor patient outcomes were derived from Agency for Healthcare Research and Quality (AHRQ) survey data, and their corresponding ICD-9-CM codes were mapped to MedDRA terms. Nonserious AEs and outcomes were not included. For each case report, either the highest AE cost or, if no eligible AE was listed, the highest outcome cost was used. All costed cases were aggregated for each drug and divided by the number of patients exposed to obtain a downstream estimated direct medical cost burden per exposure. Each drug was assigned a corresponding 1-100 point total. The 706 drugs showed an exponential distribution of downstream costs, and the data were transformed using the natural log to approximate a normal distribution. The minimum score was 8.29, and the maximum score was 99.25, with a mean of 44.32. Drugs with the highest individual scores tended to be kinase inhibitors, thalidomide analogs, and endothelin receptor antagonists. When scores were analyzed across Established Pharmacologic Class (EPC), the kinase inhibitor and endothelin receptor antagonist classes had the highest total. However, other EPCs with median scores of 75 and above included hepatitis C virus NS3/4A protease inhibitor, recombinant human interferon beta, vascular endothelial growth factor-directed antibody, and tumor necrosis factor blocker. When Anatomical Therapeutic Chemical classifications were analyzed, antineoplastic drugs were outliers with approximately 80% of their individual scores 60 and above, while approximately 20%-30% of blood and anti-infective drugs had scores of 60 and above. Within-drug class results served to differentiate similar drugs. For example, 6 serotonin reuptake inhibitors had a score range of 35 to 53. This scoring system is based on estimated direct medical costs associated with postmarketing AEs and poor patient outcomes and thereby helps fill a large information gap regarding drug safety in real-world patient populations.

Genetic Syndromes, Maternal Diseases and Antenatal Factors Associated with Autism Spectrum Disorders (ASD).

PubMed

Ornoy, Asher; Weinstein-Fudim, Liza; Ergaz, Zivanit

2016-01-01

Autism spectrum disorder (ASD) affecting about 1% of all children is associated, in addition to complex genetic factors, with a variety of prenatal, perinatal, and postnatal etiologies. In addition, ASD is often an important clinical presentation of some well-known genetic syndromes in human. We discuss these syndromes as well as the role of the more important prenatal factors affecting the fetus throughout pregnancy which may also be associated with ASD. Among the genetic disorders we find Fragile X, Rett syndrome, tuberous sclerosis, Timothy syndrome, Phelan-McDermid syndrome, Hamartoma tumor syndrome, Prader-Willi and Angelman syndromes, and a few others. Among the maternal diseases in pregnancy associated with ASD are diabetes mellitus (PGDM and/or GDM), some maternal autoimmune diseases like antiphospholipid syndrome (APLS) with anti-β2GP1 IgG antibodies and thyroid disease with anti-thyroid peroxidase (TPO) antibodies, preeclampsia and some other autoimmune diseases with IgG antibodies that might affect fetal brain development. Other related factors are maternal infections (rubella and CMV with fetal brain injuries, and possibly Influenza with fever), prolonged fever and maternal inflammation, especially with changes in a variety of inflammatory cytokines and antibodies that cross the placenta and affect the fetal brain. Among the drugs are valproic acid, thalidomide, misoprostol, and possibly SSRIs. β2-adrenergic receptor agonists and paracetamol have also lately been associated with increased rate of ASD but the data is too preliminary and inconclusive. Associations were also described with ethanol, cocaine, and possibly heavy metals, heavy smoking, and folic acid deficiency. Recent studies show that heavy exposure to pesticides and air pollution, especially particulate matter < 2.5 and 10 μm in diameter (PM2.5 and PM10) during pregnancy is also associated with ASD. Finally, we have to remember that many of the associations mentioned in this review are only partially proven, and not all are "clean" of different confounding factors. The associations described in this review emphasize again how little we know about the etiology and pathogenesis of ASD. It is obvious that we need more epidemiologic data to establish many of these associations, but if proven, they might be promising avenues for prevention.

Survival of multiple myeloma patients aged 65-70 years in the era of novel agents and autologous stem cell transplantation. A multicenter retrospective collaborative study of the Japanese Society of Myeloma and the European Myeloma Network.

PubMed

Ozaki, Shuji; Harada, Takeshi; Saitoh, Takayuki; Shimazaki, Chihiro; Itagaki, Mitsuhiro; Asaoku, Hideki; Kuroda, Yoshiaki; Chou, Takaaki; Yoshiki, Yumiko; Suzuki, Kenshi; Murakami, Hirokazu; Hayashi, Kunihiko; Mina, Roberto; Palumbo, Antonio; Shimizu, Kazuyuki

2014-01-01

Novel agents such as thalidomide, lenalidomide and bortezomib have dramatically changed the treatment paradigm of multiple myeloma (MM). However, it is not clear whether these agents improve the prognosis of elderly patients who have undergone autologous stem cell transplantation (auto-SCT). We retrospectively analyzed the outcome of 318 newly diagnosed patients aged 65–70 years who were treated between January 1, 2004, and December 31, 2009. As initial therapy, 192 patients were treated with conventional chemotherapy,88 with novel agent-containing regimens, 21 with conventional chemotherapy plus auto-SCT and the remaining 17 with novel agents plus auto-SCT. The median progression-free survival was 19.1, 24.5, 26.8 and 35.2 months, respectively, and the 5-year overall survival (OS) was 40, 62, 63 and 87%, respectively. Initial therapy with novel agents (p < 0.001) or auto-SCT (p < 0.02) significantly improved OS compared with the group without these treatment modalities. Salvage therapy with novel agents also significantly improved survival after relapse compared with conventional chemotherapy alone (p < 0.04). In a multivariate analysis, the use of novel agents was an independent prognostic factor significantly associated with extended OS(p < 0.003). These results indicate that novel agents and auto-SCT had a major impact on OS in eligible patients in this subgroup of MM. © 2014 S. Karger AG, Basel

Chemical approaches to targeted protein degradation through modulation of the ubiquitin-proteasome pathway.

PubMed

Collins, Ian; Wang, Hannah; Caldwell, John J; Chopra, Raj

2017-03-15

Manipulation of the ubiquitin-proteasome system to achieve targeted degradation of proteins within cells using chemical tools and drugs has the potential to transform pharmacological and therapeutic approaches in cancer and other diseases. An increased understanding of the molecular mechanism of thalidomide and its analogues following their clinical use has unlocked small-molecule modulation of the substrate specificity of the E3 ligase cereblon (CRBN), which in turn has resulted in the advancement of new immunomodulatory drugs (IMiDs) into the clinic. The degradation of multiple context-specific proteins by these pleiotropic small molecules provides a means to uncover new cell biology and to generate future drug molecules against currently undruggable targets. In parallel, the development of larger bifunctional molecules that bring together highly specific protein targets in complexes with CRBN, von Hippel-Lindau, or other E3 ligases to promote ubiquitin-dependent degradation has progressed to generate selective chemical compounds with potent effects in cells and in vivo models, providing valuable tools for biological target validation and with future potential for therapeutic use. In this review, we survey recent breakthroughs achieved in these two complementary methods and the discovery of new modes of direct and indirect engagement of target proteins with the proteasome. We discuss the experimental characterisation that validates the use of molecules that promote protein degradation as chemical tools, the preclinical and clinical examples disclosed to date, and the future prospects for this exciting area of chemical biology. © 2017 The Author(s).

Haematopoietic stem cell transplantation as first-line treatment in myeloma: a global perspective of current concepts and future possibilities

PubMed Central

Mactier, Catriona Elizabeth; Islam, Md Serajul

2012-01-01

Stem cell transplantation forms an integral part of the treatment for multiple myeloma. This paper reviews the current role of transplantation and the progress that has been made in order to optimize the success of this therapy. Effective induction chemotherapy is important and a combination regimen incorporating the novel agent bortezomib is now favorable. Adequate induction is a crucial adjunct to stem cell transplantation and in some cases may potentially postpone the need for transplant. Different conditioning agents prior to transplantation have been explored: high-dose melphalan is most commonly used and bortezomib is a promising additional agent. There is no well-defined superior transplantation protocol but single or tandem autologous stem cell transplantations are those most commonly used, with allogeneic transplantation only used in clinical trials. The appropriate timing of transplantation in the treatment plan is a matter of debate. Consolidation and maintenance chemotherapies, particularly thalidomide and bortezomib, aim to improve and prolong disease response to transplantation and delay recurrence. Prognostic factors for the outcome of stem cell transplant in myeloma have been highlighted. Despite good responses to chemotherapy and transplantation, the problem of disease recurrence persists. Thus, there is still much room for improvement. Treatments which harness the graft-versus-myeloma effect may offer a potential cure for this disease. Trials of novel agents are underway, including targeted therapies for specific antigens such as vaccines and monoclonal antibodies. PMID:25992212

Risks and burden of viral respiratory tract infections in patients with multiple myeloma in the era of immunomodulatory drugs and bortezomib: experience at an Australian Cancer Hospital.

PubMed

Teh, Benjamin W; Worth, Leon J; Harrison, Simon J; Thursky, Karin A; Slavin, Monica A

2015-07-01

Infections are a leading cause of morbidity and mortality in patients with multiple myeloma. The epidemiology, risk factors and outcomes of viral respiratory tract infections (vRTI) are not well described in patients with multiple myeloma managed with novel agents, the current standard of care. Patients with myeloma from 2009 to 2012 who tested positive on respiratory virus multiplex polymerase chain reaction had clinical, radiological and microbiological records reviewed. The Fourth European Conference on Infections in Leukaemia (ECIL-4) definitions of RTI were applied. Univariate and multivariate regression analysis of risk factors was performed using vRTI as the evaluable outcome. Of 330 patients, 75 (22.7%) tested positive for a total of 100 vRTI episodes. All patients received thalidomide, lenalidomide or bortezomib in combination with myeloma therapies (median of three treatment regimens). vRTI occurred most commonly in patients with progressive disease, and receipt of more than three lines of myeloma therapy was associated with an increased risk of vRTI (p < 0.01). Amongst key respiratory pathogens, influenza was associated with the highest hospital admission rate (66.7%), ICU admission rate (41.6%) and mortality (33.3%) whilst RSV was associated with prolonged hospital stay. Patients with multiple myeloma and advanced disease managed with multiple lines of therapy are at risk for vRTI, and targeted interventions for prevention/treatment are required.

Drug repurposing: translational pharmacology, chemistry, computers and the clinic.

PubMed

Issa, Naiem T; Byers, Stephen W; Dakshanamurthy, Sivanesan

2013-01-01

The process of discovering a pharmacological compound that elicits a desired clinical effect with minimal side effects is a challenge. Prior to the advent of high-performance computing and large-scale screening technologies, drug discovery was largely a serendipitous endeavor, as in the case of thalidomide for erythema nodosum leprosum or cancer drugs in general derived from flora located in far-reaching geographic locations. More recently, de novo drug discovery has become a more rationalized process where drug-target-effect hypotheses are formulated on the basis of already known compounds/protein targets and their structures. Although this approach is hypothesis-driven, the actual success has been very low, contributing to the soaring costs of research and development as well as the diminished pharmaceutical pipeline in the United States. In this review, we discuss the evolution in computational pharmacology as the next generation of successful drug discovery and implementation in the clinic where high-performance computing (HPC) is used to generate and validate drug-target-effect hypotheses completely in silico. The use of HPC would decrease development time and errors while increasing productivity prior to in vitro, animal and human testing. We highlight approaches in chemoinformatics, bioinformatics as well as network biopharmacology to illustrate potential avenues from which to design clinically efficacious drugs. We further discuss the implications of combining these approaches into an integrative methodology for high-accuracy computational predictions within the context of drug repositioning for the efficient streamlining of currently approved drugs back into clinical trials for possible new indications.

The role of the placenta in drug transport and fetal drug exposure.

PubMed

Koren, Gideon; Ornoy, Asher

2018-04-01

It was assumed for decades that the human placenta serves as a barrier, protecting the fetus from exposure to xenobiotics circulating in the mother. The thalidomide disaster completely reversed this concept. The study of the human placenta is therefore critical to understanding the mechanisms by which xenobiotics reach the fetus and exert their effects. Areas covered: This review describes mechanisms by which drugs interact with the human placenta, and experimental methods to study these interactions in humans. We have selected three areas of current clinical interest, where the placenta exhibits critical role in drug transport: The ABC transporters, the placental handling of cancer therapeutic drugs and the interaction between the placenta and immunoglobulins. Expert commentary: The optimal model to predict drug transfer and transport from the mother to the fetus is the isolated human placental lobule perfused in vitro. Unlike subcellular preparations or tissue homogenates, data obtained from a perfused intact tissue, where structural integrity and cell-cell organization are maintained, more closely reflect the in vivo situation. Moreover, confounding metabolic and physiologic influences are minimized and the experimental conditions can be controlled. It is important to remember that due to significant differences in the function of the placenta in the first two months (histiotrophic nutrition) and later in pregnancy (hemotrophic nutrition) there might be differences in the transplacental transfer of drugs. While most of our knowledge comes from studies on term placentae, we are in need of studies on young placenta that functions during the period of organogenesis.

Subacute cutaneous lupus erythematosus: 25-year evolution of a prototypic subset (subphenotype) of lupus erythematosus defined by characteristic cutaneous, pathological, immunological, and genetic findings.

PubMed

Sontheimer, Richard D

2005-06-01

Subacute cutaneous lupus erythematosus (SCLE) represents a widespread, photosensitive, nonscarring, nonindurated form of lupus erythematosus (LE)-specific skin disease. SCLE lesions are associated with a distinctive immunogenetic background including the production of Ro/SS-A autoantibodies. Individuals who have SCLE skin lesions as a component of their presenting illnesses represent a distinctive subset (subphenotype) of LE that enjoys a good prognosis with respect to life-threatening systemic manifestations of LE. SCLE skin lesions can be triggered by a number of different drugs the majority of which are capable of producing photosensitivity drug reactions in nonlupus patients. Single agent or combination aminoquinoline antimalarial therapy will suffice for 75% of SCLE patients. The remaining 25% will require other forms of systemic antiinflammatory therapy (e.g., diaminodipenylsulfone (Dapsone), thalidomide) or systemic immunosuppressive-immunomodulatory therapy. The etiopathogenesis of SCLE skin lesions is thought to result from four sequential stages: (1) inheritance of susceptibility genes (HLA 8.1 ancestral haplotype [C2, C4 deficiency, TNF-alpha-308A polymorphism], C1q deficiency); (2) loss of tolerance/induction of autoimmunity (ultraviolet light, photosensitizing drugs/chemicals, cigarette smoking, infection, psychological stress); (3) expansion/maturation of autoimmune responses (high levels of autoantibodies (Ro/SS-A), immune complexes, autoreactive T-cells); and (4) tissue injury/disease induction resulting from various autoimmune effector mechanisms (e.g., direct T cell-mediated cytotoxicity, antibody-dependent cell-mediated cytotoxicity).

Pathogenesis and therapeutic approaches for improved topical treatment in localized scleroderma and systemic sclerosis.

PubMed

Badea, I; Taylor, M; Rosenberg, A; Foldvari, M

2009-03-01

SSc is a chronic progressive disorder of unknown aetiology characterized by excess synthesis and deposition of collagen and other extracellular matrix components in a variety of tissues and organs. Localized scleroderma (LS) differs from SSc in that with LS only skin and occasionally subcutaneous tissues are involved. Although rarely life threatening, LS can be disfiguring and disabling and, consequently, can adversely affect quality of life. There is no known effective treatment for LS, and various options, including, as examples, corticosteroids and other immunomodulatory agents, ultraviolet radiation and vitamin D analogues, are of unproven efficacy. Clinical trials evaluating combination therapy such as corticosteroids with MTX or UVA1 exposure with psoralens have not been established as consistently effective. New immunomodulators such as tacrolimus and thalidomide are also being evaluated. A better understanding of the molecular and cellular mechanisms of LS has led to evaluation of new treatments that modulate profibrotic cytokines such as TGF-beta and IL-4, regulate assembly and deposition of extracellular matrix components, and restore Th1/Th2 immune balance by administering IL-12 or IFN-gamma. IFN-gamma acts by directly inhibiting collagen synthesis and by restoring immune balance. In this review, we evaluate current and future treatment options for LS and cutaneous involvement in SSc. Recent advances in therapy focus mainly on anti-fibrotic agents. Delivery of these drugs into the skin as the target tissue might be a key factor in developing more effective and safer therapy.

[Anti-TNF therapy in inflammatory bowel diseases during pregnancy and breast-feeding].

PubMed

Persić, Mladen

2013-04-01

Since the early occurrence of inflammatory bowel diseases in young people, the role of pregnancy on disease course, and the influence of different therapies on pregnancy, fetal development and the safety of breastfeeding have been one of the important questions. Biological therapy has been increasingly used and all the above mentioned questions seem to be of a great interest. The majority of research indicate that the possibility of conception in patients with IBD are the same as in a healthy population, although there is an increased risk for the child in terms of prematurity or low birth weight. Pregnancy in IBD patient should be considered as a high risk. Most medications used to achieve or maintain remission are safe in pregnancy and breastfeeding. Exceptions are thalidomide and methotrexate that are absolutely contraindicated. Anti-TNF drugs are safe but it is advised to stop the treatment after 30-32 weeks of pregnancy due to the possibility of placental transfer of medications. Infliximab is excreted into breast milk in small quantities and breastfeeding is assumed to be safe. Pregnancy in IBD patients should be planned in advance so that the medications that are contraindicated could be excluded on time and further possible complication could be prevented by constant monitoring of pregnancy. Prospective studies of monitoring throughout pregnancy and short-term and long-term forecasts of development of children whose mothers were pregnant when suffered from inflammatory bowel disease are necessary.

Salivary levels of TNF-α in patients with recurrent aphthous stomatitis: A cross-sectional study.

PubMed

Chaudhuri, Kanad; Nair, Keerthi Krishnankutty; Ashok, Lingappa

2018-01-01

Background. Recurrent aphthous stomatitis (RAS) is a disorder characterized by recurring ulcers involving the oral mucosa in patients with no other signs of disease. The current concept of etiopathogenesis is that RAS is a clinical syndrome with several possible etiologies. The process seen in RAS is probably initiated through an as yet unidentified antigenic stimulation of the mucosal keratinocytes, which stimulates secretion of T-cell activation cytokines ‒ interleukins and tumor necrosis factor alpha (TNF-α). TNF-α causes inflammation by its effect on endothelial cell adhesion and neutrophil chemotaxis. The rele-vance of TNF-α to the pathogenesis of RAS has stemmed from the observations that anti- TNF-α drugs such as thalidomide and pentoxifylline have been found to be effective in the treatment of RAS. Therefore, the present study was an attempt to measure the levels of salivary TNF-α in patients with RAS, which will reflect the local production of cytokines at the site of the disease. The aim was to evaluate the salivary levels of TNF-α in patients with recurrent aphthous stomatitis. Methods. The study comprised of 60 subjects, of whom 30 clinically proven RAS patients of either sex were selected as cases and 30 healthy, age- and gender- matched subjects were selected as controls. After taking informed consent, 5 mL of unstimulated saliva were collected from both the study and control group subjects. Determination of salivary TNF-α levels was carried out by Enzyme-Linked Immunosorbent Assay (ELISA) and expressed in pg/mL. Statistical analysis of the RAS and control groups was carried out using unpaired t-test. Gender-wise comparison of salivary TNF-α levels in the study and control groups was carried out using one-way ANOVA. Results. Mean salivary TNF-α levels were significantly higher in the RAS group compared to the control group (P<0.001). It was also revealed that the mean salivary TNF-α levels in females were significantly higher than in males in the study group (PP<0.05). Conclusion. It is fair to suggest that TNF-α plays a very important mediatory role in the pathogenesis of RAS and may play an important role in the search for a definitive treatment for the disease.

Retreatment with bortezomib alone or in combination for patients with multiple myeloma following an initial response to bortezomib.

PubMed

Sood, Raman; Carloss, Harry; Kerr, Robert; Lopez, Jose; Lee, Martin; Druck, Mark; Walters, Ian B; Noga, Stephen J

2009-10-01

This clinical trial was conducted to determine the safety and efficacy of bortezomib retreatment in patients with multiple myeloma (MM) who had previously responded to bortezomib. Patients with progressive MM who had previously tolerated bortezomib as a single agent or in combination with other drugs, with a minimum of partial response (PR; >or=50% M-protein reduction) for >or=4 months, who had not received intervening MM therapy, were retreated with bortezomib (days 1, 4, 8, and 11 of a 21-day cycle) with a starting dose being the dose at which the patient ended the initial treatment. Patients were allowed to receive bortezomib on retreatment in combination with dexamethasone, thalidomide, or doxorubicin. Thirty-two patients received bortezomib retreatment (most with added dexamethasone). The median treatment-free interval (last dose of initial bortezomib treatment to first dose of retreatment) was 9.9 (range 2.5-34.0) months. The median duration of retreatment was 2.8 (<1-7.9) months; median total duration of bortezomib treatment was 6.7 (2.5-19.8) months. Based on the investigators' assessment of best response, the overall response rate (complete plus PR) was 50%. The median time from start of retreatment to progressive disease (PD) was 6.6 (95% confidence interval: 5.1-9.6) months. Thirteen patients (41%) experienced PN; bortezomib-related SAEs were reported in four patients. Retreatment with bortezomib alone or in combination is effective and well tolerated in patients with MM who have responded to their initial bortezomib treatment. (c) 2009 Wiley-Liss, Inc.

High prevalence of psychiatric disorders in patients with skin-restricted lupus: a case-control study.

PubMed

Jalenques, I; Rondepierre, F; Massoubre, C; Haffen, E; Grand, J P; Labeille, B; Perrot, J L; Aubin, F; Skowron, F; Mulliez, A; D'Incan, M

2016-05-01

Psychiatric disorders have been extensively documented in patients with systemic lupus erythematosus (SLE). However, the prevalence of psychiatric disorders in patients with skin-restricted lupus (SRL) remains unknown, although SRL is more common than SLE. To assess current and lifetime prevalence of Axis I psychiatric disorders among outpatients with SRL and to examine the factors associated with psychiatric disorders among such patients. A multicentre case-control study involving outpatients with SRL and controls matched for sex, age and education level. The Mini International Neuropsychiatric Interview was used for psychiatric evaluation. We evaluated 75 patients and 150 controls. Of these, 49% of patients vs. 13% of controls fulfilled the criteria for at least one current psychiatric disorder (P < 0·001). The following disorders were significantly more frequent among patients than controls: current and lifetime major depressive disorder (9% vs. 0%, P < 0·001 and 44% vs. 26%, P = 0·01), generalized anxiety disorder (23% vs. 3%, P < 0·001 and 35% vs. 19%, P = 0·03), panic disorder (7% vs. 0%, P = 0·004 and 21% vs. 3%, P < 0·001), current suicide risk (24% vs. 7%, P = 0·003), alcohol dependence (7% vs. 0%, P = 0·004) and lifetime agoraphobia (20% vs. 9%, P = 0·01). Lupus duration and lupus past treatment by thalidomide were significantly higher among patients with current psychiatric disorders. This study demonstrates a high prevalence of several psychiatric disorders (anxiety, depression, suicide risk, alcohol dependence) in patients with SRL. © 2016 British Association of Dermatologists.

Hidradenitis suppurativa: A practical review of possible medical treatments based on over 350 hidradenitis patients.

PubMed

Scheinfeld, Noah

2013-04-15

Hidradenitis suppurativa (HS), a pathological follicular disease, impacts patients' lives profoundly. HS most commonly involves cutaneous intertriginous areas, such as the axilla, inner thighs, groin and buttocks, and pendulous breasts, but can appear on any follicular skin. Protean, HS manifests with variations of abscesses, folliculitis, pyogenic granulomas, scars (oval honeycombed), comedones, tracts, fistulas, and keloids. The pathophysiology might involve both defects of the innate follicular immunity and overreaction to coagulase negative Staphylococcus. Treatment depends on the morphology, extent, severity, and duration. Topical clindamycin and dapsone are often adequate for treating mild HS. For Stage 1 and 2 HS, first line treatment combines rifampin with either oral clindamycin or minocycline. Other HS treatments include: fluoroquinolones with metronidazole and rifampin, oral dapsone, zinc, acitretin, hormone blockers (oral contraceptive pills, spironolactone, finasteride, and dutasteride), and oral prednisone. For severe HS, cyclosporine, adalimumab, or infliximab (used at double psoriatic doses) and intravenous carbapenems or cephalosporins are often required. Isotretinoin, etanercept, isoniazid, lymecycline, sulfasalazine, methotrexate, metformin, colchicine, clarithromycin, IVIG, and thalidomide are less favored treatments. The role of botulinum toxin is uncertain. The most important life style modification is weight loss. De-roofing fluctuant nodules and injection of intralesional corticosteroids ameliorates the disease and perhaps, if done at regular intervals, improves HS more permanently. Surgical excision and CO2 laser ablation are more definitive treatments. The 1064 nm laser for hair removal aids in the treatment of HS. This article centers on medical therapies and will only passingly mention surgical and laser treatments. This article summarizes my treatment experience with over 350 HS patients.

Waldenstrom Macroglobulinemia☆

PubMed Central

Leleu, Xavier; Roccaro, Aldo M.; Moreau, Anne-Sophie; Dupire, Sophie; Robu, Daniela; Gay, Julie; Hatjiharissi, Evdoxia; Burwik, Nicholas; Ghobrial, Irene M.

2011-01-01

In the past years, new developments have occurred both in the understanding of the biology of Waldenstrom Macroglobulinemia (WM) and in therapeutic options for WM. WM is a B-cell disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells, along with demonstration of an IgM monoclonal gammopathy. Despite advances in therapy, WM remains incurable, with 5–6 years median overall survival of patients in symptomatic WM. Therapy is postponed for asymptomatic patients, and progressive anemia is the most common indication for initiation of treatment. The main therapeutic options include alkylating agents, nucleoside analogues, and rituximab. Studies involving combination chemotherapy are ongoing, and preliminary results are encouraging. No specific agent or regimen has been shown to be superior to another for treatment of WM. As such, novel therapeutic agents are needed for the treatment of WM. In ongoing efforts, we and others have sought to exploit advances made in the understanding of the biology of WM so as to better target therapeutics for this malignancy. These efforts have led to the development of several novel agents including the proteasome inhibitor bortezomib, and several Akt/mTor inhibitors, perifosine and Rad001, and immunomodulatory agents such as thalidomide and lenalidomide. Studies with monoclonal antibodies are ongoing and promising including the use of alemtuzumab, SGN-70, and the APRIL/BLYS blocking protein TACI-Ig atacicept. Other agents currently being tested in clinical trials include the PKC inhibitor enzastaurin, the natural product resveratrol, as well as the statin simvastatin. This report provides an update of the current preclinical studies and clinical efforts for the development of novel agents in the treatment of WM. PMID:18555588

Safety of immunomodulators and biologics for the treatment of inflammatory bowel disease during pregnancy and breast-feeding.

PubMed

Gisbert, Javier P

2010-05-01

The aim of this article is to critically review available data regarding the safety of immunomodulators and biological therapies during pregnancy and breast-feeding in women with inflammatory bowel disease. Methotrexate and thalidomide can cause congenital anomalies and are contraindicated during pregnancy (and breast-feeding). Although thiopurines have a Food and Drug Administration (FDA) rating D, available data suggest that these drugs are safe and well tolerated during pregnancy. Although traditionally women receiving azathioprine or mercaptopurine have been discouraged from breast-feeding because of theoretical potential risks, it seems that these drugs may be safe in this scenario. Treatment with cyclosporine for steroid-refractory ulcerative colitis (UC) during pregnancy can be considered safe and effective, and the use of this drug should be considered in cases of severe UC as a means of avoiding urgent surgery. Breast-feeding is contraindicated for patients receiving cyclosporine. Biological therapies appear to be safe in pregnancy, as no increased risk of malformations has been demonstrated. Therefore, the limited clinical results available suggest that the benefits of infliximab and adalimumab in attaining response and maintaining remission in pregnant patients might outweigh the theoretical risks of drug exposure to the fetus. Stopping therapy in the third trimester may be considered, as it seems that transplacental transfer of infliximab is low prior to this. Certolizumab differs from infliximab and adalimumab in that it is a Fab fragment of an antitumor necrosis factor alpha monoclonal antibody, and therefore it may not be necessary to stop certolizumab in the third trimester. The use of infliximab is probably compatible with breast-feeding.

Management of patients with multiple myeloma: emphasizing the role of high-dose therapy.

PubMed

Kyle, R A

2001-06-01

Treatment for multiple myeloma should not be given until the patient is symptomatic or at risk for the occurrence of complications of the disease. If the patient is younger than 70 years, the physician should seriously consider an autologous peripheral blood stem cell transplant. Most physicians initially administer vincristine/doxorubicin/dexamethasone (VAD) for 3 to 4 months and then collect the stem cells before exposure to alkylating agents. Following stem cell collection, one may proceed with high-dose chemotherapy and then infusion of the stem cells, or one can administer alkylating agents until a plateau is reached and delay transplantation until progressive disease occurs. There is no difference in overall survival between early and late transplantation, but the former avoids the cost and inconvenience of alkylating agent therapy. Double or tandem autologous stem cell transplants may produce better results, but the evidence is not strong. Almost all patients have a relapse after an autologous stem cell transplant, so efforts are being made to prolong the response with a2-interferon or dendritic cell therapy. Allogeneic bone marrow transplantation is feasible for only 5%-10% of patients, but the mortality is high and it is curative in only a small fraction of patients. Treatment with melphalan and prednisone results in an objective response in 50%-60% of patients. Combinations of alkylating agents produce a higher response rate, but there is no survival benefit. Thalidomide produces an objective response in about one third of patients with refractory disease. It currently is being studied in conjunction with dexamethasone for conventional initial therapy.

Thyroid Dysfunction from Antineoplastic Agents

PubMed Central

Larsen, P. Reed; Marqusee, Ellen

2011-01-01

Unlike cytotoxic agents that indiscriminately affect rapidly dividing cells, newer antineoplastic agents such as targeted therapies and immunotherapies are associated with thyroid dysfunction. These include tyrosine kinase inhibitors, bexarotene, radioiodine-based cancer therapies, denileukin diftitox, alemtuzumab, interferon-α, interleukin-2, ipilimumab, tremelimumab, thalidomide, and lenalidomide. Primary hypothyroidism is the most common side effect, although thyrotoxicosis and effects on thyroid-stimulating hormone secretion and thyroid hormone metabolism have also been described. Most agents cause thyroid dysfunction in 20%–50% of patients, although some have even higher rates. Despite this, physicians may overlook drug-induced thyroid dysfunction because of the complexity of the clinical picture in the cancer patient. Symptoms of hypothyroidism, such as fatigue, weakness, depression, memory loss, cold intolerance, and cardiovascular effects, may be incorrectly attributed to the primary disease or to the antineoplastic agent. Underdiagnosis of thyroid dysfunction can have important consequences for cancer patient management. At a minimum, the symptoms will adversely affect the patient’s quality of life. Alternatively, such symptoms can lead to dose reductions of potentially life-saving therapies. Hypothyroidism can also alter the kinetics and clearance of medications, which may lead to undesirable side effects. Thyrotoxicosis can be mistaken for sepsis or a nonendocrinologic drug side effect. In some patients, thyroid disease may indicate a higher likelihood of tumor response to the agent. Both hypothyroidism and thyrotoxicosis are easily diagnosed with inexpensive and specific tests. In many patients, particularly those with hypothyroidism, the treatment is straightforward. We therefore recommend routine testing for thyroid abnormalities in patients receiving these antineoplastic agents. PMID:22010182

Treatment of Cachexia in Oncology

PubMed Central

Tazi, EM; Errihani, H

2010-01-01

Cachexia is a complex metabolic syndrome associated with many chronic or end-stage diseases, especially cancer, and is characterized by loss of muscle with or without loss of fat mass. The management of cachexia is a complex challenge that should address the different causes underlying this clinical event with an integrated or multimodal treatment approach targeting the different factors involved in its pathophysiology. The purpose of this article was to review the current medical treatment of cancer-related cachexia, in particular focusing on combination therapy and ongoing research. Among the treatments proposed in the literature for cancer-related cachexia, some proved to be ineffective, namely, cyproheptadine, hydrazine, metoclopramide, and pentoxifylline. Among effective treatments, progestagens are currently considered the best available treatment option for cancer-related cachexia, and they are the only drugs approved in Europe. Drugs with a strong rationale that have failed or have not shown univocal results in clinical trials so far include eicosapentaenoic acid, cannabinoids, bortezomib, and anti-TNF-alpha MoAb. Several emerging drugs have shown promising results but are still under clinical investigation (thalidomide, selective cox-2 inhibitors, ghrelin mimetics, insulin, oxandrolone, and olanzapine). To date, despite several years of coordinated efforts in basic and clinical research, practice guidelines for the prevention and treatment of cancer-related muscle wasting are lacking, mainly because of the multifactorial pathogenesis of the syndrome. From all the data presented, one can speculate that one single therapy may not be completely successful in the treatment of cachexia. From this point of view, treatments involving different combinations are more likely to be successful. PMID:21218002

Central nervous system involvement in pediatric rheumatic diseases: current concepts in treatment.

PubMed

Duzova, Ali; Bakkaloglu, Aysin

2008-01-01

Central nervous system (CNS) manifestations are not rare in pediatric rheumatic diseases. They may be a relatively common feature of the disease, as in systemic lupus erythematosus (SLE) and Behçet's disease. Direct CNS involvement of a systemic rheumatic disease, primary CNS vasculitis, indirect involvement secondary to hypertension, hypoxia and metabolic changes, and drug associated adverse events may all result in CNS involvement. We have reviewed the CNS manifestations of SLE, Behçet's disease, Henoch-Schönlein purpura, polyarteritis nodosa, juvenile idiopathic arthritis, juvenile ankylosing spondylitis, familial Mediterranean fever, scleroderma, sarcoidosis, Wegener's granulomatosis, Takayasu's arteritis, CINCA syndrome, Kawasaki disease, and primary CNS vasculitis; and adverse CNS effects of anti-rheumatic drugs in pediatric patients. The manifestations are diverse; ranging from headache, seizures, chorea, changes in personality, depression, memory and concentration problems, cognitive impairment, cerebrovascular accidents to coma, and death. The value of cerebrospinal fluid (CSF) examination (pleocytosis, high level of protein), auto-antibodies in serum and CSF, electroencephalography, neuroimaging with computerized tomography, magnetic resonance imaging, SPECT, PET, and angiography depends on the disease. Brain biopsy is gold standard for the diagnosis of CNS vasculitis, however it may be inconclusive in 25% of cases. A thorough knowledge of the rheumatic diseases and therapy-related adverse events is mandatory for the management of a patient with rheumatic disease and CNS involvement. Severe CNS involvement is associated with poor prognosis, and high mortality rate. High dose steroid and cyclophosphamide (oral or intravenous) are first choice drugs in the treatment; plasmapheresis, IVIG, thalidomide, and intratechal treatment may be valuable in treatment-resistant, and serious cases.

Etiology and treatment of cough in idiopathic pulmonary fibrosis.

PubMed

Vigeland, Christine L; Hughes, Andrew H; Horton, Maureen R

2017-02-01

Idiopathic pulmonary fibrosis (IPF) is a progressive disease of dysregulated wound healing leading to unremitting scarring and loss of lung function. The predominant symptoms are dyspnea on exertion and a persistent dry cough. For patients with IPF, cough is more than just bothersome; it has a significant negative impact on quality of life and is a marker of disease severity and progression. The etiology of cough in IPF is unclear but may be due to architectural distortion of the lungs, increased sensitivity of the cough reflex, airway inflammation, or changes in mucus production and clearance. There also may be an overlap between IPF cough and cough due to other common etiologies such as asthma, gastroesophageal reflux disease, upper airway cough syndrome, and medications. There are no approved therapies to specifically treat IPF cough, and recently approved medications for IPF have not been evaluated in cough. Few clinical trials have focused on treatments for IPF cough. To date, there is only one randomized, placebo control therapeutic study for IPF cough with thalidomide, which significantly reduced IPF cough and improved quality of life. Two additional cohort studies report that interferon-α and prednisolone also decrease IPF cough. However, no medication is approved to treat IPF cough. Currently, the mainstay of therapy for IPF cough is standard cough suppressants, which have limited efficacy and often intolerable side effects. Future studies are needed to determine an effective therapy to alleviate this particularly debilitating symptom and improve overall quality of life for patients suffering with IPF. Copyright © 2016 Elsevier Ltd. All rights reserved.

Human Teratogens Update 2011: Can We Ensure Safety during Pregnancy?

PubMed Central

Rasmussen, Sonja A.

2015-01-01

Anniversaries of the identification of three human teratogens (i.e., rubella virus in 1941, thalidomide in 1961, and diethylstilbestrol in 1971) occurred in 2011. These experiences highlight the critical role that scientists with an interest in teratology play in the identification of teratogenic exposures as the basis for developing strategies for prevention of those exposures and the adverse outcomes associated with them. However, an equally important responsibility for teratologists is to evaluate whether medications and vaccines are safe for use during pregnancy so informed decisions about disease treatment and prevention during pregnancy can be made. Several recent studies have examined the safety of medications during pregnancy, including antiviral medications used to treat herpes simplex and zoster, proton pump inhibitors used to treat gastroesophageal reflux, and newer-generation antiepileptic medications used to treat seizures and other conditions. Despite the large numbers of pregnant women included in these studies and the relatively reassuring results, the question of whether these medications are teratogens remains. In addition, certain vaccines are recommended during pregnancy to prevent infections in mothers and infants, but clinical trials to test these vaccines typically exclude pregnant women; thus, evaluation of their safety depends on observational studies. For pregnant women to receive optimal care, we need to define the data needed to determine whether a medication or vaccine is “safe” for use during pregnancy. In the absence of adequate, well-controlled data, it will often be necessary to weigh the benefits of medications or vaccines with potential risks to the embryo or fetus. PMID:22328359

Human teratogens update 2011: can we ensure safety during pregnancy?

PubMed

Rasmussen, Sonja A

2012-03-01

Anniversaries of the identification of three human teratogens (i.e., rubella virus in 1941, thalidomide in 1961, and diethylstilbestrol in 1971) occurred in 2011. These experiences highlight the critical role that scientists with an interest in teratology play in the identification of teratogenic exposures as the basis for developing strategies for prevention of those exposures and the adverse outcomes associated with them. However, an equally important responsibility for teratologists is to evaluate whether medications and vaccines are safe for use during pregnancy so informed decisions about disease treatment and prevention during pregnancy can be made. Several recent studies have examined the safety of medications during pregnancy, including antiviral medications used to treat herpes simplex and zoster, proton pump inhibitors used to treat gastroesophageal reflux, and newer-generation antiepileptic medications used to treat seizures and other conditions. Despite the large numbers of pregnant women included in these studies and the relatively reassuring results, the question of whether these medications are teratogens remains. In addition, certain vaccines are recommended during pregnancy to prevent infections in mothers and infants, but clinical trials to test these vaccines typically exclude pregnant women; thus, evaluation of their safety depends on observational studies. For pregnant women to receive optimal care, we need to define the data needed to determine whether a medication or vaccine is "safe" for use during pregnancy. In the absence of adequate, well-controlled data, it will often be necessary to weigh the benefits of medications or vaccines with potential risks to the embryo or fetus. Copyright © 2012 Wiley Periodicals, Inc.

Preface to the Surface Science Topical Issue on Chirality at Surfaces

NASA Astrophysics Data System (ADS)

2014-11-01

This Topical Issue of Surface Science focuses on the rapidly growing interest in the structure and enantioselective properties of chiral surfaces and chiral organic layers on surfaces. Chirality has intrigued scientists since the time of Pasteur and his 1848 [1] demonstration of the relationship between the optical rotation of light and the atomic structure of the compounds through which it propagates. The origin of optical rotation in the structure of organic molecules and the tetrahedral nature of the carbon atom was first appreciated and articulated by van't Hoff in 1874 [2]. In biochemistry, the importance of molecular chirality arises from the fact that most naturally occurring chiral biomolecules exist in homochiral form. For example, the fundamental building blocks of proteins are the amino acids which all appear in the L-enantiomeric form in nature. The implications of biomolecular homochirality were not truly appreciated until the late 1950s [3] when the stereochemistry of the artificially produced drug thalidomide was implicated in the physical defects observed in thousands of children born to mothers who had used the drug during pregnancy. This then sparked an explosion in asymmetric synthesis and enantioselective chemical processing in general, as regulations required that chiral pharmaceuticals be manufactured in enantiomerically pure form. The development of heterogenous catalysts for industrial-scale production of enantiomerically pure molecules is still a huge challenge. Many of the studies in this Topical Issue are aimed at developing a molecular level understanding of the surface processes which direct enantioselective reactions at gas-solid and liquid-solid interfaces.

Genetic Syndromes, Maternal Diseases and Antenatal Factors Associated with Autism Spectrum Disorders (ASD)

PubMed Central

Ornoy, Asher; Weinstein- Fudim, Liza; Ergaz, Zivanit

2016-01-01

Autism spectrum disorder (ASD) affecting about 1% of all children is associated, in addition to complex genetic factors, with a variety of prenatal, perinatal, and postnatal etiologies. In addition, ASD is often an important clinical presentation of some well-known genetic syndromes in human. We discuss these syndromes as well as the role of the more important prenatal factors affecting the fetus throughout pregnancy which may also be associated with ASD. Among the genetic disorders we find Fragile X, Rett syndrome, tuberous sclerosis, Timothy syndrome, Phelan–McDermid syndrome, Hamartoma tumor syndrome, Prader-Willi and Angelman syndromes, and a few others. Among the maternal diseases in pregnancy associated with ASD are diabetes mellitus (PGDM and/or GDM), some maternal autoimmune diseases like antiphospholipid syndrome (APLS) with anti-β2GP1 IgG antibodies and thyroid disease with anti-thyroid peroxidase (TPO) antibodies, preeclampsia and some other autoimmune diseases with IgG antibodies that might affect fetal brain development. Other related factors are maternal infections (rubella and CMV with fetal brain injuries, and possibly Influenza with fever), prolonged fever and maternal inflammation, especially with changes in a variety of inflammatory cytokines and antibodies that cross the placenta and affect the fetal brain. Among the drugs are valproic acid, thalidomide, misoprostol, and possibly SSRIs. β2-adrenergic receptor agonists and paracetamol have also lately been associated with increased rate of ASD but the data is too preliminary and inconclusive. Associations were also described with ethanol, cocaine, and possibly heavy metals, heavy smoking, and folic acid deficiency. Recent studies show that heavy exposure to pesticides and air pollution, especially particulate matter < 2.5 and 10 μm in diameter (PM2.5 and PM10) during pregnancy is also associated with ASD. Finally, we have to remember that many of the associations mentioned in this review are only partially proven, and not all are “clean” of different confounding factors. The associations described in this review emphasize again how little we know about the etiology and pathogenesis of ASD. It is obvious that we need more epidemiologic data to establish many of these associations, but if proven, they might be promising avenues for prevention. PMID:27458336

Radiotherapy and "new" drugs-new side effects?

PubMed Central

2011-01-01

Background and purpose Targeted drugs have augmented the cancer treatment armamentarium. Based on the molecular specificity, it was initially believed that these drugs had significantly less side effects. However, currently it is accepted that all of these agents have their specific side effects. Based on the given multimodal approach, special emphasis has to be placed on putative interactions of conventional cytostatic drugs, targeted agents and other modalities. The interaction of targeted drugs with radiation harbours special risks, since the awareness for interactions and even synergistic toxicities is lacking. At present, only limited is data available regarding combinations of targeted drugs and radiotherapy. This review gives an overview on the current knowledge on such combined treatments. Materials and methods Using the following MESH headings and combinations of these terms pubmed database was searched: Radiotherapy AND cetuximab/trastuzumab/panitumumab/nimotuzumab, bevacizumab, sunitinib/sorafenib/lapatinib/gefitinib/erlotinib/sirolimus, thalidomide/lenalidomide as well as erythropoietin. For citation crosscheck the ISI web of science database was used employing the same search terms. Results Several classes of targeted substances may be distinguished: Small molecules including kinase inhibitors and specific inhibitors, antibodies, and anti-angiogenic agents. Combination of these agents with radiotherapy may lead to specific toxicities or negatively influence the efficacy of RT. Though there is only little information on the interaction of molecular targeted radiation and radiotherapy in clinical settings, several critical incidents are reported. Conclusions The addition of molecular targeted drugs to conventional radiotherapy outside of approved regimens or clinical trials warrants a careful consideration especially when used in conjunction in hypo-fractionated regimens. Clinical trials are urgently needed in order to address the open question in regard to efficacy, early and late toxicity. PMID:22188921

Multiple myeloma: diagnosis and treatment.

PubMed

Nau, Konrad C; Lewis, William D

2008-10-01

Multiple myeloma, the most common bone malignancy, is occurring with increasing frequency in older persons. Typical symptoms are bone pain, malaise, anemia, renal insufficiency, and hypercalcemia. Incidental discovery on comprehensive laboratory panels is common. The disease is diagnosed with serum or urine protein electrophoresis or immunofixation and bone marrow aspirate analysis. Skeletal radiographs are important in staging multiple myeloma and revealing lytic lesions, vertebral compression fractures, and osteoporosis. Magnetic resonance imaging and positron emission tomography or computed tomography are emerging as useful tools in the evaluation of patients with myeloma; magnetic resonance imaging is preferred for evaluating acute spinal compression. Nuclear bone scans and dual energy x-ray absorptiometry have no role in the diagnosis and staging of myeloma. The differential diagnosis of monoclonal gammopathies includes monoclonal gammopathy of uncertain significance, smoldering (asymptomatic) and symptomatic multiple myeloma, amyloidosis, B-cell non-Hodgkin lymphoma, Waldenström macroglobulinemia, and rare plasma cell leukemia and heavy chain diseases. Patients with monoclonal gammopathy of uncertain significance or smoldering multiple myeloma should be followed closely, but not treated. Symptomatic multiple myeloma is treated with chemotherapy followed by autologous stem cell transplantation, if possible. Melphalan, prednisolone, dexamethasone, vincristine, doxorubicin, bortezomib, and thalidomide and its analogue lenalidomide have been used successfully. It is important that family physicians recognize and appropriately treat multiple myeloma complications. Bone pain is treated with opiates, bisphosphonates, radiotherapy, vertebroplasty, or kyphoplasty; nephrotoxic nonsteroidal anti-inflammatory drugs should be avoided. Hypercalcemia is treated with isotonic saline infusions, steroids, furosemide, or bisphosphonates. Because of susceptibility to infections, patients require broad-spectrum antibiotics for febrile illness and immunization against influenza, pneumococcus, and Haemophilus influenzae B. Five-year survival rates approach 33 percent, and the median survival rate is 33 months.

Comprehensive evaluation of the revised international staging system in multiple myeloma patients treated with novel agents as a primary therapy.

PubMed

Cho, Hyungwoo; Yoon, Dok Hyun; Lee, Jung Bok; Kim, Sung-Yong; Moon, Joon Ho; Do, Young Rok; Lee, Jae Hoon; Park, Yong; Lee, Ho Sup; Eom, Hyeon Seok; Shin, Ho-Jin; Min, Chang-Ki; Kim, Jin Seok; Jo, Jae-Cheol; Kang, Hye Jin; Mun, Yeung-Chul; Lee, Won Sik; Lee, Je-Jung; Suh, Cheolwon; Kim, Kihyun

2017-12-01

The revised International Staging System (R-ISS) has recently been developed to improve the risk stratification of multiple myeloma (MM) patients over the ISS. We assessed the R-ISS in MM patients who were treated with novel agents as a primary therapy and evaluated its discriminative power and ability to reclassify patients from the ISS. A total of 514 newly diagnosed MM patients treated with novel agents including thalidomide, bortezomib, and lenalidomide as a primary therapy were included in this retrospective analysis. With a median follow-up duration of 42.3 months (range, 40.5-44.1), the median overall survival (OS) was 61.0 months. There was a significant difference in median OS (not reached, 60.9, and 50.1 months for stages 1, 2, and 3, respectively, P < 0.001) among the three stages of R-ISS. The C-statistic was significantly greater for R-ISS than for ISS (0.769 vs. 0.696, P < 0.001). The event NRI was -0.08 (95% confidence interval [CI], -0.18-0.01) and the non-event NRI was 0.05 (95% CI, -0.03-0.10), resulting in a total NRI of -0.03 (95% CI, -0.14-0.08, P = 0.602). The R-ISS performs well and has significantly better discriminative power than the ISS in MM patients treated with novel agents as a primary therapy. However, it does not better reclassify patients from the ISS, suggesting that there is still room to improve the staging system. Moreover, new statistical measures for assessing and quantifying the risk prediction of new prognostic models are necessary in future studies. © 2017 Wiley Periodicals, Inc.

Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma.

PubMed

Facon, Thierry; Dimopoulos, Meletios A; Dispenzieri, Angela; Catalano, John V; Belch, Andrew; Cavo, Michele; Pinto, Antonello; Weisel, Katja; Ludwig, Heinz; Bahlis, Nizar J; Banos, Anne; Tiab, Mourad; Delforge, Michel; Cavenagh, Jamie D; Geraldes, Catarina; Lee, Je-Jung; Chen, Christine; Oriol, Albert; De La Rubia, Javier; White, Darrell; Binder, Daniel; Lu, Jin; Anderson, Kenneth C; Moreau, Philippe; Attal, Michel; Perrot, Aurore; Arnulf, Bertrand; Qiu, Lugui; Roussel, Murielle; Boyle, Eileen; Manier, Salomon; Mohty, Mohamad; Avet-Loiseau, Herve; Leleu, Xavier; Ervin-Haynes, Annette; Chen, Guang; Houck, Vanessa; Benboubker, Lotfi; Hulin, Cyrille

2018-01-18

This FIRST trial final analysis examined survival outcomes in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) treated with lenalidomide and low-dose dexamethasone until disease progression (Rd continuous), Rd for 72 weeks (18 cycles; Rd18), or melphalan, prednisone, and thalidomide (MPT; 72 weeks). The primary endpoint was progression-free survival (PFS; primary comparison: Rd continuous vs MPT). Overall survival (OS) was a key secondary endpoint (final analysis prespecified ≥60 months' follow-up). Patients were randomized to Rd continuous (n = 535), Rd18 (n = 541), or MPT (n = 547). At a median follow-up of 67 months, PFS was significantly longer with Rd continuous vs MPT (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.59-0.79; P < .00001) and was similarly extended vs Rd18. Median OS was 10 months longer with Rd continuous vs MPT (59.1 vs 49.1 months; HR, 0.78; 95% CI, 0.67-0.92; P = .0023), and similar with Rd18 (62.3 months). In patients achieving complete or very good partial responses, Rd continuous had an ≈30-month longer median time to next treatment vs Rd18 (69.5 vs 39.9 months). Over half of all patients who received second-line treatment were given a bortezomib-based therapy. Second-line outcomes were improved in patients receiving bortezomib after Rd continuous and Rd18 vs after MPT. No new safety concerns, including risk for secondary malignancies, were observed. Treatment with Rd continuous significantly improved survival outcomes vs MPT, supporting Rd continuous as a standard of care for patients with transplant-ineligible NDMM. This trial was registered at www.clinicaltrials.gov as #NCT00689936 and EudraCT as 2007-004823-39. © 2018 by The American Society of Hematology.

Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma

PubMed Central

Dimopoulos, Meletios A.; Dispenzieri, Angela; Catalano, John V.; Belch, Andrew; Cavo, Michele; Pinto, Antonello; Weisel, Katja; Ludwig, Heinz; Bahlis, Nizar J.; Banos, Anne; Tiab, Mourad; Delforge, Michel; Cavenagh, Jamie D.; Geraldes, Catarina; Lee, Je-Jung; Chen, Christine; Oriol, Albert; De La Rubia, Javier; White, Darrell; Binder, Daniel; Lu, Jin; Anderson, Kenneth C.; Moreau, Philippe; Attal, Michel; Perrot, Aurore; Arnulf, Bertrand; Qiu, Lugui; Roussel, Murielle; Boyle, Eileen; Manier, Salomon; Mohty, Mohamad; Avet-Loiseau, Herve; Leleu, Xavier; Ervin-Haynes, Annette; Chen, Guang; Houck, Vanessa; Benboubker, Lotfi; Hulin, Cyrille

2018-01-01

This FIRST trial final analysis examined survival outcomes in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) treated with lenalidomide and low-dose dexamethasone until disease progression (Rd continuous), Rd for 72 weeks (18 cycles; Rd18), or melphalan, prednisone, and thalidomide (MPT; 72 weeks). The primary endpoint was progression-free survival (PFS; primary comparison: Rd continuous vs MPT). Overall survival (OS) was a key secondary endpoint (final analysis prespecified ≥60 months’ follow-up). Patients were randomized to Rd continuous (n = 535), Rd18 (n = 541), or MPT (n = 547). At a median follow-up of 67 months, PFS was significantly longer with Rd continuous vs MPT (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.59-0.79; P < .00001) and was similarly extended vs Rd18. Median OS was 10 months longer with Rd continuous vs MPT (59.1 vs 49.1 months; HR, 0.78; 95% CI, 0.67-0.92; P = .0023), and similar with Rd18 (62.3 months). In patients achieving complete or very good partial responses, Rd continuous had an ≈30-month longer median time to next treatment vs Rd18 (69.5 vs 39.9 months). Over half of all patients who received second-line treatment were given a bortezomib-based therapy. Second-line outcomes were improved in patients receiving bortezomib after Rd continuous and Rd18 vs after MPT. No new safety concerns, including risk for secondary malignancies, were observed. Treatment with Rd continuous significantly improved survival outcomes vs MPT, supporting Rd continuous as a standard of care for patients with transplant-ineligible NDMM. This trial was registered at www.clinicaltrials.gov as #NCT00689936 and EudraCT as 2007-004823-39. PMID:29150421

Cost-effectiveness analysis of low-molecular-weight heparin versus aspirin thromboprophylaxis in patients newly diagnosed with multiple myeloma.

PubMed

Chalayer, Emilie; Bourmaud, Aurélie; Tinquaut, Fabien; Chauvin, Franck; Tardy, Bernard

2016-09-01

The aim of this study was to assess the cost-effectiveness of low molecular weight heparin versus aspirin as primary thromboprophylaxis throughout chemotherapy for newly diagnosed multiple myeloma patients treated with protocols including thalidomide from the perspective of French health care providers. We used a modeling approach combining data from the only randomized trial evaluating the efficacy of the two treatments and secondary sources for costs, and utility values. We performed a decision-tree analysis and our base case was a hypothetical cohort of 10,000 patients. A bootstrap resampling technique was used. The incremental cost-effectiveness ratio was calculated using estimated quality-adjusted life years as the efficacy outcome. Incremental costs and effectiveness were estimated for each strategy and the incremental cost-effectiveness ratio was calculated. One-way sensitivity analyses were performed. The number of quality-adjusted life years was estimated to be 0.300 with aspirin and 0.299 with heparin. The estimated gain with aspirin was therefore approximately one day. Over 6months, the mean total cost was € 1518 (SD=601) per patient in the heparin arm and € 273 (SD=1019) in the aspirin arm. This resulted in an incremental cost of € 1245 per patient treated with heparin. The incremental cost-effectiveness ratio for the aspirin versus heparin strategy was calculated to be - 687,398 € (95% CI, -13,457,369 to -225,385). Aspirin rather than heparin thromboprophylaxis, during the first six months of chemotherapy for myeloma, is associated with significant cost savings per patient and also with an unexpected slight increase in quality of life. Copyright © 2016 Elsevier Ltd. All rights reserved.

Anorexia in end-stage renal disease: pathophysiology and treatment.

PubMed

Aguilera, A; Selgas, R; Diéz, J J; Bajo, M A; Codoceo, R; Alvarez, V

2001-11-01

Anorexia is a frequent complication of uraemic syndrome, which contributes to malnutrition in dialysis patients. Uraemic anorexia has been associated with many factors. This paper reviews the current knowledge about mechanisms responsible for uraemic anorexia, the treatments and new drugs used to control the loss of appetite. Traditionally, anorexia in dialysis patients has been considered as a sign of uraemic toxicity, therefore, two hypotheses have been proposed, the 'middle molecule' and 'peak-concentration' hypotheses, both of which are still unproved. Recently, our group proposed the tryptophan-serotonin hypothesis, which is based on a disorder in the amino acid profile acquired in the uraemic status. This is characterised by low concentrations of large neutral and branched chain amino acids (LNAA/BCAA) in the cerebrospinal fluid. This situation permits a high level of tryptophan transport across the blood-brain barrier, causing an increase in the synthesis of serotonin (responsible for appetite inhibition). There are two main treatment targets for anorexia in dialysis patients. The first is to decrease the free plasma tryptophan concentration and transport across the blood brain barrier to the cerebrospinal fluid, thus decreasing the intracerebral serotonin levels. Nutritional formulae enriched with LNAA and BCAA have this effect. Secondly, plasma levels of cytokines with cachectin effect (TNF-alpha), should be decreased. This also induces a decrease in LNAA and BCAA levels. In this group are megestrol acetate, anti-TNF-alpha antibodies, thalidomide, pentoxifyilline, n-3 fatty acids and possibly nandrolone decanoate. Additionally, other targets should be explored including antagonists of cholecystokinin (a potent anorexigen retained by renal failure), analogues of neuropeptide Y (the most potent orexigen), cannabinoids, cyproheptadine, hydrazine sulfate. In conclusion, uraemic anorexia is a complex complication associated with malnutrition, high morbidity and mortality. The pharmacological treatment should address key points in the pathogenesis of uraemic anorexia, reducing intra-cerebral concentration of serotonin with LNAA/BCAA oral diet formulae and the plasma levels of pro-inflammatory molecules. Others forms of treatment should also be explored.

Generating Gene Ontology-Disease Inferences to Explore Mechanisms of Human Disease at the Comparative Toxicogenomics Database

PubMed Central

Davis, Allan Peter; Wiegers, Thomas C.; King, Benjamin L.; Wiegers, Jolene; Grondin, Cynthia J.; Sciaky, Daniela; Johnson, Robin J.; Mattingly, Carolyn J.

2016-01-01

Strategies for discovering common molecular events among disparate diseases hold promise for improving understanding of disease etiology and expanding treatment options. One technique is to leverage curated datasets found in the public domain. The Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) manually curates chemical-gene, chemical-disease, and gene-disease interactions from the scientific literature. The use of official gene symbols in CTD interactions enables this information to be combined with the Gene Ontology (GO) file from NCBI Gene. By integrating these GO-gene annotations with CTD’s gene-disease dataset, we produce 753,000 inferences between 15,700 GO terms and 4,200 diseases, providing opportunities to explore presumptive molecular underpinnings of diseases and identify biological similarities. Through a variety of applications, we demonstrate the utility of this novel resource. As a proof-of-concept, we first analyze known repositioned drugs (e.g., raloxifene and sildenafil) and see that their target diseases have a greater degree of similarity when comparing GO terms vs. genes. Next, a computational analysis predicts seemingly non-intuitive diseases (e.g., stomach ulcers and atherosclerosis) as being similar to bipolar disorder, and these are validated in the literature as reported co-diseases. Additionally, we leverage other CTD content to develop testable hypotheses about thalidomide-gene networks to treat seemingly disparate diseases. Finally, we illustrate how CTD tools can rank a series of drugs as potential candidates for repositioning against B-cell chronic lymphocytic leukemia and predict cisplatin and the small molecule inhibitor JQ1 as lead compounds. The CTD dataset is freely available for users to navigate pathologies within the context of extensive biological processes, molecular functions, and cellular components conferred by GO. This inference set should aid researchers, bioinformaticists, and pharmaceutical drug makers in finding commonalities in disease mechanisms, which in turn could help identify new therapeutics, new indications for existing pharmaceuticals, potential disease comorbidities, and alerts for side effects. PMID:27171405

Generating Gene Ontology-Disease Inferences to Explore Mechanisms of Human Disease at the Comparative Toxicogenomics Database.

PubMed

Davis, Allan Peter; Wiegers, Thomas C; King, Benjamin L; Wiegers, Jolene; Grondin, Cynthia J; Sciaky, Daniela; Johnson, Robin J; Mattingly, Carolyn J

2016-01-01

Strategies for discovering common molecular events among disparate diseases hold promise for improving understanding of disease etiology and expanding treatment options. One technique is to leverage curated datasets found in the public domain. The Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) manually curates chemical-gene, chemical-disease, and gene-disease interactions from the scientific literature. The use of official gene symbols in CTD interactions enables this information to be combined with the Gene Ontology (GO) file from NCBI Gene. By integrating these GO-gene annotations with CTD's gene-disease dataset, we produce 753,000 inferences between 15,700 GO terms and 4,200 diseases, providing opportunities to explore presumptive molecular underpinnings of diseases and identify biological similarities. Through a variety of applications, we demonstrate the utility of this novel resource. As a proof-of-concept, we first analyze known repositioned drugs (e.g., raloxifene and sildenafil) and see that their target diseases have a greater degree of similarity when comparing GO terms vs. genes. Next, a computational analysis predicts seemingly non-intuitive diseases (e.g., stomach ulcers and atherosclerosis) as being similar to bipolar disorder, and these are validated in the literature as reported co-diseases. Additionally, we leverage other CTD content to develop testable hypotheses about thalidomide-gene networks to treat seemingly disparate diseases. Finally, we illustrate how CTD tools can rank a series of drugs as potential candidates for repositioning against B-cell chronic lymphocytic leukemia and predict cisplatin and the small molecule inhibitor JQ1 as lead compounds. The CTD dataset is freely available for users to navigate pathologies within the context of extensive biological processes, molecular functions, and cellular components conferred by GO. This inference set should aid researchers, bioinformaticists, and pharmaceutical drug makers in finding commonalities in disease mechanisms, which in turn could help identify new therapeutics, new indications for existing pharmaceuticals, potential disease comorbidities, and alerts for side effects.

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Concise Review with a Comprehensive Summary of Therapeutic Interventions Emphasizing Supportive Measures.

PubMed

Schneider, Jeremy A; Cohen, Philip R

2017-06-01

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are two of the most severe dermatologic conditions occurring in the inpatient setting. There is a lack of consensus regarding appropriate management of SJS and TEN. The scientific literature pertaining to SJS and TEN (subsequently referred to as SJS/TEN) is summarized and assessed. In addition, an interventional approach for the clinician is provided. PubMed was searched with the key words: corticosteroids, cyclosporine, etanercept, intravenous immunoglobulin, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The papers generated by the search, and their references, were reviewed. Supportive care is the most universally accepted intervention for SJS/TEN. Specific guidelines differ from the care required for patients with thermal burns. Adjuvant therapies are utilized in most severe cases, but the data are thus far underwhelming and underpowered. Using systemic corticosteroids as sole therapy is not supported. A consensus regarding combined corticosteroids and intravenous immunoglobulin (IVIG) has not been reached. Data regarding IVIG, currently the standard of care for most referral centers, is conflicting. Newer studies regarding cyclosporine and tumor necrosis factor inhibitors are promising, but not powered to provide definitive evidence of efficacy. Data regarding plasmapheresis is equivocal. Thalidomide increases mortality. Clinicians who manage SJS/TEN should seek to employ interventions with the greatest impact on their patients' condition. While supportive care measures may seem an obvious aspect of SJS/TEN patient care, providers should understand that these interventions are imperative and that they differ from the care recommended for other critically ill or burn patients. While adjuvant therapies are frequently discussed and debated for hospitalized patients with SJS/TEN, a standardized management approach is not yet clear based on the current data. Therefore, until further data are available, decisions regarding such treatments should be made on a case-by-case basis.

Pharmacovigilance and Biomedical Informatics: A Model for Future Development.

PubMed

Beninger, Paul; Ibara, Michael A

2016-12-01

The discipline of pharmacovigilance is rooted in the aftermath of the thalidomide tragedy of 1961. It has evolved as a result of collaborative efforts by many individuals and organizations, including physicians, patients, Health Authorities, universities, industry, the World Health Organization, the Council for International Organizations of Medical Sciences, and the International Conference on Harmonisation. Biomedical informatics is rooted in technologically based methodologies and has evolved at the speed of computer technology. The purpose of this review is to bring a novel lens to pharmacovigilance, looking at the evolution and development of the field of pharmacovigilance from the perspective of biomedical informatics, with the explicit goal of providing a foundation for discussion of the future direction of pharmacovigilance as a discipline. For this review, we searched [publication trend for the log 10 value of the numbers of publications identified in PubMed] using the key words [informatics (INF), pharmacovigilance (PV), phar-macovigilance þ informatics (PV þ INF)], for [study types] articles published between [1994-2015]. We manually searched the reference lists of identified articles for additional information. Biomedical informatics has made significant contributions to the infrastructural development of pharmacovigilance. However, there has not otherwise been a systematic assessment of the role of biomedical informatics in enhancing the field of pharmacovigilance, and there has been little cross-discipline scholarship. Rapidly developing innovations in biomedical informatics pose a challenge to pharmacovigilance in finding ways to include new sources of safety information, including social media, massively linked databases, and mobile and wearable wellness applications and sensors. With biomedical informatics as a lens, it is evident that certain aspects of pharmacovigilance are evolving more slowly. However, the high levels of mutual interest in both fields and intense global and economic external pressures offer opportunities for a future of closer collaboration. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

Select putative neurodevelopmental toxins modify SNAP-25 expression in primary cultures of rat cerebellar granule cells.

PubMed

Zieminska, Elzbieta; Lenart, Jacek; Lazarewicz, Jerzy W

2016-08-31

A presynaptic protein SNAP-25 belonging to SNARE complex which is instrumental in intracellular vesicular trafficking and exocytosis, has been implicated in hyperactivity and cognitive abilities in some neuropsychiatric disorders. The unclear etiology of the behavior disrupting neurodevelopmental disabilities in addition to genetic causes most likely involves environmental factors. The aim of this in vitro study was to test if various suspected developmental neurotoxins can alter SNAP-25 mRNA and protein expression in neurons. Real-time PCR and Western blotting analyses were used to assess SNAP-25 mRNA and protein levels in primary cultures of rat cerebellar granule cells (CGCs). The test substances: tetrabromobisphenol-A (TBBPA), thimerosal (TH), silver nanoparticles (NAg), valproic acid (VPA) and thalidomide (THAL), were administered to CGC cultures at subtoxic concentrations for 24h. The results demonstrated that SNAP-25 mRNA levels were increased by 49 and 66% by TBBPA and THAL, respectively, whereas VPA and NAg reduced these levels to 48 and 64% of the control, respectively. The SNAP-25 protein content in CGCs was increased by 79% by TBBPA, 25% by THAL and 21% by NAg; VPA and TH reduced these levels to 73 and 69% of the control, respectively. The variety of changes in SNAP-25 expression on mRNA and protein level suggests the diversity of the mechanism of action of the test substances. This initial study provided no data on concentration-effect relations and on functional changes in CGCs. However it is the first to demonstrate the effect of different compounds that are suspected of causing neurodevelopmental disabilities on SNAP-25 expression. These results suggest that this protein may be a common target for not only inherited but also environmental modifications linked to behavioral deficits in neurodevelopmental disabilities. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Specific features of medicines safety and pharmacovigilance in Africa

PubMed Central

Pal, Shanthi N.; Olsson, Sten; Dodoo, Alexander; Bencheikh, Rachida Soulayami

2012-01-01

The thalidomide tragedy in the late 1950s and early 1960s served as a wakeup call and raised questions about the safety of medicinal products. The developed countries rose to the challenge putting in place systems to ensure the safety of medicines. However, this was not the case for low-resource settings because of prevailing factors inherent in them. This paper reviews some of these features and the current status of pharmacovigilance in Africa. The health systems in most of the 54 countries of Africa are essentially weak, lacking in basic infrastructure, personnel, equipment and facilities. The recent mass deployment of medicines to address diseases of public health significance in Africa poses additional challenges to the health system with notable safety concerns. Other safety issues of note include substandard and counterfeit medicines, medication errors and quality of medicinal products. The first national pharmacovigilance centres established in Africa with membership of the World Health Organization (WHO) international drug monitoring programme were in Morocco and South Africa in 1992. Of the 104 full member countries in the programme, there are now 24 African countries with a further nine countries as associate members. The pharmacovigilance systems operational in African countries are based essentially on spontaneous reporting facilitated by the introduction of the new tool Vigiflow. The individual case safety reports committed to the WHO global database (Vigibase) attest to the growth of pharmacovigilance in Africa with the number of reports rising from 2695 in 2000 to over 25,000 in 2010. There is need to engage the various identified challenges of the weak pharmacovigilance systems in the African setting and to focus efforts on how to provide resources, infrastructure and expertise. Raising the level of awareness among healthcare providers, developing training curricula for healthcare professionals, provisions for paediatric and geriatric pharmacovigilance, engaging the pharmaceutical industries as well as those for herbal remedies are of primary concern. PMID:25083223

Long-Term Effects, Pathophysiological Mechanisms, and Risk Factors of Chemotherapy-Induced Peripheral Neuropathies: A Comprehensive Literature Review

PubMed Central

Kerckhove, Nicolas; Collin, Aurore; Condé, Sakahlé; Chaleteix, Carine; Pezet, Denis; Balayssac, David

2017-01-01

Neurotoxic anticancer drugs, such as platinum-based anticancer drugs, taxanes, vinca alkaloids, and proteasome/angiogenesis inhibitors are responsible for chemotherapy-induced peripheral neuropathy (CIPN). The health consequences of CIPN remain worrying as it is associated with several comorbidities and affects a specific population of patients already impacted by cancer, a strong driver for declines in older adults. The purpose of this review is to present a comprehensive overview of the long-term effects of CIPN in cancer patients and survivors. Pathophysiological mechanisms and risk factors are also presented. Neurotoxic mechanisms leading to CIPNs are not yet fully understood but involve neuronopathy and/or axonopathy, mainly associated with DNA damage, oxidative stress, mitochondria toxicity, and ion channel remodeling in the neurons of the peripheral nervous system. Classical symptoms of CIPNs are peripheral neuropathy with a “stocking and glove” distribution characterized by sensory loss, paresthesia, dysesthesia and numbness, sometimes associated with neuropathic pain in the most serious cases. Several risk factors can promote CIPN as a function of the anticancer drug considered, such as cumulative dose, treatment duration, history of neuropathy, combination of therapies and genetic polymorphisms. CIPNs are frequent in cancer patients with an overall incidence of approximately 38% (possibly up to 90% of patients treated with oxaliplatin). Finally, the long-term reversibility of these CIPNs remain questionable, notably in the case of platinum-based anticancer drugs and taxanes, for which CIPN may last several years after the end of anticancer chemotherapies. These long-term effects are associated with comorbidities such as depression, insomnia, falls and decreases of health-related quality of life in cancer patients and survivors. However, it is noteworthy that these long-term effects remain poorly studied, and only limited data are available such as in the case of bortezomib and thalidomide-induced peripheral neuropathy. PMID:28286483

Advances in the Treatment of Paraproteinemic Neuropathy.

PubMed

Nobile-Orazio, Eduardo; Bianco, Mariangela; Nozza, Andrea

2017-10-16

Purpose of review Several advances have been made on the pathogenesis and therapy of neuropathies associated with paraproteinemia (monoclonal gammopathy). It is important for the neurologist to understand the pathogenetic relevance of this association especially when the hematological disease does not require per se any therapy. Recent findings Treatment of the neuropathy in patients with malignant paraproteinemia is mainly addressed by the hematologist while the neurologist is mainly involved in the initial diagnosis and in deciding whether the neuropathy is caused by the disease or by the chemotherapy used for the disease. There is little evidence that the neuropathy is caused by the hematological condition in patients with IgG or IgA monoclonal gammopathy of undetermined significance (MGUS) unless there is an evidence of a reactivity of the paraprotein with nerve or evidence of its presence in the nerve. Patients with a chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)-like presentation should be treated as CIDP while there is no evidence that immune or chemotherapy may be effective in the other patients. In most patients with IgM paraproteinemia, that is usually a MGUS or an indolent Waldenström's macroglobulinemia, the neuropathy is induced by an immune reactivity of the paraprotein with nerve and particularly with the myelin-associated glycoprotein. There are now consistent data also from controlled studies that the anti-CD20 monoclonal antibody rituximab may improve the neuropathy in these patients. POEMS syndrome is a severe condition characterized by a disabling neuropathy whose prognosis has improved in the last few years with therapies against the proliferating plasma cell clone or vascular endothelial growth factor including local radiotherapy and chemotherapy followed by autologous stem cell transplantation. Other therapies are also available for patients not eligible or resistant to transplantation, including lenalidomide and possibly thalidomide or bortezomib. Summary Several new therapies are now available for patients with paraproteinemic neuropathy consistently improving the prognosis of these neuropathies. In most instances, however, their efficacy needs to be confirmed in controlled trials.

Classical Hodgkin lymphoma arising in the setting of iatrogenic immunodeficiency: a clinicopathologic study of 10 cases.

PubMed

Loo, Eric Y; Medeiros, L Jeffrey; Aladily, Tariq N; Hoehn, Daniela; Kanagal-Shamanna, Rashmi; Young, Ken H; Lin, Pei; Bueso-Ramos, Carlos E; Manning, John T; Patel, Keyur; Thomazy, Vilmos; Brynes, Russell K; Goswami, Maitrayee; Fayad, Luis E; Miranda, Roberto N

2013-08-01

Iatrogenic immunodeficiency-associated lymphoproliferative disorders are rare. A small subset of these lesions resembles classical Hodgkin lymphoma (CHL), but there are few data in the literature about these lesions. We describe 10 patients with autoimmune diseases treated with immunomodulator therapeutic agents who developed CHL. The autoimmune diseases included rheumatoid arthritis (n=5), systemic lupus erythematosus (n=2), dermatomyositis (n=1), autoimmune hepatitis (n=1), and Crohn disease (n=1), and the immunomodulatory therapies were methotrexate, azathioprine, tumor necrosis factor-α inhibitors, and thalidomide alone or in various combinations. The study group included 9 women and 1 man with a median age of 50 years (range, 25 to 77 y). The histologic features supported CHL in all cases with Reed-Sternberg (RS) and Hodgkin (H) cells in an inflammatory cell background, although the neoplasm could only be subclassified in 3 patients: 2 nodular sclerosis and 1 mixed cellularity. Immunohistochemical analysis supported the diagnosis of CHL. In all cases the RS-H cells were CD30. Nine of 10 cases were CD15, whereas CD20 was expressed variably in 4/10 cases. CD45/LCA was negative in 8 cases assessed. In situ hybridization for Epstein-Barr virus-encoded RNA was positive in the RS-H cells in 8/10 cases. The microenvironment of these lesions depicted a predominance of T-regulatory cells and M2 histiocytes. Clinical follow-up data were available for 7 patients, with a median posttreatment period of 27 months (range, 12 mo to 7 y). In all 7 patients immunomodulatory drug therapy was discontinued, and chemotherapy for CHL was administered; 2 patients also received local radiation. All 7 patients achieved complete remission and are alive. We conclude that iatrogenic immunodeficiency-associated CHL is highly associated with Epstein-Barr virus infection, and patients usually have a good outcome after discontinuation of immunomodulatory agents and chemotherapy for CHL.

Phase II study of metronomic chemotherapy for recurrent malignant gliomas in adults

PubMed Central

Kesari, Santosh; Schiff, David; Doherty, Lisa; Gigas, Debra C.; Batchelor, Tracy T.; Muzikansky, Alona; O’Neill, Alison; Drappatz, Jan; Chen-Plotkin, Alice S.; Ramakrishna, Naren; Weiss, Stephanie E.; Levy, Brenda; Bradshaw, Joanna; Kracher, Jean; Laforme, Andrea; Black, Peter McL.; Folkman, Judah; Kieran, Mark; Wen, Patrick Y.

2007-01-01

Preclinical evidence suggests that continuous low-dose daily (metronomic) chemotherapy may inhibit tumor endothelial cell proliferation (angiogenesis) and prevent tumor growth. This phase II study evaluated the feasibility of this antiangiogenic chemotherapy regimen in adults with recurrent malignant gliomas. The regimen consisted of low-dose etoposide (35 mg/m2 [maximum, 100 mg/day] daily for 21 days), alternating every 21 days with cyclophosphamide (2 mg/kg [maximum, 100 mg/day] daily for 21 days), in combination with daily thalidomide and celecoxib, in adult patients with recurrent malignant gliomas. Serum and urine samples were collected for measurement of angiogenic peptides. Forty-eight patients were enrolled (15 female, 33 male). Twenty-eight patients had glioblastoma multiforme (GBMs), and 20 had anaplastic gliomas (AGs). Median age was 53 years (range, 33–74 years), and median KPS was 70 (range, 60–100). Therapy was reasonably well tolerated in this heavily pretreated population. Two percent of patients had partial response, 9% had a minor response, 59% had stable disease, and 30% had progressive disease. For GBM patients, median progression-free survival (PFS) was 11 weeks, six-month PFS (6M-PFS) was 9%, and median overall survival (OS) was 21 weeks. For AG patients, median PFS was 14 weeks, 6M-PFS was 26%, and median OS was 41.5 weeks. In a limited subset of patients, serum and urine angiogenic peptides did not correlate with response or survival (p > 0.05). Although there were some responders, this four-drug, oral metronomic regimen did not significantly improve OS in this heavily pretreated group of patients who were generally not eligible for conventional protocols. While metronomic chemotherapy may not be useful in patients with advanced disease, further studies using metronomic chemotherapy combined with more potent antiangiogenic agents in patients with less advanced disease may be warranted. PMID:17452651

Beneficial Effect of the Nitric Oxide Donor Compound 3-(1,3-Dioxoisoindolin-2-yl)Benzyl Nitrate on Dysregulated Phosphodiesterase 5, NADPH Oxidase, and Nitrosative Stress in the Sickle Cell Mouse Penis: Implication for Priapism Treatment.

PubMed

Silva, Fábio H; Karakus, Serkan; Musicki, Biljana; Matsui, Hotaka; Bivalacqua, Trinity J; Dos Santos, Jean L; Costa, Fernando F; Burnett, Arthur L

2016-11-01

Patients with sickle cell disease (SCD) display priapism, and dysregulated nitric oxide (NO) pathway may contribute to this condition. However, current therapies offered for the prevention of priapism in SCD are few. The 3-(1,3-dioxoisoindolin-2-yl)benzyl nitrate (compound 4C) was synthesized through molecular hybridization of hydroxyurea and thalidomide, which displays an NO-donor property. This study aimed to evaluate the effects of compound 4C on functional and molecular alterations of erectile function in murine models that display low NO bioavailability, SCD transgenic mice, and endothelial NO synthase and neuronal NO synthase double gene-deficient (dNOS -/ ) mice, focusing on the dysregulated NO-cGMP- phosphodiesterase type 5 (PDE5) pathway and oxidative stress in erectile tissue. Wild-type, SCD, and dNOS -/- mice were treated with compound 4C (100 μmol/kg/d, 3 weeks). Intracavernosal pressure in anesthetized mice was evaluated. Corpus cavernosum tissue was dissected free and mounted in organ baths. SCD and dNOS -/- mice displayed a priapism phenotype, which was reversed by compound 4C treatment. Increased corpus cavernosum relaxant responses to acetylcholine and electrical-field stimulation were reduced by 4C in SCD mice. Likewise, increased sodium nitroprusside-induced relaxant responses were reduced by 4C in cavernosal tissue from SCD and dNOS -/- mice. Compound 4C reversed PDE5 protein expression and reduced protein expressions of reactive oxygen species markers, NADPH oxidase subunit gp91 phox , and 3-nitrotyrosine in penises from SCD and dNOS -/- mice. In conclusion, 3-week therapy with the NO donor 4C reversed the priapism in murine models that display lower NO bioavailability. NO donor compounds may constitute an additional strategy to prevent priapism in SCD. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Gateways to clinical trials.

PubMed

Bayés, M; Rabasseda, X; Prous, J R

2005-06-01

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abiraterone acetate, acyline, adalimumab, adenosine triphosphate, AEE-788, AIDSVAX gp120 B/B, AK-602, alefacept, alemtuzumab, alendronic acid sodium salt, alicaforsen sodium, alprazolam, amdoxovir, AMG-162, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, aminophylline hydrate, anakinra, anecortave acetate, anti-CTLA-4 MAb, APC-8015, aripiprazole, aspirin, atazanavir sulfate, atomoxetine hydrochloride, atorvastatin calcium, atrasentan, AVE-5883, AZD-2171; Betamethasone dipropionate, bevacizumab, bimatoprost, biphasic human insulin (prb), bortezomib, BR-A-657, BRL-55730, budesonide, busulfan; Calcipotriol, calcipotriol/betamethasone dipropionate, calcium folinate, capecitabine, capravirine, carmustine, caspofungin acetate, cefdinir, certolizumab pegol, CG-53135, chlorambucil, ciclesonide, ciclosporin, cisplatin, clofarabine, clopidogrel hydrogensulfate, clozapine, co-trimoxazole, CP-122721, creatine, CY-2301, cyclophosphamide, cypher, cytarabine, cytolin; D0401, darbepoetin alfa, darifenacin hydrobromide, DASB, desipramine hydrochloride, desloratadine, desvenlafaxine succinate, dexamethasone, didanosine, diquafosol tetrasodium, docetaxel, doxorubicin hydrochloride, drotrecogin alfa (activated), duloxetine hydrochloride, dutasteride; Ecallantide, efalizumab, efavirenz, eletriptan, emtricitabine, enfuvirtide, enoxaparin sodium, estramustine phosphate sodium, etanercept, ethinylestradiol, etonogestrel, etonogestrel/ethinylestradiol, etoposide, exenatide; Famciclovir, fampridine, febuxostat, filgrastim, fludarabine phosphate, fluocinolone acetonide, fluorouracil, fluticasone propionate, fluvastatin sodium, fondaparinux sodium; Gaboxadol, gamma-hydroxybutyrate sodium, gefitinib, gelclair, gemcitabine, gemfibrozil, glibenclamide, glyminox; Haloperidol, heparin sodium, HPV 16/HPV 18 vaccine, human insulin, human insulin; Icatibant, imatinib mesylate, indium 111 (111In) ibritumomab tiuxetan, infliximab, INKP-100, iodine (I131) tositumomab, IoGen, ipratropium bromide, ixabepilone; L-870810, lamivudine, lapatinib, laquinimod, latanoprost, levonorgestrel, licochalcone a, liposomal doxorubicin, lopinavir, lopinavir/ritonavir, lorazepam, lovastatin; Maraviroc, maribavir, matuzumab, MDL-100907, melphalan, methotrexate, methylprednisolone, mitomycin, mitoxantrone hydrochloride, MK-0431, MN-001, MRKAd5 HIV-1 gag/pol/nef, MRKAd5gag, MVA.HIVA, MVA-BN Nef, MVA-Muc1-IL-2, mycophenolate mofetil; Nelfinavir mesilate, nesiritide, NSC-330507; Olanzapine, olmesartan medoxomil, omalizumab, oral insulin, osanetant; PA-457, paclitaxel, paroxetine, paroxetine hydrochloride, PCK-3145, PEG-filgrastim, peginterferon alfa-2a, peginterferon alfa-2b, perillyl alcohol, pexelizumab, pimecrolimus, pitavastatin calcium, porfiromycin, prasterone, prasugrel, pravastatin sodium, prednisone, pregabalin, prinomastat, PRO-2000, propofol, prostate cancer vaccine; Rasagiline mesilate, rhBMP-2/ACS, rhBMP-2/BCP, rhC1, ribavirin, rilpivirine, ritonavir, rituximab, Ro-26-9228, rosuvastatin calcium, rosuvastatin sodium, rubitecan; Selodenoson, simvastatin, sirolimus, sitaxsentan sodium, sorafenib, SS(dsFv)-PE38, St. John's Wort extract, stavudine; Tacrolimus, tadalafil, tafenoquine succinate, talaglumetad, tanomastat, taxus, tegaserod maleate, telithromycin, tempol, tenofovir, tenofovir disoproxil fumarate, testosterone enanthate, TH-9507, thalidomide, tigecycline, timolol maleate, tiotropium bromide, tipifarnib, torcetrapib, trabectedin, travoprost, travoprost/timolol, treprostinil sodium; Valdecoxib, vardenafil hydrochloride hydrate, varenicline, VEGF-2 gene therapy, venlafaxine hydrochloride, vildagliptin, vincristine sulfate, voriconazole, VRX-496, VX-385; Warfarin sodium; Ximelagatran; Yttrium 90 (90Y) ibritumomab tiuxetan; Zanolimumab, zidovudine. Copyright (c) 2005 Prous Science. All rights reserved.

Anophthalmia and microphthalmia.

PubMed

Verma, Amit S; Fitzpatrick, David R

2007-11-26

Anophthalmia and microphthalmia describe, respectively, the absence of an eye and the presence of a small eye within the orbit. The combined birth prevalence of these conditions is up to 30 per 100,000 population, with microphthalmia reported in up to 11% of blind children. High-resolution cranial imaging, post-mortem examination and genetic studies suggest that these conditions represent a phenotypic continuum. Both anophthalmia and microphthalmia may occur in isolation or as part of a syndrome, as in one-third of cases. Anophthalmia/microphthalmia have complex aetiology with chromosomal, monogenic and environmental causes identified. Chromosomal duplications, deletions and translocations are implicated. Of monogenic causes only SOX2 has been identified as a major causative gene. Other linked genes include PAX6, OTX2, CHX10 and RAX. SOX2 and PAX6 mutations may act through causing lens induction failure. FOXE3 mutations, associated with lens agenesis, have been observed in a few microphthalmic patients. OTX2, CHX10 and RAX have retinal expression and may result in anophthalmia/microphthalmia through failure of retinal differentiation. Environmental factors also play a contributory role. The strongest evidence appears to be with gestational-acquired infections, but may also include maternal vitamin A deficiency, exposure to X-rays, solvent misuse and thalidomide exposure. Diagnosis can be made pre- and post-natally using a combination of clinical features, imaging (ultrasonography and CT/MR scanning) and genetic analysis. Genetic counselling can be challenging due to the extensive range of genes responsible and wide variation in phenotypic expression. Appropriate counselling is indicated if the mode of inheritance can be identified. Differential diagnoses include cryptophthalmos, cyclopia and synophthalmia, and congenital cystic eye. Patients are often managed within multi-disciplinary teams consisting of ophthalmologists, paediatricians and/or clinical geneticists, especially for syndromic cases. Treatment is directed towards maximising existing vision and improving cosmesis through simultaneous stimulation of both soft tissue and bony orbital growth. Mild to moderate microphthalmia is managed conservatively with conformers. Severe microphthalmia and anophthalmia rely upon additional remodelling strategies of endo-orbital volume replacement (with implants, expanders and dermis-fat grafts) and soft tissue reconstruction. The potential for visual development in microphthalmic patients is dependent upon retinal development and other ocular characteristics.

Anophthalmia and microphthalmia

PubMed Central

Verma, Amit S; FitzPatrick, David R

2007-01-01

Anophthalmia and microphthalmia describe, respectively, the absence of an eye and the presence of a small eye within the orbit. The combined birth prevalence of these conditions is up to 30 per 100,000 population, with microphthalmia reported in up to 11% of blind children. High-resolution cranial imaging, post-mortem examination and genetic studies suggest that these conditions represent a phenotypic continuum. Both anophthalmia and microphthalmia may occur in isolation or as part of a syndrome, as in one-third of cases. Anophthalmia/microphthalmia have complex aetiology with chromosomal, monogenic and environmental causes identified. Chromosomal duplications, deletions and translocations are implicated. Of monogenic causes only SOX2 has been identified as a major causative gene. Other linked genes include PAX6, OTX2, CHX10 and RAX. SOX2 and PAX6 mutations may act through causing lens induction failure. FOXE3 mutations, associated with lens agenesis, have been observed in a few microphthalmic patients. OTX2, CHX10 and RAX have retinal expression and may result in anophthalmia/microphthalmia through failure of retinal differentiation. Environmental factors also play a contributory role. The strongest evidence appears to be with gestational-acquired infections, but may also include maternal vitamin A deficiency, exposure to X-rays, solvent misuse and thalidomide exposure. Diagnosis can be made pre- and post-natally using a combination of clinical features, imaging (ultrasonography and CT/MR scanning) and genetic analysis. Genetic counselling can be challenging due to the extensive range of genes responsible and wide variation in phenotypic expression. Appropriate counselling is indicated if the mode of inheritance can be identified. Differential diagnoses include cryptophthalmos, cyclopia and synophthalmia, and congenital cystic eye. Patients are often managed within multi-disciplinary teams consisting of ophthalmologists, paediatricians and/or clinical geneticists, especially for syndromic cases. Treatment is directed towards maximising existing vision and improving cosmesis through simultaneous stimulation of both soft tissue and bony orbital growth. Mild to moderate microphthalmia is managed conservatively with conformers. Severe microphthalmia and anophthalmia rely upon additional remodelling strategies of endo-orbital volume replacement (with implants, expanders and dermis-fat grafts) and soft tissue reconstruction. The potential for visual development in microphthalmic patients is dependent upon retinal development and other ocular characteristics. PMID:18039390

Ulcerated necrobiosis lipoidica to a teenager with diabetes mellitus and obesity.

PubMed

Pătraşcu, Virgil; Giurcă, Claudia; Ciurea, Raluca Niculina; Georgescu, Corneliu Cristian; Ciurea, Marius Eugen

2014-01-01

Many skin lesions are associated with diabetes mellitus (DM) type 1 or 2, due to the use of antidiabetics or to metabolic and endocrine disorders caused by this disease. Necrobiosis lipoidica (NL) occurs more frequently in patients with DM. Painful ulcerations may occur on NL areas in about 20-25% of the cases and usually they are related to trauma. We present the case of a teenager, male, 17-year-old, having NL with multiple plaques, some of them spontaneously ulcerated after about 33 months of onset. He is known with type 1 DM from 2.5 years and the NL preceding the diagnosis of diabetes mellitus with about six months, presented erythematous-infiltrative skin plaques, some ulcerated for about three months, interesting both shins. Based on clinical, histopathological and paraclinical examinations, we established the following diagnoses: ulcerated NL, type 1 DM, moderate mixed dyslipidemia, class I obesity; commissural candidiasis, juvenile acne. Under treatment with Pentoxifyllinum, Sulodexidum, Ketotifenum and topical therapy with 0.2% Hyaluronic acid two months later, we have managed to heal two of the three ulcerated plaques and of the third has become superficial. We applied 0.5% Fluocortolonum on non-ulcerated plaques recording an improvement after two weeks of treatment. NL is a skin disease with a predilection for the shins, more frequent in patients with diabetes and is a part of palisading granulomatous dermatitis, which leads to skin atrophy. NL is found in the 0.3-1.2% of diabetic patients and is rare in children with diabetes (0.006%). It is more common in the patients with type 1 DM. The onset is in the third decade in diabetic patients and in the fourth decade in non-diabetics. There is no consensus concerning the treatment of NL, and the results are often modest. Antiplatelet agents, corticosteroids (local and general), immunomodulatory drugs, cyclins, wide synthetic antipaludics, heparin, Thalidomide are used. NL treatment is very difficult, especially in the ulcerated forms. Many of the drugs listed have proven efficacy only in isolated cases. Studies are necessary on large series of patients to determine the optimal therapy of NL.

Intravenous Immunoglobulins Improve Survival in Monoclonal Gammopathy-Associated Systemic Capillary-Leak Syndrome.

PubMed

Pineton de Chambrun, Marc; Gousseff, Marie; Mauhin, Wladimir; Lega, Jean-Christophe; Lambert, Marc; Rivière, Sophie; Dossier, Antoine; Ruivard, Marc; Lhote, François; Blaison, Gilles; Alric, Laurent; Agard, Christian; Saadoun, David; Graveleau, Julie; Soubrier, Martin; Lucchini-Lecomte, Marie-Josée; Christides, Christine; Bosseray, Annick; Levesque, Hervé; Viallard, Jean-François; Tieulie, Nathalie; Lovey, Pierre-Yves; Le Moal, Sylvie; Bibes, Béatrice; Malizia, Giuseppe; Abgueguen, Pierre; Lifermann, François; Ninet, Jacques; Hatron, Pierre-Yves; Amoura, Zahir

2017-10-01

Monoclonal gammopathy-associated systemic capillary-leak syndrome, also known as Clarkson disease, is a rare condition characterized by recurrent life-threatening episodes of capillary hyperpermeability in the context of a monoclonal gammopathy. This study was conducted to better describe the clinical characteristics, natural history, and long-term outcome of monoclonal gammopathy-associated systemic capillary-leak syndrome. We conducted a cohort analysis of all patients included in the European Clarkson disease (EurêClark) registry between January 1997 and March 2016. From diagnosis to last follow-up, studied outcomes (eg, the frequency and severity of attacks, death, and evolution toward multiple myeloma) and the type of preventive treatments administered were monitored every 6 months. Sixty-nine patients (M/F sex ratio 1:1; mean ± SD age at disease onset 52 ± 12 years) were included in the study. All patients had monoclonal gammopathy of immunoglobulin G type, with kappa light chains in 47 (68%). Median (interquartile range) follow-up duration was 5.1 (2.5-9.7) years. Twenty-four patients (35%) died after 3.3 (0.9-8) years. Fifty-seven (86%) patients received at least one preventive treatment, including intravenous immunoglobulins (IVIg) n = 48 (73.8%), theophylline n = 22 (33.8%), terbutaline n = 22 (33.8%), and thalidomide n = 5 (7.7%). In the 65 patients with follow-up, 5- and 10-year survival rates were 78% (n = 35) and 69% (n = 17), respectively. Multivariate analysis found preventive treatment with IVIg (hazard ratio 0.27; 95% confidence interval, 0.10-0.70; P = .007) and terbutaline (hazard ratio 0.35; 95% confidence interval, 0.13-0.96; P = .041) to be independent predictors of mortality. We describe the largest cohort to date of patients with well-defined monoclonal gammopathy-associated systemic capillary-leak syndrome. Preventive treatment with IVIg was the strongest factor associated with survival, suggesting the use of IVIg as the first line in prevention therapy. Copyright © 2017 Elsevier Inc. All rights reserved.

Risk management strategies in the Physicians' Desk Reference product labels for pregnancy category X drugs.

PubMed

Uhl, Kathleen; Kennedy, Dianne L; Kweder, Sandra L

2002-01-01

Drugs that carry a concern for teratogenicity are often classified as pregnancy category X in the drug label and contraindicated for use during pregnancy. Many drug labels can be found in the Physicians' Desk Reference (PDR), a widely used source of drug information by American clinicians and patients. To review product labelling in the electronic PDR for the pregnancy category X products for pregnancy prevention risk management components in labelling. The electronic version of the 2001 and 2002 PDR was searched for 'pregnancy category X' products using the full text search feature. All product labels identified were retrieved and reviewed for trade name, generic name, manufacturer and indication. Product labels were manually searched for any pregnancy prevention risk management strategies included in labelling. Those labels that had specific pregnancy prevention risk management strategies were further evaluated. One hundred and seventeen pregnancy category X products were obtained from 2249 products searched in the 2001 PDR database and 124 pregnancy category X products were obtained from the 2150 products in the 2002 PDR database. All pregnancy category X products identified were drug products. The label/package insert for each drug was reviewed to identify risk management strategies for pregnancy prevention. The majority of the labels include as the sole risk management strategy either a black box warning and/or a contraindication for use in women who are or may become pregnant. Only 13 drugs contained specific pregnancy prevention risk management strategies in the label directing the clinician and/or patient, e.g. frequency of pregnancy testing, number and type of contraception methods. Two drugs, bexarotene capsules and gel, were only included in the 2001 PDR. Three drugs, isotretinoin, acitretin, and thalidomide, have formal pregnancy prevention risk management programmes. This study demonstrates the varied risk management approaches in labelling for pregnancy prevention for pregnancy category X drugs. There is a need for consistency in the classification of pregnancy category X products and the pregnancy prevention risk management strategies utilised in the labelling for them.

Management of oral lesions in HIV-positive patients.

PubMed

Baccaglini, Lorena; Atkinson, Jane C; Patton, Lauren L; Glick, Michael; Ficarra, Giuseppe; Peterson, Douglas E

2007-03-01

HIV/AIDS is currently the leading cause of death in Africa and the fourth leading cause of death worldwide. This systematic review of the literature was conducted to evaluate the evidence for treatment of the most common oral lesions associated with HIV: oral candidiasis with or without oropharyngeal involvement (OPC), oral hairy leukoplakia (OHL), recurrent aphthous-like ulcerations (RAU), oral Kaposi's sarcoma (OKS), orolabial herpes simplex infection (HSV), oral herpes zoster infection (VZV), intraoral or perioral warts (HPV), and HIV-associated periodontal diseases. Treatment of HIV-associated salivary gland disease is addressed in a different section of this World Workshop. We found the largest body of evidence for treatment of OPC in HIV patients. Future trials will be needed to test drugs currently in development for treatment of Candida strains that are resistant to existing therapies. There were no double blind, placebo-controlled randomized clinical trials (RCT) for topical treatment of OHL, and only one RCT for systemic treatment of the lesion with desciclovir. Systemic thalidomide was the only drug tested in RCT for treatment or prevention of RAU. Only 1 double-blind RCT comparing vinblastine and sodium tetradecyl sulfate was identified for localized treatment of OKS. Three drugs (famciclovir, acyclovir, and valaciclovir) were shown to be effective in randomized, double-blind trials for treatment or suppression of mucocutaneous HSV lesions in HIV patients. In all 3 trials, the effects of these medications on orolabial HSV lesions were not reported separately. There were no double-blind, placebo-controlled RCT testing topical treatments for orolabial HSV lesions in HIV patients. No trials testing treatments of oral VZV were identified. There were no double-blind, placebo-controlled RCT for treatment of HIV-associated intraoral or perioral warts or periodontal diseases. In conclusion, there is a need for well-designed RCTs to assess the safety and efficacy of topical and systemic treatments of most oral mucosal and perioral lesions in HIV patients. There is also a need to develop newer drugs for treatment of resistant fungal and viral microorganisms. Finally, standardized outcome measures should be developed for future clinical trials to allow comparisons of studies using different populations.

26 CFR 1.513-3 - Qualified convention and trade show activity.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 26 Internal Revenue 7 2013-04-01 2013-04-01 false Qualified convention and trade show activity. 1... Organizations § 1.513-3 Qualified convention and trade show activity. (a) Introduction—(1) In general. Section 513(d) and § 1.513-3(b) provide that convention and trade show activities carried on by a qualifying...

26 CFR 1.513-3 - Qualified convention and trade show activity.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 26 Internal Revenue 7 2012-04-01 2012-04-01 false Qualified convention and trade show activity. 1... Organizations § 1.513-3 Qualified convention and trade show activity. (a) Introduction—(1) In general. Section 513(d) and § 1.513-3(b) provide that convention and trade show activities carried on by a qualifying...

Assessment of digestive enzymes activity during the fry development of the endangered Caspian brown trout Salmo caspius.

PubMed

Zamani, A; Hajimoradloo, A; Madani, R; Farhangi, M

2009-09-01

The study of digestive enzymes activity at Salmo caspius fry showed that enzymes were available at the moment of mouth opening on the first day post hatching (dph) and the activity of enzymes showed no significant difference from the hatching day 28 dph. An increased activity was seen between 32 and 43 dph and this activity was significantly higher than the activity during the first 28 days. In the primary stages after yolk sac resorption (43-58 dph), enzymes activity showed an increased profile, however none of them showed a significant difference between 43 and 58 dph.

Screening of some Palestinian medicinal plants for antibacterial activity.

PubMed

Essawi, T; Srour, M

2000-06-01

Antibacterial activity of organic and aqueous extracts of 15 Palestinian medicinal plants were carried against eight different species of bacteria: Bacillus subtilis, two Escherichia coli species, Staphylococcus aureus (methicillin resistant), two S. aureus (methicillin sensitive) species, Pseudomonas aeruginosa, and Enterococcus fecalis. Of the 15 plants tested, eight showed antibacterial activity. Each plant species has unique against different bacteria. The most active antibacterial plants against both gram-positive and gram-negative bacteria were Thymus vulgaris and Thymus origanium. The organic and aqueous extract from the same plants showed different activities; the organic extract showed the same or greater activity than the aqueous extract. Finally, the hole-plate diffusion method showed larger activity than the disc diffusion method.

Inhibitory effects of Citrus hassaku extract and its flavanone glycosides on melanogenesis.

PubMed

Itoh, Kimihisa; Hirata, Noriko; Masuda, Megumi; Naruto, Shunsuke; Murata, Kazuya; Wakabayashi, Keitaro; Matsuda, Hideaki

2009-03-01

The 50% ethanolic extract (CH-ext) obtained from the unripe fruit of Citrus hassaku exhibited significant tyrosinase inhibitory activity. The CH-ext showed antioxidant activity, such as superoxide dismutase (SOD)-like activity and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activity. Activity-guided fractionation of the CH-ext indicated that flavanone glycoside-rich fractions showed potent tyrosinase inhibitory activity. Further examination revealed that the tyrosinase inhibitory activity and antioxidant activity of the CH-ext were attributable to naringin and neohesperidin, respectively. The CH-ext showed inhibition of melanogenesis without any effects on cell proliferation in cultured murine B16 melanoma cells after glucosamine exposure. The topical application of the CH-ext to the dorsal skin of brownish guinea pigs showed in vivo preventive effects against UVB-induced pigmentation.

Antimicrobial activity of antihypertensive food-derived peptides and selected alanine analogues.

PubMed

McClean, Stephen; Beggs, Louise B; Welch, Robert W

2014-03-01

This study evaluated four food-derived peptides with known antihypertensive activities for antimicrobial activity against pathogenic microorganisms, and assessed structure-function relationships using alanine analogues. The peptides (EVSLNSGYY, barley; PGTAVFK, soybean; TTMPLW, α-casein; VHLPP, α-zein) and the six alanine substitution peptides of PGTAVFK were synthesised, characterised and evaluated for antimicrobial activity using the bacteria, Escherichia coli, Staphylococcus aureus, and Micrococcus luteus and the yeast, Candida albicans. The peptides TTMPLW and PGTAVFK inhibited growth of all four microorganisms tested, with activities of a similar order of magnitude to ampicillin and ethanol controls. EVSLNSGYY inhibited the growth of the bacteria, but VHLPP showed no antimicrobial activity. The alanine analogue, PGAAVFK showed the highest overall antimicrobial activity and PGTAVFA showed no activity; overall, the activities of the analogues were consistent with their structures. Some peptides with antihypertensive activity also show antimicrobial activity, suggesting that food-derived peptides may exert beneficial effects via a number of mechanisms. Copyright © 2013 Elsevier Ltd. All rights reserved.

Antimicrobial and antioxidant activity of essential oil and different plant extracts of Psidium cattleianum Sabine.

PubMed

Scur, M C; Pinto, F G S; Pandini, J A; Costa, W F; Leite, C W; Temponi, L G

2016-02-01

The goals of the study were to determinethe antimicrobial and antioxidant activities of essential oil and plant extracts aqueous and ethanolic of Psidium cattleianum Sabine; the chemical composition of the essential oil of P. cattleianum; and the phytochemical screening of aqueous and ethanolic extracts of the same plant. Regarding the antimicrobial activity, the ethanolic extract exhibited moderate antimicrobial activity with respect to bacteria K. pneumoniae and S. epidermidis, whereas, regarding other microorganisms, it showed activity considered weak. The aqueous extract and the essential oil showed activity considered weak, although they inhibited the growth of microorganisms. About the antioxidant potential, the ethanolic and aqueous extracts exhibited a scavenging index exceeding 90%, while the essential oil didn´t show significant antioxidant activity. Regarding the phytochemical composition, the largest class of volatile compounds identified in the essential oil of P. cattleianum included the following terpenic hydrocarbons: α-copaene (22%); eucalyptol (15%), δ-cadinene (9.63%) and α-selinene (6.5%). The phytochemical screening of extracts showed the presence of tannins, flavonoids, and triterpenoids for aqueous and ethanolic extracts. The extracts and essential oils inhibit the growth of microrganisms and plant extracts showed significant antioxidant activity. Also, the phytochemical characterization of the essential oil showed the presence of compounds interest commercial, as well as extracts showed the presence of important classes and compounds with biological activities.

The proteinase-activated receptor-2 mediates phagocytosis in a Rho-dependent manner in human keratinocytes.

PubMed

Scott, Glynis; Leopardi, Sonya; Parker, Lorelle; Babiarz, Laura; Seiberg, Miri; Han, Rujiing

2003-09-01

Recent work shows that the G-protein-coupled receptor proteinase activated receptor-2 activates signals that stimulate melanosome uptake in keratinocytes in vivo and in vitro. The Rho family of GTP-binding proteins is involved in cytoskeletal remodeling during phagocytosis. We show that proteinase-activated receptor-2 mediated phagocytosis in human keratinocytes is Rho dependent and that proteinase-activated receptor-2 signals to activate Rho. In contrast, Rho activity did not affect either proteinase-activated receptor-2 activity or mRNA and protein levels. We explored the signaling mechanisms of proteinase-activated receptor-2 mediated Rho activation in human keratinocytes and show that activation of proteinase-activated receptor-2, either through specific proteinase-activated receptor-2 activating peptides or through trypsinization, elevates cAMP in keratinocytes. Proteinase-activated receptor-2 mediated Rho activation was pertussis toxin insensitive and independent of the protein kinase A signaling pathway. These data are the first to show that proteinase-activated receptor-2 mediated phagocytosis is Rho dependent and that proteinase-activated receptor-2 signals to Rho and cAMP in keratinocytes. Because phagocytosis of melanosomes is recognized as an important mechanism for melanosome transfer to keratinocytes, these results suggest that Rho is a critical signaling intermediate in melanosome uptake in keratinocytes.

New amides from seeds of Silybum marianum with potential antioxidant and antidiabetic activities.

PubMed

Qin, Ning-Bo; Jia, Cui-Cui; Xu, Jun; Li, Da-Hong; Xu, Fan-Xing; Bai, Jiao; Li, Zhan-Lin; Hua, Hui-Ming

2017-06-01

Two new amide compounds, mariamides A and B (1-2), were obtained together with fourteen known compounds from the seeds of milk thistle (Silybum marianum). Their structures were established on the basis of extensive 1D and 2D NMR analyses, as well as HR-ESI-MS data. Most of the compounds showed significant antioxidant activities than positive control in ABTS and FRAP assays. However, only amide compounds 1-4 showed moderate DPPH radical scavenging activity and compounds 7 and 16 showed the most potent activity against DPPH. Most of the compounds showed moderate to stronger α-glucosidase inhibitory activities. Nevertheless, only flavonoids showed strong PTP1B inhibitory activities. These results indicate a use of milk thistle seed extracts as promising antioxidant and antidiabetic agents. Copyright © 2017 Elsevier B.V. All rights reserved.

Isolation, screening and partial purification of antimicrobial antibiotics from soil Streptomyces sp. SCA 7.

PubMed

Saravana Kumar, P; Duraipandiyan, V; Ignacimuthu, S

2014-09-01

Thirty-seven actinomycetes strains were isolated from soil samples collected from an agriculture field in Vengodu, Thiruvannamalai District, Tamil Nadu, India (latitude: 12° 54' 0033″, North; longitude: 79° 78' 5216″, East; elevation: 228.6/70.0 ft/m). The isolates were assessed for antagonistic activity against five Gram-positive bacteria, seven Gram-negative bacteria, and two pathogenic fungi. During the initial screening, 43% of the strains showed weak activity, 16% showed moderate activity, 5% showed good activity, and 35% showed no antagonistic activity. Among the strains tested, SCA 7 showed strong antimicrobial activity. Maximum biological activity was obtained on modified nutrient glucose agar (MNGA) medium. The mycelia of SCA 7 were extracted with methanol and tested against microbial pathogens using the disc diffusion method. The crude extract was purified partially using column chromatography and assessed for antimicrobial activity. Fraction 10 showed good activity against Staphylococcus epidermidis (31.25 μg/mL) and Malassezia pachydermatis (500 μg/mL) and the active principle (fraction 10) was identified as 2,4-bis (1,1-dimethylethyl) phenol. Based on morphological, physiological, biochemical, cultural, and molecular characteristics (16S rDNA sequencing), this strain was identified as Streptomyces sp. SCA 7. It could be used in the development of new substances for pharmaceutical or agricultural purposes. Copyright © 2014. Published by Elsevier B.V.

Synthesis of Amide and Ester Derivatives of Cinnamic Acid and Its Analogs: Evaluation of Their Free Radical Scavenging and Monoamine Oxidase and Cholinesterase Inhibitory Activities.

PubMed

Takao, Koichi; Toda, Kazuhiro; Saito, Takayuki; Sugita, Yoshiaki

2017-01-01

A series of cinnamic acid derivatives, amides (1-12) and esters (13-22), were synthesized, and structure-activity relationships for antioxidant activity, and monoamine oxidases (MAO) A and B, acetylcholinesterase, and butyrylcholinesterase (BChE) inhibitory activities were analyzed. Among the synthesized compounds, compounds 1-10, 12-18, and rosmarinic acid (23), which contained catechol, o-methoxyphenol or 5-hydroxyindole moieties, showed potent 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity. Compounds 9-11, 15, 17-22 showed potent and selective MAO-B inhibitory activity. Compound 20 was the most potent inhibitor of MAO-B. Compounds 18 and 21 showed moderate BChE inhibitory activity. In addition, compound 18 showed potent antioxidant activity and MAO-B inhibitory activity. In a comparison of the cinnamic acid amides and esters, the amides exhibited more potent DPPH free radical scavenging activity, while the esters showed stronger inhibitory activities against MAO-B and BChE. These results suggested that cinnamic acid derivatives such as compound 18, p-coumaric acid 3,4-dihydroxyphenethyl ester, and compound 20, p-coumaric acid phenethyl ester, may serve as lead compounds for the development of novel MAO-B inhibitors and candidate lead compounds for the prevention or treatment of Alzheimer's disease.

Effect of dietary fiber from banana (Musa paradisiaca) on metabolism of carbohydrates in rats fed cholesterol free diet.

PubMed

Usha, V; Vijayammal, P L; Kurup, P A

1989-05-01

Effect of feeding isolated dietary fiber from M. paradisiaca on the metabolism of carbohydrates in the liver has been studied. Fiber fed rats showed significantly lower levels of fasting blood glucose and higher concentration of liver glycogen. Activity of glycogen phosphorylase, glucose-1-phosphate, uridyl transferase and glycogen synthase was significantly higher while phosphoglucomutase activity showed lower activity. Activity of some glycolytic enzymes, viz. hexokinase and pyruvic kinase was lower. Glucose-6-phosphatase showed higher activity while fructose 1-6 diphosphatase activity was not affected. Glucose-6-phosphate dehydrogenase on the other hand showed higher activity. The changes in these enzyme activities have been attributed due to the effect of higher concentration of bile acids produced in the liver as a result of feeding fiber. Evidence for this has been obtained by studying the in vitro effect of cholic acid and chenodeoxy cholic acid.

Further evaluation of Rwandan medicinal plant extracts for their antimicrobial and antiviral activities.

PubMed

Cos, P; Hermans, N; De Bruyne, T; Apers, S; Sindambiwe, J B; Vanden Berghe, D; Pieters, L; Vlietinck, A J

2002-02-01

A total of 45 Rwandan plant extracts, belonging to 37 different plant species out of 21 families, were investigated for their antibacterial, antifungal, and antiviral properties. The plants were selected on the base of their ethnomedicinal use against infections and autoimmune diseases. From all the plant extracts tested, only Clematis hirsuta (leaves) showed a pronounced antifungal activity against Candida albicans and the dermatophytes Trichophyton rubrum, Epidermophyton floccosum, and Microsporum canis. Seven plant extracts showed a high antiviral activity against the DNA-virus Herpes simplex type 1, while five and three plant extracts were highly active against the RNA-viruses Coxsackie and Polio, respectively. Only Macaranga kilimandscharica (leaves) showed an interesting anti-measles activity, whereas Eriosema montanum (leaves) and Entada abyssinica (leaves) were highly active against Semliki forest virus. Some plant extracts showed an antibacterial activity against Gram-positive bacteria and Mycobacterium fortuitum, but none of them were active against the Gram-negative bacteria tested.

Asymmetric total synthesis of 6-Tuliposide B and its biological activities against tulip pathogenic fungi.

PubMed

Shigetomi, Kengo; Omoto, Shoko; Kato, Yasuo; Ubukata, Makoto

2011-01-01

The structure-activity relationship was investigated to evaluate the antifungal activities of tuliposides and tulipalins against tulip pathogenic fungi. 6-Tuliposide B was effectively synthesized via the asymmetric Baylis-Hillman reaction. Tuliposides and tulipalins showed antifungal activities against most of the strains tested at high concentrations (2.5 mM), while Botrytis tulipae was resistant to tuliposides. Tulipalin formation was involved in the antifungal activity, tulipalin A showed higher inhibitory activity than 6-tuliposide B and tulipalin B. Both the tuliposides and tulipalins showed pigment-inducing activity against Gibberella zeae and inhibitory activity against Fusarium oxysporum f. sp tulipae. These activities were induced at a much lower concentration (0.05 mM) than the antifungal MIC values.

Comparison of antioxidant, anticholinesterase, and antidiabetic activities of three curcuminoids isolated from Curcuma longa L.

PubMed

Kalaycıoğlu, Zeynep; Gazioğlu, Işıl; Erim, F Bedia

2017-12-01

Antioxidant, anticholinesterase and antidiabetic activities of three curcuminoids isolated from the Curcuma longa were simultaneously tested and compared in this study. The highest antioxidant power was detected for curcumin with the applied methods. The drug potentials of curcuminoids for Alzheimer's disease were controlled. Bisdemethoxycurcumin (BDMC) showed substantial inhibitory activity. The activity of demethoxycurcumin (DMC) followed BDMC, whereas curcumin showed very little acetylcholinesterase inhibition activity. Antidiabetic activity of curcuminoids was evaluated by their α-glucosidase inhibitory activities. All curcuminoids show activities with decreasing order as BDMC > curcumin > DMC. The significant activities of BDMC compared to its isomers and examination of chemical structures of isomers might be a starting point in designing new drugs for Alzheimer's and Diabetes Mellitus.

Is Peer Interaction Necessary for Optimal Active Learning?

ERIC Educational Resources Information Center

Linton, Debra L.; Farmer, Jan Keith; Peterson, Ernie

2014-01-01

Meta-analyses of active-learning research consistently show that active-learning techniques result in greater student performance than traditional lecture-based courses. However, some individual studies show no effect of active-learning interventions. This may be due to inexperienced implementation of active learning. To minimize the effect of…

Prospective evaluation of femoral head viability following femoral neck fracture

DOE Office of Scientific and Technical Information (OSTI.GOV)

Binkert, B.; Kroop, S.A.; Nepola, I.V.

1984-01-01

The bone scans of 33 patients (pts) with recent subcapital fractures (fx) of the femur were evaluated prospectively to determine their value in predicting femoral head visability. Each of the 33 pts (ll men, 22 women, age range 30-92) had a pre-operative bone scan within 72 hrs of the fx (23 pts within 24 hrs). Anterior and posterior planar views of both hips and pinhole views (50% of pts) were obtained 2 hrs after administration of Tc-99m HDP. The femoral head was classified as perfused if it showed the same activity as the opposite normal side or if it showedmore » only slightly decreased activity. Femoral heads showing absent activity were classified as nonperfused. Overall, 20 of the 33 pts showed a photopenic femoral head on the side of the fx. Only 2 pts showed increased activity at hte site of the fx. Internal fixation of the fx was performed in 23 pts, 12 of whom had one or more follow-up scans. Five of these 12 pts showed absent femoral head activity on their initial scan, but 2 showed later reperfusion. The other 7 pts showed good perfusion initially, with only 1 later showing decreased femoral head activity. The other 10 pts (7 of whom had absent femoral head activity) had immediate resection of the femoral head and insertion of a Cathcart prosthesis. The results suggest that femoral head activity seen on a bone scan in the immediate post-fx period is not always a reliable indicator of femoral head viability. Decreased femoral head activity may reflect, in part, compromised perfusion secondary to post-traumatic edema, with or without anatomic disruption of the blood supply.« less

Antioxidant activity of hydroalcholic extract of Ferula gummosa Boiss roots.

PubMed

Ebrahimzadeh, M A; Nabavi, S M; Nabavi, S F; Dehpour, A A

2011-06-01

Ferula gummosa Boiss is native to central Asia. This plant has traditionally been used in the treatment of many diseases. The antihypoxic and antioxidant activities of Ferula gummosa roots were investigated. 1,1-diphenyl-2-picryl hydrazyl radical (DPPH), nitric oxide and hydrogen peroxide scavenging activities, Fe2+ chelating ability, reducing power and hemoglobin-induced linoleic acid peroxidation were used to evaluate antioxidant activities. Antihemolytic activity was evaluated by H2O2 induced hemolysis in rat erythrocytes. The total amount of phenolic compounds was determined as gallic acid equivalents and total flavonoid contents were calculated as quercetin equivalents from a calibration curve. The extracts showed moderate antioxidant activity in some models. IC50 for DPPH radical-scavenging activity was 579.6 +/- 19.4 microg/ml. The extracts showed weak nitric oxide-scavenging activity between 0.1 and 1.6 mg ml(-1) but showed good Fe2+ chelating ability. IC50 was 895.5 +/- 24.1 microg/ml. The extract also exhibited low antioxidant activity in the linoleic acid model but were capable of scavenging hydrogen peroxide in a concentration dependent manner. Tested extract show moderate activity in H2O2 induced hemolysis in rat erythrocytes which was not comparable with vitamin C. F. gummosa Boiss root showed different level antioxidant and antihemolytic activities. Biological effects may be attributed, at least in part, to the presence of phenols and flavonoids in the extract.

Anti-dermatitis, anxiolytic and analgesic effects of Rhazya stricta from Balochistan.

PubMed

Ahmad, Mansoor; Muhammed, Shafi; Mehjabeen; Jahan, Noor; Jan, Syed Umer; Qureshi, Zia-Ul-Rehaman

2014-05-01

Current study was carried out on Rhazya stricta. Plant material was collected from Jhalmagsi Dist. Balochistan, Pakistan. Methanolic extract of Rhazya stricta was tested for anti-dermatitis, analgesic, anxiolytic effects, insecticidal activity and Brine shrimp Bioassay. Crude extract showed significant anti-dermatitis activity, as the results of intensity score showed mild Excoriation or erosion, moderate Edema or populations and absence of Erythema or hemorrhage, Scratching time was decreased to 1.45 and histological observations of mice treated with crude extract showed mild changes and few inflammatory cells in several microscopic fields. The results of analgesic activity were significant and the percentage inhibition of writhes were 73.54% and 69.38% at 300mg/kg and 500mg/kg respectively. The overall response of crude extract in anxiolytic activities were depressive and crude extract showed sedative effects. In Brine shrimp (Artemsia salina) lethality bioassay crude extract showed dose depended significant activity, and showed positive lethality with LD(50) 3.3004μg/ml. Insecticidal activity was positive against Callosbruchus analis, the percent mortality was 40%.

Effect of low-level laser therapy on the modulation of the mitochondrial activity of macrophages

PubMed Central

Souza, Nadhia H. C.; Ferrari, Raquel A. M.; Silva, Daniela F. T.; Nunes, Fabio D.; Bussadori, Sandra K.; Fernandes, Kristianne P. S.

2014-01-01

BACKGROUND: Macrophages play a major role among the inflammatory cells that invade muscle tissue following an injury. Low-level laser therapy (LLLT) has long been used in clinical practice to accelerate the muscle repair process. However, little is known regarding its effect on macrophages. OBJECTIVE: This study evaluated the effect of LLLT on the mitochondrial activity (MA) of macrophages. METHOD: J774 macrophages were treated with lipopolysaccharide (LPS) and interferon - gamma (IFN-γ) (activation) for 24 h to simulate an inflammatory process, then irradiated with LLLT using two sets of parameters (780 nm; 70 mW; 3 J/cm2 and 660 nm; 15 mW; 7.5 J/cm2). Non-activated/non-irradiated cells composed the control group. MA was evaluated by the cell mitochondrial activity (MTT) assay (after 1, 3 and 5 days) in three independent experiments. The data were analyzed statistically. RESULTS: After 1 day of culture, activated and 780 nm irradiated macrophages showed lower MA than activated macrophages, but activated and 660 nm irradiated macrophages showed MA similar to activated cells. After 3 days, activated and irradiated (660 nm and 780 nm) macrophages showed greater MA than activated macrophages, and after 5 days, the activated and irradiated (660 nm and 780 nm) macrophages showed similar MA to the activated macrophages. CONCLUSIONS: These results show that 660 nm and 780 nm LLLT can modulate the cellular activation status of macrophages in inflammation, highlighting the importance of this resource and of the correct determination of its parameters in the repair process of skeletal muscle. PMID:25076002

Sex differences in functional activation patterns revealed by increased emotion processing demands.

PubMed

Hall, Geoffrey B C; Witelson, Sandra F; Szechtman, Henry; Nahmias, Claude

2004-02-09

Two [O(15)] PET studies assessed sex differences regional brain activation in the recognition of emotional stimuli. Study I revealed that the recognition of emotion in visual faces resulted in bilateral frontal activation in women, and unilateral right-sided activation in men. In study II, the complexity of the emotional face task was increased through tje addition of associated auditory emotional stimuli. Men again showed unilateral frontal activation, in this case to the left; whereas women did not show bilateral frontal activation, but showed greater limbic activity. These results suggest that when processing broader cross-modal emotional stimuli, men engage more in associative cognitive strategies while women draw more on primary emotional references.

Cloning and heterologous expression of cellulose free thermostable xylanase from Bacillus brevis.

PubMed

Goswami, Girish K; Krishnamohan, Medichtrla; Nain, Vikrant; Aggarwal, Chetana; Ramesh, Bandarupalli

2014-01-01

Xylanase gene isolated from Bacillus brevis was expressed in E. coli BL21. Sequencing of the gene (Gen Bank accession number: HQ179986) showed that it belongs to family 11 xylanases. The recombinant xylanase was predominantly secreted to culture medium and showed mesophilic nature (optimum activity at 55°C and pH 7.0). The cell free culture medium exhibited 30 IU/ml xylanse activity. The enzyme did not show any cellulose activity and was active under wide range of temperature (40°C to 80°C) and pH (4 to 9). The enzyme showed considerable thermo stability and regained over 90% of activity, when returned to 55°C after boiling for 5 min. These physiochemical properties of B. brevis xylanse show high potential of its applications in paper and pulp industry.

Glyceraldehyde-3-phosphate dehydrogenase from Chironomidae showed differential activity towards metals.

PubMed

Chong, Isaac K W; Ho, Wing S

2013-09-01

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is known to interact with different biomolecules and was implicated in many novel cellular activities including programmed cell death, nuclear RNA transport unrelated to the commonly known carbohydrate metabolism. We reported here the purification of GAPDH from Chironomidae larvae (Insecta, Diptera) that showed different biologic activity towards heavy metals. It was inhibited by copper, cobalt nickel, iron and lead but was activated by zinc. The GAPDH was purified by ammonium sulphate fractionation and Chelating Sepharose CL-6B chromatography followed by Blue Sepharose CL-6B chromatography. The 150-kDa tetrameric GAPDH showed optimal activity at pH 8.5 and 37°C. The multiple alignment of sequence of the Chironomidae GAPDH with other known species showed 78 - 88% identity to the conserved regions of the GADPH. Bioinformatic analysis unveils substantial N-terminal sequence similarity of GAPDH of Chironomidae larvae to mammalian GADPHs. However, the GADPH of Chironomidae larvae showed different biologic activities and cytotoxicity towards heavy metals. The GAPDH enzyme would undergo adaptive molecular changes through binding at the active site leading to higher tolerance to heavy metals.

Effects of age and gender on neural networks of motor response inhibition: from adolescence to mid-adulthood.

PubMed

Rubia, Katya; Lim, Lena; Ecker, Christine; Halari, Rozmin; Giampietro, Vincent; Simmons, Andrew; Brammer, Michael; Smith, Anna

2013-12-01

Functional inhibitory neural networks mature progressively with age. However, nothing is known about the impact of gender on their development. This study employed functional magnetic resonance imaging (fMRI) to investigate the effects of age, sex, and sex by age interactions on the brain activation of 63 healthy males and females, between 13 and 38 years, performing a Stop task. Increasing age was associated with progressively increased activation in typical response inhibition areas of right inferior and dorsolateral prefrontal and temporo-parietal regions. Females showed significantly enhanced activation in left inferior and superior frontal and striatal regions relative to males, while males showed increased activation relative to females in right inferior and superior parietal areas. Importantly, left frontal and striatal areas that showed increased activation in females, also showed significantly increased functional maturation in females relative to males, while the right inferior parietal activation that was increased in males showed significantly increased functional maturation relative to females. The findings demonstrate for the first time that sex-dimorphic activation patterns of enhanced left fronto-striatal activation in females and enhanced right parietal activation in males during motor inhibition appear to be the result of underlying gender differences in the functional maturation of these brain regions. © 2013. Published by Elsevier Inc. All rights reserved.