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Sample records for thalidomide

  1. Thalidomide neurotoxicity

    DEFF Research Database (Denmark)

    Clemmensen, O J; Olsen, P Z; Andersen, Klaus Ejner

    1984-01-01

    therapy. Since reports on thalidomide neurotoxicity have shown that the neurological symptoms are long standing and possibly irreversible, it is obviously important to inform patients of this possible side effect and to evaluate them closely for the symptoms and electrophysiological signs of evolving...

  2. Thalidomide and Pregnancy

    Science.gov (United States)

    Thalidomide In every pregnancy, a woman starts out with a 3-5% chance of having a baby ... risk. This sheet talks about whether exposure to thalidomide may increase the risk for birth defects over ...

  3. Thalidomide pharmacokinetics in sheep.

    Science.gov (United States)

    Smith, S L; Singh, P; Harding, D; Lun, D; Chambers, J P

    2016-07-01

    To determine the half life (T1/2), time taken to reach maximum plasma concentration (Tmax) and maximum plasma concentration (Cmax) of thalidomide in sheep following I/V, oral and topical treatment with a single dose of thalidomide. Three groups of 4-6-month-old ram lambs were treated with thalidomide dissolved in dimethylsulphoxide (DMSO). The first group (n=10) was treated I/V with 100 mg thalidomide in 2 mL DMSO; the second group (n=8) received 400 mg thalidomide in 2 mL DMSO orally, and the third group (n=8) had 400 mg thalidomide in 4 mL DMSO applied topically. Plasma samples were collected up to 36 hours after treatment, snap-frozen at -80°C and analysed for concentrations of thalidomide using high performance liquid chromatography. Following I/V administration, T1/2 was 5.0 (SEM 0.4) hours, volume of distribution was 3,372.0 (SEM 244.3) mL/kg and clearance was 487.1 (SEM 46.1) mL/hour.kg. Topical application of 400 mg thalidomide did not increase plasma concentrations. Following oral administration, thalidomide bioavailability was 89%, with T1/2, Tmax, and Cmax being 7.2 (SEM 0.8) hours, 3.0 (SEM 0.4) hours and 1,767.3 (SEM 178.1) ng/mL, respectively. Topical administration using DMSO as a solvent did not increase concentrations of thalidomide in plasma. The mean pharmacokinetic parameters determined following oral treatment with 400 mg of thalidomide were similar to those reported in humans receiving a single 400 mg oral dose (T1/2 7.3 hours; Tmax 4.3 hours and Cmax 2,820 ng/mL). There is potential for thalidomide to be used as a model for the treatment of chronic inflammatory conditions in sheep, such as Johne's disease, where tumour necrosis factor alpha plays a pathogenic role.

  4. Thalidomide Celgene Corp.

    Science.gov (United States)

    Bruyn, G A

    1998-08-01

    Thalidomide, in development by Celgene, inhibits the effects of elevated TNFalpha and may consequently be of use in a range of diseases including cachexia, bacterial meningitis, rheumatoid arthritis, septic shock, AIDS, tuberculosis, multiple sclerosis, ulcerative colitis, graft-versus-host disease and systemic lupus erythematosus. In July 1998, Celgene received clearance from the US FDA to market and sell Thalomid (thalidomide) for the treatment of erythema nodosum leprosum (a severe and debilitating condition associated with leprosy) [291919], following a recommendation for approval by the FDA advisory committee in September 1997 [261846,263970]. In that same month, Celgene filed an IND for the treatment of the chronic autoimmune disorders Behcet's disease, and aphthosis [264366]. The trial will be conducted by investigators at the Mayo Clinic and Bowman Gray School of Medicine. It will be divided into two phases, the first phase lasting 4 weeks in which patients will receive 100 mg thalidomide or placebo, and a second open-label phase which will call back all patients to receive the same dose of thalidomide over a 24-week period. It will be determined whether the drug significantly reduces existing ulcerations and inhibits the formation of new lesions. Positive results of a National Institute of Allergy and Infectious Diseases trial for aphthous ulceration of the mouth in HIV-infected patients prompted Celgene to commence a pivotal trial for the same indication. A total of 84 patients will be randomized to 100 mg, 200 mg or 400 mg thalidomide/day for 4 weeks. Patients achieving a full response after 4 weeks will be re-randomized on 100 mg thalidomide or placebo for up to another year [248356]. The company has also completed the pivotal phase III trial for AIDS-related cachexia [225437]. Results from a pivotal phase II/III trial showed that the drug significantly increased body weight in AIDS patients, but also increased viral load initially. A total of 99

  5. Thalidomide-associated thrombocytopenia

    NARCIS (Netherlands)

    Duyvendak, M; Naunton, M.; Kingma, B.J; Brouwers, J.R.B.J.

    2005-01-01

    OBJECTIVE: To report thrombocytopenia in a patient prescribed thalidomide for multiple myeloma (MM). CASE SUMMARY: A 70-year-old woman was diagnosed in 2003 with MM. At diagnosis, melphalan 0.25 mg/kg/day and prednisolone 2 mg/kg/day were started; however, the patient became refractory to therapy.

  6. Forgive sins: rise of thalidomide

    Directory of Open Access Journals (Sweden)

    Yugandar Inakanti

    2014-04-01

    Full Text Available Thalidomide was originally used as a Wonder Drug to treat morning sickness and insomnia in pregnant women in late 1950s. It became apparent in early 1960s that thalidomide treatment resulted in severe birth defects in thousands of children. Then it was banned in most of countries. Later on discovered anti-inflammatory and anti-angiogenic properties of Thalidomide proved to be useful for treatment of leprosy and multiple myeloma. A series of immunomodulatory drugs created by chemical modification of thalidomide have been developed to overcome the original devastating side effects. It’s being investigated extensively as a treatment for many other severe cutaneous disorders and advanced cancers. We briefly review pharmacological and the therapeutic profile of thalidomide.

  7. Thalidomide-induced severe hepatotoxicity.

    Science.gov (United States)

    Hanje, A James; Shamp, Jennifer L; Thomas, Fred B; Meis, Greg M

    2006-07-01

    Thalidomide is a relatively safe and efficacious form of therapy in the treatment of advanced, refractory multiple myeloma. Hepatotoxicity is listed as an extremely rare adverse effect associated with its use. We describe a 76-year-old woman with multiple myeloma who was treated with dexamethasone and thalidomide. By week 6 of therapy, she had developed acute increases in her aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels to more than 50 times the upper limit of normal. Her liver function test results had been within the normal ranges before and immediately after the start of therapy, and the patient had no known history of underlying liver disease. A liver biopsy specimen demonstrated evidence of acute injury with chronic changes of underlying steatosis and bridging fibrosis due to previously undiagnosed nonalcoholic steatohepatitis. Immediately after discontinuing thalidomide, her liver function test results began trending downward. Seven days later, her AST and ALT levels had improved to 86 and 165 U/L, respectively. This case and a limited number of other reports demonstrate severe hepatotoxicity as a rare but potentially serious adverse effect of thalidomide therapy. With the expanding use of thalidomide as a therapeutic agent, clinicians must recognize severe hepatotoxicity as a potential complication. Whether patients with preexisting liver disease are at increased risk when receiving thalidomide remains to be seen.

  8. [Thalidomide teratogenicity and its direct target identification].

    Science.gov (United States)

    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.

  9. Thalidomide for inflammatory bowel disease

    Science.gov (United States)

    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

  10. Pharmacoepidemiology and thalidomide embryopathy surveillance in Brazil.

    Science.gov (United States)

    Sales Luiz Vianna, Fernanda; de Oliveira, Marcelo Zagonel; Sanseverino, Maria Teresa Vieira; Morelo, Elaine Faria; de Lyra Rabello Neto, Dacio; Lopez-Camelo, Jorge; Camey, Suzi Alves; Schuler-Faccini, Lavinia

    2015-06-01

    Thalidomide causes congenital defects in children, such as limb reduction defects. Currently, it is used for a few indications; in Brazil, where leprosy is endemic, thalidomide is used for the treatment of erythema nodosum leprosum, and recent cases of thalidomide embryopathy have been reported. We analyzed the frequency of births with phenotypes consistent with thalidomide embryopathy (TEP) and correlated this with the distribution of thalidomide and the prevalence of leprosy between 2005 and 2010 in Brazil. A total of 5,889,210 thalidomide tablets were distributed; the prevalence of limb reduction defects was 1.60 (CI95%: 1.54-1.66) and TEP was 0.11 (CI95%: 0.10-0.13) per 10,000 births. Poisson regression showed an increase in cases of TEP and limb reduction defects per 100,000 tablets dispensed. Clusters and geographical isolates were identified in several regions. There is a correlation between thalidomide and TEP showing that thalidomide embryopathy should be monitored in countries where this medication is available. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Nitric oxide rescues thalidomide mediated teratogenicity

    Science.gov (United States)

    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

  12. Anti-inflammatory effect of thalidomide dithiocarbamate and dithioate analogs.

    Science.gov (United States)

    Talaat, Roba; El-Sayed, Waheba; Agwa, Hussein S; Gamal-Eldeen, Amira M; Moawia, Shaden; Zahran, Magdy A H

    2015-08-05

    Thalidomide has anti-inflammatory, immunomodulatory, and anti-angiogenic properties. It has been used to treat a variety of cancers and autoimmune diseases. This study aimed to characterize anti-inflammatory activities of novel thalidomide analogs by exploring their effects on splenocytes proliferation and macrophage functions and their antioxidant activity. MTT assay was used to assess the cytotoxic effect of thalidomide analogs against splenocytes. Tumor necrosis factor (TNF-α) and nuclear factor kappa B (NF-κB-P65) were determined by enzyme-linked immunosorbent assay (ELISA). Nitric oxide (NO) was estimated by colorimetric assay. Antioxidant activity was examined by ORAC assay. Our results demonstrated that thalidomide dithioate analog 2 and thalidomide dithiocarbamate analog 4 produced a slight increase in splenocyte proliferation compared with thalidomide. Thalidomide dithiocarbamate analog 1 is a potent inhibitor of TNF-α production, whereas thalidomide dithiocarbamate analog 5 is a potent inhibitor of both TNF-α and NO. Analog 2 has a pronounced inhibitory effect on NF-κB-P65 production level. All thalidomide analogs showed prooxidant activity against hydroxyl (OH) radical. Analog 1 and thalidomide dithioate analog 3 have prooxidant activity against peroxyl (ROO) radical in relation to thalidomide. On the other hand, analog 4 has a potent scavenging capacity against peroxyl (ROO) radical compared with thalidomide. Taken together, the results of this study suggest that thalidomide analogs might have valuable anti-inflammatory activities with more pronounced effect than thalidomide itself. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  13. Thalidomide for treatment of multiple myeloma: 10 years later

    NARCIS (Netherlands)

    A. Palumbo (Antonio); T. Facon (Thierry); P. Sonneveld (Pieter); J. Bladé (Joan); M. Offidani (Massimo); F. Gay (Francesca); P. Moreau; A. Waage (Anders); A. Spencer (Andrew); H. Ludwig (Heinz); M. Boccadoro (Mario); J-L. Harousseau (Jean-Luc)

    2008-01-01

    textabstractThalidomide, bortezomib, and lenalidomide have recently changed the treatment paradigm of myeloma. In young, newly diagnosed patients, the combination of thalidomide and dexamethasone has been widely used as induction treatment before autologous stem cell transplantation (ASCT). In 2

  14. Organizer formation in Hydra is disrupted by thalidomide treatment

    National Research Council Canada - National Science Library

    Brooun, Maria; Manoukian, Armen; Shimizu, Hiroshi; Bode, Hans R; McNeill, Helen

    2013-01-01

    .... Surprisingly, thalidomide does not have teratogenic effects on mouse development. We investigated the effect of thalidomide on patterning in hydra, an early metazoan with a very simple axial symmetry...

  15. The thalidomide disaster, lessons from the past.

    Science.gov (United States)

    Ridings, James E

    2013-01-01

    It is close to 60 years since thalidomide was created by the German company, Chemie-Grünenthal, and launched as "Contergan." This was soon to be followed in England by the launch of "Distaval." Of all the drugs developed in the intervening years, thalidomide has undoubtedly had the greatest influence on shaping the Pharmaceutical Industry as we know it today.Strong marketing pressure in an Industry hungry for new medicines brought an inadequately tested drug to the market, targeted outsourcing quickly expanded the client base and finally market forces prevented timely withdrawal, even when evidence was emerging of disastrous side-effects. The full story of thalidomide was told by the Sunday Times in "Suffer The Children" (Kingsley et al., Suffer the children: the story of thalidomide, the insight team of the Sunday times (UK), 1979).Many preventative measures have been taken in the intervening years in light of the lessons learned with thalidomide. However, many of the pressures that led to the thalidomide disaster exist today with record high management and shareholder pressures to achieve success, parallel worldwide marketing, increased numbers of targeted outsourcing by small companies forming alliances with "Big Pharma" and, according to some commentators, a breakdown in the system of checks and balances that have existed in the regulatory authorities in the intervening years.Using thalidomide as a point of reference, this chapter looks at drug development and testing, regulatory authorities and guidelines, outsourcing and in-licensing, pharmacovigilance, and factors that influence withdrawal of a drug from the market.

  16. Thalidomide

    Science.gov (United States)

    ... will not have any sexual contact with a male for 4 weeks before your treatment, during your treatment, and for 4 weeks after your treatment.Some medications can cause hormonal contraceptives to be less effective. If you plan to ...

  17. Thalidomide

    Science.gov (United States)

    ... affect the skin, such as cutaneous lupus and Behcet's disease HIV-related mouth and throat ulcers, as well ... March 22, 2016. Lebwohl MG, et al., eds. Behcet disease. In: Treatment of Skin Disease: Comprehensive Therapeutic Strategies. ...

  18. [Thalidomide-associated hypothyroidism in a patient with multiple myeloma].

    Science.gov (United States)

    Okamura, Ikue; Ikeda, Takashi; Sato, Ken; Kimura, Fumihiko

    2015-01-01

    Thalidomide is highly effective against multiple myeloma, but some patients must discontinue this medication due to adverse effects. We present herein an instructive case report on thalidomide-associated hypothyroidism in a patient with multiple myeloma. Thyroid hormone replacement therapy allowed us to restart administration of thalidomide, a potentially life-saving therapy. Known adverse effects of thalidomide, such as lethargy, constipation, and bradycardia, are potential symptoms of hypothyroidism, but we tend to overlook drug-associated hypothyroidism. Our case highlights the importance of routinely testing thyroid function in patients receiving thalidomide therapy.

  19. [Thalidomide (Contergan) induced limb deficiency in Hungary?].

    Science.gov (United States)

    Gidai, János; Bács, Eva; Czeizel, Endre

    2009-06-21

    A 47 year old female with severe deficiency of three limbs visited our Genetic Counselling Clinic and asked us to give her a certificate that her complex limb deficiency was caused by thalidomide (Contergan). According to her explanation, her mother used this drug during pregnancy which was given to her by her sister, who lived in West Germany. The characteristic signs of thalidomide embryopathy are: radial type limb deficiency including most severe forms of phocomelia and amelia, ear abnormalities. In the case of this woman, however, FFU (femoral-fibula-ulna) complex was found: bilateral femur hypoplasia (F), and fibular hypoplasia (F) with the lack of Vth and IVth toes, in addition with ulnar hypoplasia (U) with the deficiency of Vth and IVth fingers in her right upper limb. The left upper limb was not affected. Besides that, she was treated with schizophrenia. In conclusion, there is no association between the supposed thalidomide use during pregnancy and FFU complex.

  20. Systematic review: thalidomide and thalidomide analogues for treatment of inflammatory bowel disease.

    Science.gov (United States)

    Yang, C; Singh, P; Singh, H; Le, M-L; El-Matary, W

    2015-06-01

    It has been reported that thalidomide may be effective in treating inflammatory bowel disease (IBD). To review the evidence examining the efficacy and safety of thalidomide for inducing and maintaining remission in Crohn's disease (CD) and ulcerative colitis (UC). The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PubMed (1950-August 2014), EMBASE (1984-August 2014), Scopus, and Web of knowledge were searched for randomised controlled trials (RCTs), observational studies and case series. The primary outcomes were induction of remission or response for active IBD or relapse rate for patients in remission and subsequently on thalidomide/analogues for at least 3 months. Twelve studies (2 RCTs and 10 case series) met the inclusion criteria for inducing remission and included 248 patients (10 with UC, 238 with CD). Only one RCT of paediatric CD achieved high quality scores (remission rate thalidomide: 46%, placebo: 12%; p=0.01). The crude pooled remission rate for thalidomide was 49% and 25% in luminal and perianal CD respectively. For UC, 50% achieved remission and 10% had partial response. One case series reported 21 patients (17 CD, four UC) who maintained remission for 6 months. Many adverse events were reported including sedation (32%) and peripheral neuropathy (20%). One high quality RCT showed that thalidomide is effective for inducing remission in paediatric CD. The current evidence is insufficient to support using thalidomide to induce remission in UC or adult CD, or to maintain remission in IBD. Significant adverse events may occur, necessitating discontinuation of thalidomide. © 2015 John Wiley & Sons Ltd.

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

    Science.gov (United States)

    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...

  2. Antitumorigenic Evaluation of Thalidomide Alone and in Combination with Cisplatin in DBA2/J Mice

    Directory of Open Access Journals (Sweden)

    Jean Marie B. Ruddy

    2002-01-01

    thalidomide failed to inhibit cell proliferation. However, cisplatin treatment with or without thalidomide, significantly inhibited the multiplication of both cell lines in a dose dependent manner. Thalidomide does not appear to be a beneficial adjuvant to cisplatin treatment.

  3. Therapeutic potential of thalidomide for gemcitabine-resistant bladder cancer.

    Science.gov (United States)

    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.

  4. Neuroprotective effect of thalidomide on MPTP-induced toxicity.

    Science.gov (United States)

    Palencia, Guadalupe; Garcia, Esperanza; Osorio-Rico, Laura; Trejo-Solís, Cristina; Escamilla-Ramírez, Angel; Sotelo, Julio

    2015-03-01

    Thalidomide is a sedative with unique pharmacological properties; studies on epilepsy and brain ischemia have shown intense neuroprotective effects. We analyzed the effect of thalidomide treatment on the neurotoxicity caused by the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahidropyridine (MPTP) in mice. Thalidomide was administered at two times; before and after the exposure to MPTP. In both circumstances thalidomide improved the neurotoxicity induced by MPTP as seen by a significant raise of the striatal contents of dopamine and simultaneous decrease of monoamine-oxidase-B (MAO-B). These results indicate that in the experimental model of Parkinson's disease the administration of thalidomide improves the functional damage on the nigrostriatal cell substratum as seen by the production of dopamine. This neuroprotective effect seems to be mediated by inhibition of excitotoxicity. Our results suggest that thalidomide could be investigated as potential adjuvant therapy for Parkinson's disease. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Thalidomide induces mucosal healing in postoperative Crohn disease endoscopic recurrence

    Science.gov (United States)

    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

  6. The impact of thalidomide use in birth defects in Brazil.

    Science.gov (United States)

    Sales Luiz Vianna, Fernanda; Kowalski, Thayne Woycinck; Fraga, Lucas Rosa; Sanseverino, Maria Teresa Vieira; Schuler-Faccini, Lavinia

    2017-01-01

    Although the thalidomide tragedy occurred more than 50 years ago, the medication is still being used worldwide for different reasons, and several aspects regarding its teratogenicity remain unsolved. Despite the strict regulation implemented, new cases of thalidomide embryopathy (TE) are still being registered in Brazil. Furthermore, the molecular processes that lead to malformations when the embryo is exposed to thalidomide have not yet been fully identified. In this article, we perform a critical analysis of thalidomide's history in Brazil, highlighting aspects of the occurrence of TE over the decades. Finally, we present the main perspectives and challenges for ongoing surveillance and prevention of TE in Brazil. The effective control of dispensing thalidomide, especially in areas where leprosy is endemic, is one of the most important and challenging points. Furthermore, the emergence of thalidomide analogues is fast approaching, and their availability would pose additional concerns. The understanding of the molecular mechanisms and targets of thalidomide in both experimental and human models is essential for generating new insights into teratogenic mechanisms, so that safer thalidomide analogues can be developed. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  7. Bleeding recurrence in patients with gastrointestinal vascular malformation after thalidomide.

    Science.gov (United States)

    Chen, Haiying; Fu, Sengwang; Feng, Nan; Chen, Huimin; Gao, Yunjie; Zhao, Yunjia; Xue, Hanbing; Zhang, Yao; Li, Xiaobo; Dai, Jun; Fang, Jingyuan; Ge, Zhizheng

    2016-08-01

    Thalidomide may be used for the treatment of gastrointestinal vascular malformation (GIVM), but the long-term response and adverse effects are unknown. Aim to study the recurrence rate of GIVM bleeding after thalidomide treatment, the response to treatment, and the adverse effects.This was a retrospective study of 80 patients with GIVM treated with thalidomide between November 2003 and November 2013. Patients received a course of 100 mg/day of thalidomide for 4 months and were followed up for at least 1 year. The response rate during follow-up, the recurrence rate after the 1st course of treatment, and the rate of retreatment were assessed. Comorbidities, the need for blood transfusion, yearly bleeding episodes, hemoglobin levels, hospitalization after thalidomide treatment, and the rate of adverse effects were also examined.The overall response rate during follow-up was 79.5% (62/78). The recurrence rate was 21.0% after the 1st course of thalidomide. The response rate of retreatment was 100%. After thalidomide treatment, yearly blood transfusion amounts, yearly bleeding episodes, and yearly hospitalization numbers were significantly decreased, while hemoglobin levels were significantly increased (P Thalidomide showed a good response rate and low adverse effect rate in patients with recurrent gastrointestinal bleeding due to GIVM.

  8. Organizer formation in Hydra is disrupted by thalidomide treatment.

    Science.gov (United States)

    Brooun, Maria; Manoukian, Armen; Shimizu, Hiroshi; Bode, Hans R; McNeill, Helen

    2013-06-01

    Thalidomide is a drug that is well known for its teratogenic properties in humans. Surprisingly, thalidomide does not have teratogenic effects on mouse development. We investigated the effect of thalidomide on patterning in hydra, an early metazoan with a very simple axial symmetry. Hydra develops asexually via Wnt-dependent organizer formation, leading to the budding of a new organism. We observe both induction and inhibition of organizer formation depending on cellular context. Interestingly, thalidomide treatment altered budding and the developing organizer, but had little effect on the adult. Expression of Hybra1, a marker of the organizer increased upon thalidomide treatment. However when the organizer is induced by ectopic activation of Wnt signaling via GSK3 inhibition, thalidomide suppresses induction. We show that inhibition of Wnt signaling is not mediated by induction of the BMP pathway. We show that thalidomide activity on organizer formation in hydra depends on the activity of casein kinase1 and the abundance of β-catenin. Finally, we find that interstitial cells, multipotent cells which give rise to nemoatocytes, neural, digestive and germline cells, are partially responsible for the inhibitory effect of thalidomide. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. Treatment of pediatric refractory Crohn’s disease with thalidomide

    Science.gov (United States)

    Zheng, Cui-Fang; Xu, Jia-Hua; Huang, Ying; Leung, Ying-Kit

    2011-01-01

    AIM: To assess the efficacy and tolerability of thalidomide in pediatric Crohn’s disease (CD). METHODS: Six patients with refractory CD received thalidomide at an initial dose of 2 mg/kg per day for one month, then increased to 3 mg/kg per day or decreased to 1 mg/kg per day, and again further reduced to 0.5 mg/kg per day, according to the individual patient’s response to the drug. RESULTS: Remission was achieved within three months. Dramatic clinical improvement was demonstrated after thalidomide treatment. Endoscopic and pathological improvements were also observed after thalidomide treatment, which was well tolerated by all patients. CONCLUSION: Thalidomide is a useful drug for pediatric refractory CD. PMID:21455327

  10. Thalidomide-induced Stroke in a Child With Thalassemia Major.

    Science.gov (United States)

    Gunaseelan, Sushil; Prakash, Anand

    2017-11-01

    β-thalassemia major is a hereditary anemia resulting from defects in β-globin production. It is also characterized by a hypercoagulable state with an increased risk of thrombosis. Thalidomide, a drug known for its immunomodulating and antiangiogenic properties, has recently been demonstrated to induce γ-globin gene expression and to increase the proliferation of erythroid cells. An increasing incidence of thromboembolic events in thalidomide-treated patients has been reported. This is often in the context of thalidomide combinations with other drugs, including steroids and particularly anthracycline-based chemotherapy, and with very low incidence of thrombosis with single-agent thalidomide treatment. We report a case of stroke in a β-thalassemic child who had received a course of thalidomide.

  11. The clinical implications of thalidomide in inflammatory bowel diseases.

    Science.gov (United States)

    Diamanti, Antonella; Capriati, Teresa; Papadatou, Bronislava; Knafelz, Daniela; Bracci, Fiammetta; Corsetti, Tiziana; Elia, Domenica; Torre, Giuliano

    2015-06-01

    Thalidomide has anti-inflammatory and anti-angiogenetic activity that makes it suitable for treating inflammatory bowel diseases (IBD). The recent guidelines from the European Crohn's and Colitis Organization/European Society for Pediatric Gastroenterology Hepatology and Nutrition conclude that thalidomide cannot be recommended in refractory pediatric Crohn's disease but that it may be considered in selected cohorts of patients who are not anti-TNFα agent responders. The main adverse effect is the potential teratogenicity that renders the long-term use of thalidomide problematic in young adults due to the strict need for contraceptive use. In short-term use it is relatively safe; the most likely adverse effect is the neuropathy, which is highly reversible in children. So far the use of thalidomide is reported in 223 adult and pediatric IBD patients (206 with Crohn's disease). In the following sections, the authors will discuss efficacy and safety of thalidomide, in the short-term treatment of IBD.

  12. Potential novel uses of thalidomide: focus on palliative care.

    Science.gov (United States)

    Peuckmann, V; Fisch, M; Bruera, E

    2000-08-01

    Thalidomide, after being banned from the market in the early 1960s because of the worldwide teratogenesis disaster, is currently being rediscovered because of its multiple therapeutic effects in various serious diseases and symptoms. Original studies examined the anxiolytic, mild hypnotic, anti-emetic and adjuvant analgesic properties of this drug. Subsequently, thalidomide was found to be highly effective in managing the cutaneous manifestations of leprosy (erythema nodosum leprosum) and even to be superior to aspirin (acetylsalicylic acid) in controlling leprosy-associated fever. Recent research shows promising results with thalidomide in patients with progressive bodyweight loss related to advanced cancer and HIV infection. Thalidomide therapy of diseases such as tuberculosis, sarcoidosis, aphthous ulcers in HIV syndrome and Behcet's disease, rheumatoid arthritis, multiple myeloma, graft-versus-host disease, pyoderma gangrenosum, inflammatory bowel disease, Sjögren's syndrome, lupus erythematosus and a variety of solid tumours is currently being explored. Furthermore, in preliminary studies, thalidomide has been found to be effective in several syndromes related to advanced cancer, such as the cancer cachexia syndrome, chronic nausea, insomnia, profuse sweating and pain. Whether thalidomide has a therapeutic effect on neoplastic fever has yet to be elucidated. These intriguing features make the use of the drug potentially attractive for palliative care. In addition, by a distinct mechanism of action compared with most other drugs, thalidomide offers the possibility of combined treatment with other agents with non-overlapping toxicities. The mechanism of action of thalidomide is probably based on the suppression of tumour necrosis factor-alpha and the modulation of interleukins. However, it is not possible to identify a single dominant mechanism, since the action of cytokines and the effect of thalidomide appear to be complex. This review article discusses the

  13. Thalidomide and thalidomide analogues for maintenance of remission in Crohn's disease

    NARCIS (Netherlands)

    Akobeng, Anthony K.; Stokkers, Pieter C.

    2009-01-01

    Maintenance of remission is a major issue in the management of Crohn's disease. Thalidomide, a tumour necrosis factor-alpha (TNF-alpha) inhibitor and its analogue, lenalidomide, may have a role in the management of Crohn's disease, but it is not clear whether it is an effective maintenance therapy.

  14. Thalidomide in treatment of connective diseases and vasculities

    Directory of Open Access Journals (Sweden)

    D. Ribatti

    2011-09-01

    Full Text Available Thalidomide is an immunomodulatory, anti-inflammatory and anti-angiogenic drug. Thalidomide exerts its effects by decreasing circulating CD4 positive T-cells and stimulating CD8 positive T-cells, by increasing the number of Natural Killer cells and T-helper 2 cells. Thalidomide also inhibits proliferation of stimulated T-cells and leukocyte chemotaxis. It modifies a number of integrin receptors and other leukocytic surface receptors and down-modulates cell-adhesion molecules involved in leukocyte migration. It has been demonstrated that thalidomide inhibits TNFa, IL-5, IL-6, IL-8, IL-12 production and increases production of IL-2, IL-10 and INFg. Moreover thalidomide plays an important role in inhibition of VEGF and FGF-2 mediated angiogenesis. Although the exact mechanism of action is not fully understood and only limited treatment opinions exist, thalidomide plays a role also in connective diseases and vasculities. Thalidomide has been seen efficacious in the treatment of cutaneous disorders in patients with systemic lupus erythematosus and in mucocutaneous disease in Behçet’s disease with a not dose-dependent response, even if it should be restricted to selected patients because of its important side effects.

  15. Thalidomide protects mice against LPS-induced shock

    Directory of Open Access Journals (Sweden)

    Moreira A.L.

    1997-01-01

    Full Text Available Thalidomide has been shown to selectively inhibit TNF-a production in vitro by lipopolysaccharide (LPS-stimulated monocytes. TNF-a has been shown to play a pivotal role in the pathophysiology of endotoxic shock. Using a mouse model of LPS-induced shock, we investigated the effects of thalidomide on the production of TNF-a and other cytokines and on animal survival. After injection of 100-350 µg LPS into mice, cytokines including TNF-a, IL-6, IL-10, IL-1ß, GM-CSF and IFN-g were measured in the serum. Administration of 200 mg/kg thalidomide to mice before LPS challenge modified the profile of LPS-induced cytokine secretion. Serum TNF-a levels were reduced by 93%, in a dose-dependent manner, and TNF-a mRNA expression in the spleens of mice was reduced by 70%. Serum IL-6 levels were also inhibited by 50%. Thalidomide induced a two-fold increase in serum IL-10 levels. Thalidomide treatment did not interfere with the production of GM-CSF, IL-1ß or IFN-g. The LD50 of LPS in this model was increased by thalidomide pre-treatment from 150 µg to 300 µg in 72 h. Thus, at otherwise lethal doses of LPS, thalidomide treatment was found to protect animals from death

  16. Thalidomide for the treatment of chronic refractory pruritus.

    Science.gov (United States)

    Sharma, Divya; Kwatra, Shawn G

    2016-02-01

    Pruritus is a common and often times difficult to treat symptom in many dermatologic and systemic diseases. For pruritus with an inflammatory or autoimmune origin, therapies such as topical corticosteroids and antihistamines are often initiated. However, in the case that these and additional systemic therapies are ineffective, thalidomide, an immunomodulator and neuromodulator, may be a useful alternative treatment. Considerable relief of chronic pruritus has been demonstrated with thalidomide in case reports, case series, and controlled trials. Double-blind controlled studies demonstrated thalidomide's efficacy as an antipruritic agent in patients with uremic pruritus, primary biliary cirrhosis, and prurigo nodularis. In case reports, case series, and open-label trials, thalidomide significantly reduced pruritus associated with conditions such as actinic prurigo and paraneoplastic pruritus. Because of variations in study design and evaluation of antipruritic effect, it is difficult to fully understand thalidomide's role based on the evidence described to date in the medical literature. In this review, we provide an overview of the reported findings and evaluate thalidomide's utility in managing refractory pruritus in the context of its adverse risk profile. We propose that thalidomide can be an alternative or combination antipruritic treatment for patients who do not obtain enough relief from conservative therapy. Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  17. Randomised comparison of thalidomide versus placebo in toxic epidermal necrolysis.

    Science.gov (United States)

    Wolkenstein, P; Latarjet, J; Roujeau, J C; Duguet, C; Boudeau, S; Vaillant, L; Maignan, M; Schuhmacher, M H; Milpied, B; Pilorget, A; Bocquet, H; Brun-Buisson, C; Revuz, J

    1998-11-14

    Toxic epidermal necrolysis (TEN) is associated with a 30% death rate. Tumour necrosis factor alpha (TNF-alpha) has been implicated in the pathogenesis of TEN. Thalidomide is a potent inhibitor of TNF-alpha action. We did a double-blind, randomised, placebo-controlled study of thalidomide in TEN. The patients received a 5-day course of thalidomide 400 mg daily or placebo. The main endpoint was the progression of skin detachment after day 7. Secondary endpoints were the severity of the disease, evaluated with the simplified acute physiology score (SAPS), and the mortality. TNF-alpha and interleukin 6 were measured. The study was stopped because there was excess mortality in the thalidomide group--ten of 12 patients died compared with three of ten in the placebo group (Fisher's exact test with Katz's approximation, relative risk=2.78, p=0.03). After adjustment for SAPS, mortality remained significantly higher in the thalidomide group than in the placebo group (exact logistic regression mid-p=0.007; 95% CI for odds ratio 2.7 to infinity). Plasma TNF-alpha concentration was higher in the thalidomide group than the placebo group on day 2, though the difference was not significant (Wilcoxon rank-sum test p=0.07). Even though few patients were included, our data suggest that thalidomide is detrimental in TEN, possibly because of a paradoxical enhancement of TNF-alpha production.

  18. Characterization of Thalidomide using Raman Spectroscopy

    Science.gov (United States)

    Cipriani, Penelope; Smith, Candace Y.

    2008-02-01

    Thalidomide is a potent anticancer therapeutic drug whose mechanism of action has not yet been elucidated. In this report, experimental Raman spectroscopy is used to determine and characterize the vibrational frequencies of the drug. These normal modes are then compared to their quantum mechanical counterparts, which have been computed using density functional theory. Upon analysis of the spectra, we found that there was a high level of agreement between the wavenumbers. As such, this spectroscopic technique may be a viable tool for examining the way in which this drug interacts with its target molecules.

  19. A Novel Green Synthesis of Thalidomide and Analogs

    Directory of Open Access Journals (Sweden)

    Ellis Benjamin

    2017-01-01

    Full Text Available Thalidomide and its derivatives are currently under investigation for their antiangiogenic, immunomodulative, and anticancer properties. Current methods used to synthesize these compounds involve multiple steps and extensive workup procedures. Described herein is an efficient microwave irradiation green synthesis method that allows preparation of thalidomide and its analogs in a one-pot multicomponent synthesis system. The multicomponent synthesis system developed involves an array of cyclic anhydrides, glutamic acid, and ammonium chloride in the presence of catalytic amounts of 4-N,N-dimethylaminopyridine (DMAP to produce thalidomide and structurally related compounds within minutes in good isolated yields.

  20. Effective treatment of gastrointestinal bleeding with thalidomide- Chances and limitations

    National Research Council Canada - National Science Library

    Juergen Bauditz

    2016-01-01

    .... Thalidomide, which caused severe deformities in newborn children in the 1960 s, is now increasingly used after it was shown to suppress tumor necrosis factor alpha, inhibi t angiogenesis and to be...

  1. Thalidomide combined with irradiation alters the activity of two proteases.

    Science.gov (United States)

    Şimşek, Ece; Aydemir, Esra; Korcum, Aylin Fidan; Fişkın, Kayahan

    2015-02-01

    The aim of the present study was to investigate the effects of thalidomide, a drug known for its anti‑angiogenic and antitumor properties, at its cytotoxic dose previously determined as 40 µg/ml (according to four cytotoxic test results). The effect of the drug alone and in combination with radiotherapy using Cobalt 60 (60Co) at 45 Gy on the enzymatic activity of substance‑P degrading A disintegrin and metalloproteinase (ADAM)10 and neprilysin (NEP) was investigated in the mouse breast cancer cell lines 4T1 and 4T1 heart metastases post‑capsaicin (4THMpc). Thalidomide (40 µg/ml) exerted differing effects on the activities of ADAM10 and NEP enzymes. In 4T1 cells, 40 µg/ml thalidomide alone did not alter ADAM10 enzyme activity. 60Co irradiation at 45 Gy alone caused a 42% inhibition in ADAM10 activity, however, the inhibition increased to 89% when combined therapy was used. By contrast, in the 4THMpc cell line, 40 µg/ml thalidomide alone induced a 66.6% increase in ADAM10 enzyme activity. Radiotherapy alone and thalidomide with 60Co combined therapy caused a 33.3 and 40% inhibition of ADAM10 activity, respectively. In 4T1 cells, thalidomide alone caused a 40.9% increase in NEP activity. Radiation therapy alone or in combination with the drug caused a 40.7% increase in NEP activity. In more aggressive 4THMpc cells, thalidomide alone caused a 26.6% increase in NEP activity. Radiotherapy alone and combined therapy caused a 33.3 and 37% increase in enzyme activity, respectively. To the best of our knowledge, the present study is the first to demonstrate that thalidomide alone or in combination with radiotherapy exhibits significant cytotoxic effects on 4T1 and 4THMpc mouse breast cancer cell lines indicating that this drug affects the enzymatic activity of ADAM10 and NEP in vitro.

  2. Long-term outcomes of thalidomide in refractory Crohn's disease.

    Science.gov (United States)

    Gerich, M E; Yoon, J L; Targan, S R; Ippoliti, A F; Vasiliauskas, E A

    2015-03-01

    Several open-label and retrospective studies have indicated that thalidomide may be beneficial in patients with refractory Crohn's disease (CD). To report our long-term experience with the use of thalidomide for adults with refractory Crohn's disease. We conducted a retrospective study of long-term clinical and safety outcomes among adults treated with thalidomide for refractory Crohn's disease. Response was defined as a clinician's assessment of improvement after at least 7 days treatment of one or more of the following: bowel movement frequency, fistula output, rectal bleeding, abdominal pain, extraintestinal manifestations, or well-being. Remission required all of the following: thalidomide for a median of 4.4 months and followed up for a median of 58 months. Clinical response and remission rates were 54% and 19%, respectively. About 40% of patients were able to stop steroids. Response rates were higher for those treated with more than 50 mg/day (85%) than for those treated with a maximum of 50 mg/day (40%; P = 0.01). An adverse event occurred in 68% of patients. Approximately one-third of patients (38%) experienced neuropathy. Thalidomide appears to be safe and effective in some patients with refractory Crohn's disease. Although side effects may limit long-term use, thalidomide has potential to induce significant clinical responses. © 2014 John Wiley & Sons Ltd.

  3. Longitudinal Patterns of Thalidomide Neuropathy in Children and Adolescents.

    Science.gov (United States)

    Liew, Wendy K M; Pacak, Christina A; Visyak, Nicole; Darras, Basil T; Bousvaros, Athos; Kang, Peter B

    2016-11-01

    To characterize the longitudinal clinical and electrophysiological patterns of thalidomide neuropathy in children and adolescents. Retrospective analysis of clinical records at a tertiary care children's hospital, including serial electrophysiological studies. Sixteen patients aged 6-24 years received thalidomide to treat Crohn's disease from 2002 to 2012. Nine subjects had electrophysiological evidence of sensorimotor axonal polyneuropathy, 8 of whom had sensory and/or motor symptoms. The patients with polyneuropathy received thalidomide for 5 weeks to 52 months, with cumulative doses ranging from 1.4 to 207.7 g. All subjects with cumulative doses greater than 60 g developed polyneuropathy, and 4 of the 5 subjects who received thalidomide for more than 20 months developed polyneuropathy. The 7 subjects who had normal neurophysiological studies received therapy for 1 week to 25 months, with cumulative doses ranging from 0.7 to 47 g. In contrast to some previous reports, several patients had sensorimotor polyneuropathies, rather than pure sensory neuropathies. In patients with neuropathy who received therapy for more than 24 months and had 3 or more electromyography studies, the severity of the neuropathy plateaued. Factors in addition to the total dose may contribute to the risk profile for thalidomide neuropathy, including pharmacogenetic susceptibilities. The severity of the neuropathy does not worsen relentlessly. Children, adolescents, and young adults receiving thalidomide should undergo regular neurophysiological studies to monitor for neuropathy. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Lenalidomide and thalidomide in the treatment of chronic pain.

    Science.gov (United States)

    Asher, Christopher; Furnish, Timothy

    2013-05-01

    The immunomodulatory and anti-inflammatory drug thalidomide was first introduced in 1957 as a sleep aid and treatment for morning sickness. It was subsequently removed from the market due to severe teratogenic side effects and then returned to the market as a treatment for myelodysplastic syndrome and multiple myeloma. Lenalidomide is an analog of thalidomide with similar efficacy but improved side-effect profile. There are reports and studies of both agents for the treatment of chronic pain, especially complex regional pain syndrome (CRPS). Effective medical and interventional therapies for CRPS are limited. The use of novel immunomodulatory and anti-inflammatory drugs such as thalidomide and lenalidomide may offer a new approach to the treatment of CRPS. The mechanism of action, adverse effect profile, and regulatory history of thalidomide and lenalidomide will be reviewed. The literature search for pain treatment includes case series and preliminary trials for CRPS, and case reports and case series for other chronic pain conditions. Lenalidomide has a more favorable adverse effect profile compared to its parent compound thalidomide. Both agents, however, have significant potential adverse effects. Evidence of efficacy for chronic pain syndromes such as CRPS remains limited. Further studies are needed before these agents can be recommended for use in CRPS or other chronic pain syndromes.

  5. Clarithromycin Synergistically Enhances Thalidomide Cytotoxicity in Myeloma Cells.

    Science.gov (United States)

    Qiu, Xu-Hua; Shao, Jing-Jing; Mei, Jian-Gang; Li, Han-Qing; Cao, Hong-Qin

    2016-01-01

    Clarithromycin (CAM) is a macrolide antibiotic that is widely used in the treatment of respiratory tract infections, sexually transmitted diseases and infections caused by the Helicobacter pylori and Mycobacterium avium complex. Recent studies showed that CAM was highly effective against multiple myeloma (MM) when used in combination with immunomodulatory drugs and dexamethasone. However, the related mechanism is still unknown. As 3 immunomodulatory agents are all effective in the respective regimen, we postulated that CAM might enhance the effect of immunomodulatory drugs. We evaluated the interaction effects of CAM and thalidomide on myeloma cells. Taking into consideration that thalidomide did not affect the proliferation of myeloma cells in vitro, we cocultured myeloma cells with peripheral blood monocytes and evaluated the effects of CAM and thalidomide on the cocultured cell model. Data showed that thalidomide and CAM synergistically inhibited the proliferation of the cells. On this same model, we also found that thalidomide and CAM synergistically decreased the secretion of tumor necrosis factor-α and interleukin-6. This might be caused by the effect of the 2 drugs on inhibiting the activation of ERK1/2 and AKT. These data suggest that the efficacy of CAM against MM was partly due to its synergistic action with the immunomodulatory agents. © 2015 S. Karger AG, Basel.

  6. Review of thalidomide use in the pediatric population.

    Science.gov (United States)

    Yang, Catherine S; Kim, Changhyun; Antaya, Richard J

    2015-04-01

    Thalidomide is resurging in the management of adult rheumatologic skin conditions, especially lupus erythematosus. Although use in pediatric patients is reported since the 1990s, there are no systematic reviews describing treatment in children. Thalidomide has immunomodulatory and anti-tumor necrosis factor-α effects as well as antiangiogenic properties, making it useful for a broad spectrum of inflammatory disorders. Thalidomide is second-line treatment for aphthous stomatitis and chronic graft-versus-host disease in children and has been prescribed for many other conditions including actinic prurigo and epidermolysis bullosa pruriginosa. Systemic lupus erythematosus may be less responsive to thalidomide in children than adults. Peripheral neuropathy is observed in both idiosyncratic and dose-dependent relationships; children older than 12 years may be more susceptible to developing this adverse effect than younger patients. There are rare reports of thrombotic complications in children treated for nonmalignant indications. We review the mechanism of action and propose that thalidomide is an alternative treatment for patients who fail or have contraindications to anti-tumor necrosis factor-α biologics. Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  7. Effective treatment of gastrointestinal bleeding with thalidomide - Chances and limitations

    Science.gov (United States)

    Bauditz, Juergen

    2016-01-01

    For more than 50 years bleeding from gastrointestinal angiodysplasias has been treated by hormonal therapy with estrogens and progesterons. After a randomized study finally demonstrated that hormones have no effect on bleeding events and transfusion requirements, therapy has switched to endoscopic coagulation. However, angiodysplasias tend to recur over months to years and endoscopy often has to be repeated for long time periods. Thalidomide, which caused severe deformities in newborn children in the 1960s, is now increasingly used after it was shown to suppress tumor necrosis factor alpha, inhibit angiogenesis and to be also effective for treatment of multiple myeloma. In 2011 thalidomide was proven to be highly effective for treatment of bleeding from gastrointestinal angiodysplasias in a randomized study. Further evidence by uncontrolled studies exists that thalidomide is also useful for treatment of bleeding in hereditary hemorrhagic telangiectasia. In spite of this data, endoscopic therapy remains the treatment of choice in many hospitals, as thalidomide is still notorious for its teratogenicity. However, patients with gastrointestinal bleeding related to angiodysplasias are generally at an age in which women have no child-bearing potential. Teratogenicity is therefore no issue for these elderly patients. Other side-effects of thalidomide like neurotoxicity may limit treatment options but can be monitored safely. PMID:27003992

  8. Evaluation of stability difference between asymmetric homochiral dimer in (S)-thalidomide crystal and symmetric heterochiral dimer in (RS)-thalidomide crystal

    Science.gov (United States)

    Suzuki, Toshiya; Tanaka, Masahito; Shiro, Motoo; Shibata, Norio; Osaka, Tetsuya; Asahi, Toru

    2010-03-01

    This article discusses differences in physicochemical properties such as solubility and melting point between (S)-thalidomide and (RS)-thalidomide based on crystal structures determined by X-ray diffraction experiments. Investigation of such differences is of great importance because thalidomide has attracted considerable attention again due to its wide-range bioactivity for intractable diseases. In this article, structures of hydrogen-bonded rings were compared between asymmetric homochiral dimers in (S)-thalidomide crystal and symmetric heterochiral dimers in (RS)-thalidomide crystal. The heterochiral dimer was evaluated to be more stable than the homochiral dimer by the energy calculations for hydrogen-bonded rings in those dimers. These results indicate that differences in physicochemical properties between enantiomeric and racemic thalidomides originate from the difference of structural stability between homochiral and heterochiral dimers.

  9. The place of thalidomide in the treatment of multiple myeloma

    Directory of Open Access Journals (Sweden)

    Alessandro Corso

    2011-12-01

    Full Text Available Thalidomide represents the first attempt in multiple myeloma (MM patients to overcome resistance to chemotherapy through a biological agent. The exciting results reported in the first study by Singhal et al. in 1999 [1] led to several other studies which aimed to evaluate its efficacy in different settings and disease phases, to define its toxicity, and to establish the optimal dose. Some of these questions have already been answered while others, such as the best dosage or the best schedule to obtain the highest efficacy with the lowest toxicity, still remain. Thalidomide has been studied as a single agent or in association with other drugs (dexamethasone, chemotherapy and new drugs showing a synergic activity. We review the results of the main studies on the efficacy and toxicity of thalidomide used as a single agent or in association with other drugs, reflect on its present role, and consider its future contribution to the treatment of MM.

  10. Thalidomide induces complete remission of advanced hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Cheng-Hung Chien

    2014-06-01

    Full Text Available Hepatocellular carcinoma (HCC is one of the most prevalent human cancers in the world, but its prognosis is extremely poor. HCC is considered a hypervascular tumor. Thalidomide, which has been known to inhibit growth factor-induced neovascularization, is a convenient alternative to target therapy such as sorafenib. We report a 65-year-old male patient with alcoholic liver cirrhosis that was diagnosed having multiple HCCs during surveillance. The patient was assessed as inoperable and unsuited for transhepatic arterial chemoembolization or systemic chemotherapy. After discussing the therapeutic alternatives, he decided to receive low-dose thalidomide (100 mg daily therapy. Fortunately, follow-up liver biochemical tests, serum α-fetoprotein level, and dynamic computed tomography showed complete remission of the HCCs 4.5 months after thalidomide treatment and this was documented for more than 22 months without evidence of tumor recurrence.

  11. Immune modulatory effect of thalidomide on T cells.

    Science.gov (United States)

    Kim, B S; Kim, J Y; Lee, J G; Cho, Y; Huh, K H; Kim, M S; Kim, Y S

    2015-04-01

    Thalidomide was originally used to alleviate morning sickness in pregnant women, but was banned due to severe adverse effects. Since the discovery of its anticancer and anti-inflammatory properties, it has regained research interest. However, its mechanism of action is still unknown. Therefore, we examined the effects of thalidomide on effector T (Teff) and regulatory T (Treg) cells in splenocytes of mice. Splenic CD4(+), CD44(low), and CD62L(high) T lymphocytes (Tnaives) isolated from C57BL/6 mice were cultured for T-cell proliferation and Treg conversion. For T-cell proliferation, naive T cells (Tnaives) were cultured for 72 hours with anti-CD3 and anti-CD28 antibodies, and carboxyfluorescein succinimidyl ester (CFSE) labeling method was used. For Treg conversion, Tnaives were cultured for 72 hours with transforming growth factor-β1 (TGF-β1) and interleukin-2 (IL-2). Naïve T cells were plated at 1.5 × 10(5) cells on 96-well plates with 0, 1, 10, 50, or 100 μmol/L thalidomide. All samples were analyzed by flow cytometry after staining with CFSE, APC-conjugated anti-mouse CD4, and FITC-conjugated anti-mouse FoxP3. Thalidomide significantly decreased the proliferation of CD4(+) Teffs in a dose-dependent manner (P thalidomide treatment, although the increase was not statistically significant. These findings suggest that thalidomide may have an immune modulatory effect by selectively suppressing CD4(+) Teff proliferation. Further studies will be needed to elucidate the underlying signaling pathway. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Thalidomide and its analogues in the treatment of Multiple Myeloma

    Directory of Open Access Journals (Sweden)

    Latif Tahir

    2012-09-01

    Full Text Available Abstract Multiple myeloma is an incurable malignant disorder of mature B-cells that predominantly affects the elderly. The immunomodulatory drug (IMiD thalidomide and its newer analogs demonstrate increased antitumor activity, and have had a positive impact on the natural history of multiple myeloma. Recent advances in the clinical application of these agents and in our understanding of their mechanism of action, and toxicity have made safer and smarter use of these drugs possible. This review discusses the available information regarding mechanisms of action, toxicity and clinical results on thalidomide, lenalidomide and pomalidomide in the therapy of multiple myeloma.

  13. Thalidomide in type-2 lepra reaction--a clinical experience.

    Science.gov (United States)

    Jadhav, V H; Patki, A H; Mehta, J M

    1990-01-01

    A clinical experience of using thalidomide in type-2 lepra reaction (ENL) in 90 male patients--57 with lepromatous leprosy (LL) and 33 with borderline lepromatous leprosy (BL)--is described. All the patients responded well although some took a longer time to improve. No major side effects were observed except for giddiness in 10 and gastrointestinal upsets in 7 patients. Thalidomide thus appears to be a very effective drug in the treatment of severe type-2 lepra reaction and apart from its historically well-documented embryopathic effects, does not seem to have any other serious side effects in the patients under study.

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

    Science.gov (United States)

    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 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.

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

    Directory of Open Access Journals (Sweden)

    Hong-xia Xue

    2015-01-01

    Full Text Available 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.

  16. Elotuzumab in combination with thalidomide and low-dose dexamethasone

    DEFF Research Database (Denmark)

    Mateos, Maria-Victoria; Granell, Miguel; Oriol, Albert

    2016-01-01

    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-...

  17. Use of thalidomide in the management of three HIV seroreactive ...

    African Journals Online (AJOL)

    These cases demonstrate the holistic approach of palliative care, addressing physical, psychological, social and spiritual aspects of patient care. They are also examples of very sick children who have responded well to antiretrovirals (ART) and thalidomide and show the effectiveness of good symptom control on quality of ...

  18. [Weight gain during treatment with thalidomide: a case report].

    Science.gov (United States)

    Comte, Hélène; Béné, Johana; Auffret, Marine; Gautier, Sophie; Salle-Staumont, Delphine

    2014-01-01

    We report a case of weight gain induced by thalidomide in a 39-year-old female patient with Behçet's disease treated for an indication of severe, bipolar, aphthous stomatitis. © 2014 Société Française de Pharmacologie et de Thérapeutique.

  19. Inhibition of thalidomide teratogenicity by acetylsalicylic acid: evidence for prostaglandin H synthase-catalyzed bioactivation of thalidomide to a teratogenic reactive intermediate.

    Science.gov (United States)

    Arlen, R R; Wells, P G

    1996-06-01

    Thalidomide is a teratogenic sedative-hypnotic drug that is structurally similar to phenytoin, which is thought to be bioactivated by prostaglandin H synthase (PHS) and other peroxidases to a teratogenic reactive intermediate. The relevance of this mechanism to thalidomide teratogenicity was evaluated in pregnant New Zealand White rabbits treated with thalidomide at 11:00 A.M. on gestational days 8 to 11, with day 0 indicating the time when sperm were observed in the vaginal fluid. Thalidomide (7.5 mg/kg i.v.) produced mainly fetal limb anomalies analogous to those observed in humans. Thalidomide (25-200 mg/kg i.p.), produced a dose-related increase in a spectrum of fetal anomalies, and in postpartum lethality, but did not produce a reliable incidence of limb anomalies. In subsequent studies, pregnant does received the irreversible PHS inhibitor acetylsalicylic acid (ASA), 75 mg/kg i.p., or its vehicle, followed 2 hr later by thalidomide, 7.5 mg/kg i.v., or its vehicle. ASA pretreatment was remarkably embryoprotective, resulting in respective 61.2 and 61.4% decreases in thalidomide-initiated fetal limb anomalies (P = .002) and postpartum fetal lethality (P teratogenicity, suggesting that thalidomide may be bioactivated by PHS to a teratogenic reactive intermediate.

  20. Anticancer Properties of a Novel Class of Tetrafluorinated Thalidomide Analogues.

    Science.gov (United States)

    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

    2015-10-01

    Thalidomide has demonstrated clinical activity in various malignancies affecting immunomodulatory and angiogenic 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 analogues (Gu973 and Gu998) and tetrafluorobenzamides (Gu1029 and Gu992). In this study, we demonstrate the antiangiogenic properties of these newly synthesized compounds. We examined the specific antiangiogenic characteristics in vitro using rat aortic rings with carboxyamidotriazole as a positive control. In addition, further in vitro efficacy was evaluated using human umbilical vein endothelial cells (HUVEC) and PC3 cells treated with 5 and 10 μmol/L doses of each compound. All compounds were seen to reduce microvessel outgrowth in rat aortic rings as well as to inhibit HUVECs to a greater extent, at lower concentrations than previously tested thalidomide analogs. The antiangiogenic properties of the compounds were 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, whereas Gu998 and Gu992 showed no difference. The compounds' antitumor 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 analogues as a promising immunomodulatory class with anticancer effects that warrant further development to characterize their mechanisms of action. ©2015 American Association for Cancer Research.

  1. Thalidomide inhibits alternative activation of macrophages in vivo and in vitro: a potential mechanism of anti-asthmatic effect of thalidomide.

    Science.gov (United States)

    Lee, Hyun Seung; Kwon, Hyouk-Soo; Park, Da-Eun; Woo, Yeon Duk; Kim, Hye Young; Kim, Hang-Rae; Cho, Sang-Heon; Min, Kyung-Up; Kang, Hye-Ryun; Chang, Yoon-Seok

    2015-01-01

    Thalidomide is known to have anti-inflammatory and immunomodulatory actions. However, the effect and the anti-asthmatic mechanism of thalidomide in the pathogenesis of asthmatic airways are not fully understood. This study is designed to determine the effect and the potential mechanism of thalidomide in the pathogenesis of asthmatic airways using animal model of allergic asthma. Six-week-old female BALB/C mice were sensitized with alum plus ovalbumin (OVA) and were exposed to OVA via intranasal route for 3 days for challenge. Thalidomide 200 mg/kg was given via gavage twice a day from a day before the challenge and airway hyperresponsivenss (AHR), airway inflammatory cells, and cytokines in bronchoalveolar lavage fluids (BALF) were evaluated. The expression levels of pro-inflammatory cytokines and other mediators were evaluated using ELISA, real time (RT)-qPCR, and flow cytometry. CRL-2456, alveolar macrophage cell line, was used to test the direct effect of thalidomide on the activation of macrophages in vitro. The mice with thalidomide treatment showed significantly reduced levels of allergen-induced BALF and lung inflammation, AHR, and the expression of a number of pro-inflammatory cytokines and mediators including Th2 related, IL-17 cytokines, and altered levels of allergen-specific IgG1/IgG2a. Of interesting note, thalidomide treatment significantly reduced expression levels of allergen- or Th2 cytokine-stimulated alternative activation of macrophages in vivo and in vitro. These studies highlight a potential use of thalidomide in the treatment of allergic diseases including asthma. This study further identified a novel inhibitory effect of thalidomide on alternative activation of macrophages as a potential mechanism of anti-asthmatic effect of thalidomide.

  2. Thalidomide inhibits alternative activation of macrophages in vivo and in vitro: a potential mechanism of anti-asthmatic effect of thalidomide.

    Directory of Open Access Journals (Sweden)

    Hyun Seung Lee

    Full Text Available Thalidomide is known to have anti-inflammatory and immunomodulatory actions. However, the effect and the anti-asthmatic mechanism of thalidomide in the pathogenesis of asthmatic airways are not fully understood.This study is designed to determine the effect and the potential mechanism of thalidomide in the pathogenesis of asthmatic airways using animal model of allergic asthma.Six-week-old female BALB/C mice were sensitized with alum plus ovalbumin (OVA and were exposed to OVA via intranasal route for 3 days for challenge. Thalidomide 200 mg/kg was given via gavage twice a day from a day before the challenge and airway hyperresponsivenss (AHR, airway inflammatory cells, and cytokines in bronchoalveolar lavage fluids (BALF were evaluated. The expression levels of pro-inflammatory cytokines and other mediators were evaluated using ELISA, real time (RT-qPCR, and flow cytometry. CRL-2456, alveolar macrophage cell line, was used to test the direct effect of thalidomide on the activation of macrophages in vitro.The mice with thalidomide treatment showed significantly reduced levels of allergen-induced BALF and lung inflammation, AHR, and the expression of a number of pro-inflammatory cytokines and mediators including Th2 related, IL-17 cytokines, and altered levels of allergen-specific IgG1/IgG2a. Of interesting note, thalidomide treatment significantly reduced expression levels of allergen- or Th2 cytokine-stimulated alternative activation of macrophages in vivo and in vitro.These studies highlight a potential use of thalidomide in the treatment of allergic diseases including asthma. This study further identified a novel inhibitory effect of thalidomide on alternative activation of macrophages as a potential mechanism of anti-asthmatic effect of thalidomide.

  3. Thalidomide Inhibits Alternative Activation of Macrophages In Vivo and In Vitro: A Potential Mechanism of Anti-Asthmatic Effect of Thalidomide

    Science.gov (United States)

    Park, Da-Eun; Woo, Yeon Duk; Kim, Hye Young; Kim, Hang-Rae; Cho, Sang-Heon; Min, Kyung-Up; Kang, Hye-Ryun; Chang, Yoon-Seok

    2015-01-01

    Background Thalidomide is known to have anti-inflammatory and immunomodulatory actions. However, the effect and the anti-asthmatic mechanism of thalidomide in the pathogenesis of asthmatic airways are not fully understood. Objective This study is designed to determine the effect and the potential mechanism of thalidomide in the pathogenesis of asthmatic airways using animal model of allergic asthma. Methods Six-week-old female BALB/C mice were sensitized with alum plus ovalbumin (OVA) and were exposed to OVA via intranasal route for 3 days for challenge. Thalidomide 200 mg/kg was given via gavage twice a day from a day before the challenge and airway hyperresponsivenss (AHR), airway inflammatory cells, and cytokines in bronchoalveolar lavage fluids (BALF) were evaluated. The expression levels of pro-inflammatory cytokines and other mediators were evaluated using ELISA, real time (RT)-qPCR, and flow cytometry. CRL-2456, alveolar macrophage cell line, was used to test the direct effect of thalidomide on the activation of macrophages in vitro. Results The mice with thalidomide treatment showed significantly reduced levels of allergen-induced BALF and lung inflammation, AHR, and the expression of a number of pro-inflammatory cytokines and mediators including Th2 related, IL-17 cytokines, and altered levels of allergen-specific IgG1/IgG2a. Of interesting note, thalidomide treatment significantly reduced expression levels of allergen- or Th2 cytokine-stimulated alternative activation of macrophages in vivo and in vitro. Conclusion These studies highlight a potential use of thalidomide in the treatment of allergic diseases including asthma. This study further identified a novel inhibitory effect of thalidomide on alternative activation of macrophages as a potential mechanism of anti-asthmatic effect of thalidomide. PMID:25905462

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

    OpenAIRE

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

    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 tha...

  5. Thalidomide for prevention of chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy

    Directory of Open Access Journals (Sweden)

    Geng Song

    2017-03-01

    Full Text Available Background Antiemetic guidelines recommend co-administration of agents to maximize the prevention of chemotherapyinduced nausea and vomiting (CINV, however, the control of delayed CINV is still not satisfactory. The purpose of this study was to evaluate the effectiveness and safety of thalidomide in the prevention of CINV. Methods Of 89 patients enrolled, 83 chemotherapy-naïve patients receiving highly emetogenic chemotherapy (cisplatin 70mg/m2 were randomized into two groups: standard therapy group (ondansetron on day 1, metoclopramide and dexamethasone on days one to five and thalidomide group (in addition to standard emesis prevention, patients received oral 100mg thalidomide on days one to five. Patients recorded nausea and vomiting episodes in a diary. The primary end point was the efficacy of thalidomide in controlling vomiting and nausea on days one to five post cisplatin, and the secondary end point was the safety of the thalidomide. Results No significant differences of complete response rates (no emesis, no use of rescue therapy and no nausea were observed between the two groups, while the percentages of patients with complete response of delayed vomiting on day four and day five were higher in the thalidomide group, furthermore, the complete response rate of delayed nausea for thalidomide group and standard therapy group showed significant differences. Thalidomide group showed a similar safety profile as standard emesis prevention group. Conclusion Addition of thalidomide was generally well tolerated and improved prevention of CINV in patients receiving cisplatinbased chemotherapy to some degree, especially for delayed nausea.

  6. Transcriptomic changes in mouse embryonic stem cells exposed to thalidomide during spontaneous differentiation

    Directory of Open Access Journals (Sweden)

    Xiugong Gao

    2015-09-01

    Full Text Available Thalidomide is a potent developmental toxicant that induces a range of birth defects, notably severe limb malformations. To unravel the molecular mechanisms underpinning the teratogenic effects of thalidomide, we used microarrays to study transcriptomic changes induced by thalidomide in an in vitro model based on the differentiation of mouse embryonic stem cells (mESCs, and published the major findings in a research article entitled “Thalidomide induced early gene expression perturbations indicative of human embryopathy in mouse embryonic stem cells” [1]. The data presented herein contains complementary information related to the aforementioned research article.

  7. Involvement of peripheral TRPV1 channels in the analgesic effects of thalidomide.

    Science.gov (United States)

    Song, Tieying; Wang, Liwen; Gu, Kunfeng; Yang, Yunliang; Yang, Lijun; Ma, Pengyu; Ma, Xiaojing; Zhao, Jianhui; Yan, Ruyv; Guan, Jiao; Wang, Chunping; Qi, Yan; Ya, Jian

    2015-01-01

    Thalidomide was introduced to the market in 1957 as a sedative and antiemetic agent, and returned to the market for the treatment of myelodysplastic syndrome and multiple myeloma. There are reports and studies of thalidomide as an analgesic or analgesic adjuvant in clinic. However, the underlying mechanism is quite elusive. Many studies suggest that the analgesic effect of thalidomide may be due to its immunomodulatory and anti-inflammatory properties as it suppresses the production of tumor necrosis factor α (TNF-α) selectively. However, it is not clear whether any other mechanisms are implicated in the pain relief. In this study, we demonstrated that the peripheral vanilloid receptor 1 (TRPV1) channel was also involved in the analgesic effect of thalidomide in different cell and animal models. During the activation by its agonist capsaicin, the cation inward influx through TRPV1 channels and the whole-cell current significantly decreased after TRPV1-overexpressed HEK293 cells or dorsal root ganglion (DRG) neurons were pre-treated with thalidomide for 20 minutes. And such attenuation in the TRPV1 activity was in a dose-dependent manner of thalidomide. In an acetic acid writhing test, pre-treatment of thalidomide decreased the writhing number in the wild type mice, while it did not happen in TRPV1 knockout mice, suggesting that the TRPV1 channel was involved in the pain relief by thalidomide. Taken together, the study showed that TRPV1 channels were involved in the analgesic effects of thalidomide. Such alteration in the action of TRPV1 channels by thalidomide may help understand how thalidomide takes analgesic effect in the body in addition to its selective inhibition of TNF-α production. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Chronic Recurrent Multifocal Osteomyelitis and Thalidomide in Chronic Granulomatous Disease.

    Science.gov (United States)

    Martín-Nalda, Andrea; Roca, Isabel; Fontecha, Cesar Galo; Fernández-Polo, Aurora; Barber, Ignasi; Martinez-Gallo, Mónica; Soler-Palacin, Pere

    2016-08-01

    Chronic granulomatous disease (CGD) is a primary immunodeficiency that leads to severe recurrent infection and inflammatory complications that are usually difficult to diagnose and treat. Several hyperinflammation mechanisms, such as decreased neutrophil apoptosis, toll-like receptor activation imbalance, Th17 cell induction, Nrf2 activity deficiency, and inflammasome activation, have been described in CGD patients However, there have been no reports of chronic recurrent multifocal osteomyelitis as an inflammatory complication in CGD, and the differential diagnosis of this condition with infectious osteomyelitis is challenging. Thalidomide has been used to treat several inflammatory manifestations in CGD patients with good clinical results. Here, we report the case of a previously asymptomatic 11-year-old boy who consulted for difficulty walking and pain at the back of the right thigh, with increased inflammatory markers. Multifocal bone involvement was seen on bone scintigraphy, and acute-phase reactants were elevated. On the basis of a suspected diagnosis of infectious osteomyelitis, broad-spectrum antibiotic therapy was started, with no clinical response. Bone biopsy and microbiological tests yielded negative results; at that point, chronic recurrent multifocal osteomyelitis was suspected. The patient was unresponsive to nonsteroidal antiinflammatory drugs and corticosteroids. Thalidomide was started, and within 6 months, clinical and radiologic resolution of the condition was achieved with no adverse effects. More than 1 year after stopping thalidomide, the patient remained free of symptoms and inflammatory parameters are within normal levels. Thalidomide has a favorable safety profile compared with other alternatives and could be considered a feasible therapeutic option for this type of condition in selected patients. Copyright © 2016 by the American Academy of Pediatrics.

  9. Oncogenic CUL4A determines the response to thalidomide treatment in prostate cancer

    Science.gov (United States)

    Ren, Shancheng; Xu, Chuanliang; Cui, Zilian; Yu, Yongwei; Xu, Weidong; Wang, Fubo; Lu, Ji; Wei, Min; Lu, Xin; Gao, Xu; Liang, You

    2013-01-01

    Thalidomide is experimentally used to treat various human cancers; however, clinical responses to thalidomide are sporadic. Here we demonstrate that CUL4A plays an oncogenic role in prostate cancer development and prostate cancer cells with higher level of CUL4A are particularly sensitive to thalidomide treatment. We show that CUL4A is frequently overexpressed in human primary prostate cancer and cell lines. Notably, subjects with tumors that highly expressed CUL4A had poor overall survival. CUL4A downregulation inhibited cell proliferation and induced apoptosis in vitro and in vivo, whereas CUL4A overexpression transformed human normal prostate epithelial cells and promoted invasion, which was attenuated by the extracellular signal-regulated kinase (ERK) inhibitor. We further show that the sensitivity to thalidomide is positively correlated with CUL4A expression in a panel of prostate cell lines. Ectopic CUL4A expression greatly enhanced sensitivity to thalidomide, while its downregulation conferred resistance to this drug. Mechanistically, thalidomide decreased CUL4A in a time- and dose-dependent manner, consequently leading to inaction of ERK pathway. Finally, we show that cereblon level is correlated with CUL4A expression and downregulated in thalidomide-resistant prostate cancer cell. Our results offer the first evidence that CUL4A is a potential therapeutic target for prostate cancer and may serve as a biomarker for assessing prognosis of human prostate cancer and response to thalidomide treatment. PMID:22422151

  10. Thalidomide inhibits granulocyte responses in healthy humans after ex vivo stimulation with bacterial antigens

    NARCIS (Netherlands)

    Juffermans, N. P.; Verbon, A.; Schultz, M. J.; Hack, C. E.; van Deventer, S. J.; Speelman, P.; van der Poll, T.

    2001-01-01

    Ingestion of thalidomide was associated with a reduction in the upregulation of the granulocyte activation marker CD11b and a reduced capacity to release elastase and lactoferrin after stimulation with lipopolysaccharide or lipoteichoic acid. A single oral dose of thalidomide attenuates neutrophil

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

    Science.gov (United States)

    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...

  12. Anticancer effect of thalidomide in vitro on human osteosarcoma cells.

    Science.gov (United States)

    Zhu, Jianwei; Yang, Ya; Liu, Sihong; Xu, Huihua; Wu, Yong; Zhang, Guiqiang; Wang, Yuxuan; Wang, Yan; Liu, Yamin; Guo, Qifeng

    2016-12-01

    Osteosarcoma is a high‑grade malignant tumor frequently found in children and adolescents. Thalidomide has been reported for treatment of various malignancies. Thalidomide was added to osteosarcoma cells and studied by cytotoxicity assay, evaluating apoptosis, cell cycle arrest, mitochondrial membrane potential (ΔΨm), and reactive oxygen species (ROS) levels and the expression of Bcl‑2, Bax, caspase‑3 and NF‑κB. The results showed that thalidomide could inhibit the proliferation of MG‑63 and U2OS cells in a concentration‑ and time‑dependent manner. Morphological changes of apoptosis were also observed. Thalidomide increased the apoptosis rate of MG‑63 cells and induced cell cycle arrest by increasing the number of cells in the G0/G1 phase and decreasing the percentage of S phase in MG‑63 cells. Further investigation showed that a disruption of ΔΨm and upregulation of ROS were induced by thalidomide in high concentration. By western blot analysis, thalidomide resulted in the decreasing expression of Bcl‑2 and NF‑κB, and the increasing expression of Bcl‑2/Bax and caspase‑3. Here, we provide evidence that thalidomide could cause apoptosis in osteosarcoma cells. Taken together, these results indicate that thalidomide could be an antitumor drug in the therapy of osteosarcoma.

  13. [Novel potential uses of thalidomide in the management of pain? A review of the literature].

    Science.gov (United States)

    Peuckmann, V; Strumpf, M; Zenz, M; Bruera, E

    2003-06-01

    Thalidomide was introduced as a sedative and antiemetic agent to the European market in the late 1950s. However, it soon became clear that a hitherto unheard-of incidence of severe birth defects was due to the maternal use of thalidomide and the drug was withdrawn from the market. Despite its teratogenesis, thalidomide is currently being rediscovered because of its known spectrum of anticachectic, antiemetic, mildly hypnotic, anxiolytic, anti-inflammatory, antiangiogenic, and analgesic properties. The mechanism of action of thalidomide is probably based on its immunomodulatory effect, namely the suppression of production of tumor necrosis factor alpha and the modulation of interleukins. A striking but not well-known finding is the effectiveness of thalidomide as an analgesic or analgesic adjuvant. During the early era of thalidomide use, the drug was shown to enhance the analgesic efficacy of a combined treatment with acetylsalicylic acid, phenacetin, and caffeine (APC) by testing "normal volunteers, using electrical stimulation of teeth." The combination of thalidomide and APC was superior to other combinations (APC alone, APC and codeine) with respect to both the total analgesic effect and the duration of this analgesic effect. In 1965 thalidomide was found to be effective in treating the painful subcutaneous manifestations of the leprosy-associated erythema nodosum leprosum, a condition for which it eventually was approved by the United States Food and Drug Administration in 1998. In an animal model of neuropathic pain (chronic constriction injury), thalidomide was shown to reduce both mechanical allodynia and thermal hyperalgesia. Recent studies documented the analgesic efficacy of thalidomide in treating painful mucocutaneous aphthous ulcers associated with HIV syndrome and Behcet's disease.However, to date there are no recent clinical trials that are specifically designed to explore the analgesic potential of thalidomide. In view of the current basic research

  14. Clinical trial of thalidomide combined with radiotherapy in patients with esophageal cancer.

    Science.gov (United States)

    Yu, Jing-Ping; Sun, Su-Ping; Sun, Zhi-Qiang; Ni, Xin-Chu; Wang, Jian; Li, Yi; Hu, Li-Jun; Li, Dong-Qing

    2014-05-07

    To investigate the short-term efficacy and tolerability of radiotherapy plus thalidomide in patients with esophageal cancer (EC). Serum samples from 86 EC patients were collected before, during, and after radiotherapy, and the vascular endothelial growth factor (VEGF) level was examined by ELISA. According to the change in serum VEGF level during radiotherapy, the patients were divided into two groups: in the drug group, VEGF level was increased or remained unchanged, and thalidomide was administered up to the end of radiotherapy; in the non-drug group, VEGF level was decreased and radiotherapy was given alone. Thirty healthy volunteers served as controls. The efficacy and safety of radiotherapy plus thalidomide therapy were investigated. The 86 EC patients had a significantly higher level of VEGF compared with the 30 healthy controls before radiotherapy (P Thalidomide can down-regulate serum VEGF level in EC patients, and combined with radiotherapy may improve treatment outcome. Thalidomide was well tolerated by EC patients.

  15. Thalidomide inhibits inflammatory and angiogenic activation of human intestinal microvascular endothelial cells (HIMEC)

    Science.gov (United States)

    Stein, Daniel J.; Nelson, Victoria M.; Otterson, Mary F.; Shaker, Reza; Binion, David G.

    2010-01-01

    The glutamic acid derivative thalidomide is a transcriptional inhibitor of TNF-α but is also known to affect human blood vessels, which may underlie its teratogenicity. Thalidomide has been used in the treatment of refractory Crohn's disease (CD), but the therapeutic mechanism is not defined. We examined the effect of thalidomide on primary cultures of human intestinal microvascular endothelial cells (HIMEC), the relevant endothelial cell population in inflammatory bowel disease (IBD), to determine its effect on endothelial activation, leukocyte interaction, and VEGF-induced angiogenesis. HIMEC cultures were pretreated with thalidomide before activation with either TNF-α/LPS or VEGF. A low-shear-stress flow adhesion assay with either U-937 or whole blood was used to assess HIMEC activation following TNF-α/LPS, and a Wright's stain identified adherent leukocytes. Expression of cell adhesion molecules (E-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1) was assessed using radioimmunoassay. Effects of thalidomide on NF-κB activation, cyclooxygenase (COX)-2, and inducible nitric oxide synthase (iNOS) expression in TNF-α/LPS-activated HIMEC were determined by RT-PCR and Western blotting. Thalidomide blocked adhesion of both U-937 and whole blood leukocytes by 50% in HIMEC, inhibiting binding of all classes of leukocytes. Thalidomide also blocked NF-κB and cell adhesion molecule expression in HIMEC. In marked contrast, thalidomide did not affect either iNOS or COX-2 expression, two key molecules that play a role in the downregulation of HIMEC activation. VEGF-induced HIMEC transmigration, growth, proliferation, tube formation, and Akt phosphorylation were significantly inhibited by thalidomide. In summary, thalidomide exerted a potent effect on HIMEC growth and activation, suggesting that it may also function via an endothelial mechanism in the treatment of CD. PMID:19926820

  16. Biological evaluation of both enantiomers of fluoro-thalidomide using human myeloma cell line H929 and others.

    Science.gov (United States)

    Tokunaga, Etsuko; Akiyama, Hidehiko; Soloshonok, Vadim A; Inoue, Yuki; Hara, Hideaki; Shibata, Norio

    2017-01-01

    Over the last few years, thalidomide has become one of the most important anti-tumour drugs for the treatment of relapsed-refractory multiple myeloma. However, besides its undesirable teratogenic side effect, its configurational instability critically limits any further therapeutic improvements of this drug. In 1999, we developed fluoro-thalidomide which is a bioisostere of thalidomide, but, in sharp contrast to the latter, it is configurationally stable and readily available in both enantiomeric forms. The biological activity of fluoro-thalidomide however, still remains virtually unstudied, with the exception that fluoro-thalidomide is not teratogenic. Herein, we report the first biological evaluation of fluoro-thalidomide in racemic and in both (R)- and (S)-enantiomerically pure forms against (in vitro) H929 cells of multiple myeloma (MM) using an annexin V assay. We demonstrate that all fluoro-thalidomides inhibited the growth of H929 MM cells without any in-vivo activation. Furthermore, we report that the enantiomeric forms of fluoro-thalidomide display different anti-tumour activities, with the (S)-enantiomer being noticeably more potent. The angiogenesis of fluoro-thalidomides is also investigated and compared to thalidomide. The data obtained in this study paves the way towards novel pharmaceutical research on fluoro-thalidomides.

  17. Embryo-fetal exposure and developmental outcome of thalidomide following oral and intravaginal administration to pregnant rabbits.

    Science.gov (United States)

    Hui, Julia Y; Hoffmann, Matthew; Kumar, Gondi

    2014-09-01

    Studies in pregnant rabbits were conducted to evaluate if there are any differences in the uptake of thalidomide into the intrauterine compartment and developmental toxicity risk following oral and intravaginal administration. Thalidomide concentrations in maternal plasma, yolk sac cavity (YSC) fluid and embryo following intravaginal administration were 2- to 7-fold lower than their respective levels after oral administration. Ratios of thalidomide concentration in YSC fluid to maternal plasma were similar between these two routes, indicating no difference in uptake into the intrauterine compartment. A rabbit embryo-fetal development study using oral and intravaginal thalidomide administration at 2mg/kg/day (a dose >10,000-fold higher than the expected amount of thalidomide in human semen) did not result in any developmental abnormalities. These data demonstrated no preferential transfer mechanism of thalidomide from vagina to conceptus, and no additional embryo-fetal developmental toxicity risks with thalidomide exposure via the vaginal route. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Therapeutic Potential of Thalidomide and Its Analogues in the Treatment of Cancer.

    Science.gov (United States)

    Sherbet, Gajanan V

    2015-11-01

    Thalidomide was synthesised and launched several decades ago as a drug against respiratory infections and was administered to pregnant women for relief of morning sickness. The drug was withdrawn when its teratogenic effects came to light. Thalidomide and its analogues suppressed cell proliferation and angiogenesis and controlled invasion and metastasis of tumours in pre-clinical studies. With the recognition of its immunomodulatory and anti-inflammatory, properties, thalidomide may have found a place in the treatment of many forms of cancer and autoimmune conditions. Herein the signalling pathways modulated by thalidomides via the mediation of vascular endothelial growth factor, phosphoinositide-kinase/protein kinase B and nuclear factor kappa B, and mammalian target of rapamycin, which integrates these signalling systems, are discussed. The mode of action of thalidomides and their strategic utility in therapy are evaluated in the context of potential clinical benefits. Notwithstanding the perceived benefits, the side-effects of thalidomides need to be taken into account; they do exert teratogenic effects in animal models, although being effective at lower doses, the drugs seem to show comparatively manageable and reduced toxicity. Combination therapy of thalidomides and modulators of signaling that they influence may further reduce the severity of the side-effects by delivering inhibitory effects at reduced drug dosages. Pre-clinical evaluations of this kind seem warranted. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  19. Effect of sorafenib combined with thalidomide on angiogenesis in chick chorioallantoic membrane

    Directory of Open Access Journals (Sweden)

    GUO Zhenya

    2016-05-01

    Full Text Available ObjectiveTo investigate the effect of sorafenib and/or thalidomide on angiogenesis in chick chorioallantoic membrane (CAM. MethodsWhite eggs incubated for 7 days were used to establish a CAM model. The model eggs were randomly divided blank control group, sorafenib group, thalidomide group, and sorafenib/thalidomide group. After treatment, each egg was incubated for another 2 days. The CAM samples were collected and fixed to take their pictures under a microscope, and the vascular coverage of each sample was calculated. Comparison between these groups was made by analysis of variance, and comparison between each two groups was made by SNK-q test. ResultsThe thalidomide group or sorafenib group had significantly lower vascular coverage than the blank control group (30.2%±2.9% or 26.5%±2.1% vs 38.3%±2.7%, P<0.05. The sorafenib/thalidomide group had significantly lower vascular coverage than the thalidomide group or sorafenib group (12.6%±1.5% vs 30.2%±2.9% or 26.5%±2.1%, P<0.05. ConclusionBoth sorafenib and thalidomide have a good anti-angiogenic effect on CAM, but a combination of the two drugs shows better efficacy.

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

    Science.gov (United States)

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

    2015-12-01

    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. © FASEB.

  1. Human Cytochrome P450 Oxidation of 5-Hydroxythalidomide and Pomalidomide, an Amino Analog of Thalidomide

    Science.gov (United States)

    Chowdhury, Goutam; Shibata, Norio; Yamazaki, Hiroshi; Guengerich, F. Peter

    2014-01-01

    The sedative and antiemetic drug thalidomide [α-(N-phthalimido)glutarimide] was withdrawn in the early 1960s due to its potent teratogenic effects but was approved for the treatment of lesions associated with leprosy in 1998 and multiple myeloma in 2006. The mechanism of teratogenicity of thalidomide still remains unclear, but it is well established that metabolism of thalidomide is important for both teratogenicity and cancer treatment outcome. Thalidomide is oxidized by various cytochrome P450 (P450) enzymes, the major being P450 2C19, to 5-hydroxy-, 5’-hydroxy-, and dihydroxythalidomide. We previously reported that P450 3A4 oxidizes thalidomide to the 5-hydroxy and dihydroxy metabolites, with the second oxidation step involving a reactive intermediate, possible an arene oxide, that can be trapped by glutathione (GSH) to GSH adducts. We now show that the dihydroxythalidomide metabolite can be further oxidized to a quinone intermediate. Human P450s 2J2, 2C18, and 4A11 were also found to oxidize 5-hydroxythalidomide to dihydroxy products. Unlike P450s 2C19 and 3A4, neither P450 2J2, 2C18, nor 4A11 oxidized thalidomide itself. A recently approved amino analog of thalidomide, pomalidomide (CC-4047, Actimid™), was also oxidized by human liver microsomes and P450s 2C19, 3A4, and 2J2 to the corresponding phthalimide ring-hydroxylated product. PMID:24350712

  2. Free radical-mediated oxidative DNA damage in the mechanism of thalidomide teratogenicity.

    Science.gov (United States)

    Parman, T; Wiley, M J; Wells, P G

    1999-05-01

    The sedative drug thalidomide ([+]-alpha-phthalimidoglutarimide), once abandoned for causing birth defects in humans, has found new therapeutic license in leprosy and other diseases, with renewed teratological consequences. Although the mechanism of teratogenesis and determinants of risk remain unclear, related teratogenic xenobiotics are bioactivated by embryonic prostaglandin H synthase (PHS) to a free-radical intermediates that produce reactive oxygen species (ROS), which cause oxidative damage to DNA and other cellular macromolecules. Similarly, thalidomide is bioactivated by horseradish peroxidase, and oxidizes DNA and glutathione, indicating free radical-mediated oxidative stress. Furthermore, thalidomide teratogenicity in rabbits is reduced by the PHS inhibitor acetylsalicylic acid, indicating PHS-catalyzed bioactivation. Here, we show in rabbits that thalidomide initiates embryonic DNA oxidation and teratogenicity, both of which are abolished by pre-treatment with the free radical spin trapping agent alpha-phenyl-N-t-butylnitrone (PBN). In contrast, in mice, a species resistant to thalidomide teratogenicity, thalidomide does not enhance DNA oxidation, even at a dose 300% higher than that used in rabbits, providing insight into an embryonic determinant of species-dependent susceptibility. In addition to their therapeutic implications, these results constitute direct evidence that the teratogenicity of thalidomide may involve free radical-mediated oxidative damage to embryonic cellular macromolecules.

  3. Psychological and mental health problems in patients with thalidomide embryopathy in Japan.

    Science.gov (United States)

    Imai, Koubun; Iida, Toshiharu; Yamamoto, Maki; Komatsu, Kensuke; Nukui, Yuko; Yoshizawa, Atsuto

    2014-06-01

    The aim of the study was to examine the presence of psychological and mental health problems in patients with thalidomide embryopathy in Japan in order to develop and build future support systems. The present study examined the presence/absence of electroencephalographic abnormalities, intellectual/cognitive functions, and mental health problems in 22 participants (nine men, 13 women) with thalidomide embryopathy. Participants completed the electroencephalograph instrument. Participants were also assessed using the Wechsler Adult Intelligence Scale-III; the Autism-Spectrum Quotient; the General Health Questionnaire-28, and the Mini-International Neuropsychiatric Interview. The results suggest the following: (i) electroencephalographic abnormality observed in several thalidomide embryopathy participants is unlikely to be the direct result of thalidomide; (ii) the cognitive functions of working memory and processing speed are lower in thalidomide embryopathy patients than in healthy individuals; and (iii) 40.9% of the thalidomide embryopathy participants have possible mental disorders, with more mental problems observed than in healthy individuals. Deterioration of mental health in patients with thalidomide embryopathy is indicated. Anxiety, insomnia, and physical symptoms were especially remarkable and may have resulted in restriction of social activities. Therefore, careful examination and active support of patients' psychological and mental problems is essential. © 2014 The Authors. Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology.

  4. Langerhans cell histiocytosis: An uncommon presentation, successfully treated by thalidomide

    Directory of Open Access Journals (Sweden)

    Mohammad Shahidi-Dadras

    2011-01-01

    Full Text Available Langerhans cell histiocytosis (LCH is a rare disease and generally affects children under 15 years of age. Adult onset form and cutaneous features at presentation are uncommon. There are some options for treatment of the skin lesions of LCH such as topical and intralesional corticosteroid, nitrogen mustard, etc., which are not completely curative. Herein, we report a case of perianal LCH in a 20-year-old man with one-year history of recalcitrant well-demarcated, erythematous, and ulcerated plaque surrounding the anal orifice, with pain and difficulty in defecation that was successfully treated with thalidomide.

  5. Safety of thalidomide in newly diagnosed elderly myeloma patients

    DEFF Research Database (Denmark)

    Palumbo, Antonio; Waage, Anders; Hulin, Cyrille

    2013-01-01

    Background. Melphalan-prednisone-thalidomide (MPT) improves outcome in multiple myeloma (MM) patients, and it is now considered a standard of care for patients not eligible for transplantation. However, this treatment is a major source of morbidity. Design and Methods. An individual patient data...... was documented in patients treated with MPT vs MP. Grade 3-4 non-hematologic AEs were significantly increased in patients with poor performance status. Occurrence of grade 3-4 non-hematologic AEs negatively impacted on progression-free survival (PFS) (HR 1.24, 95%CI 1.07-1.45) and overall survival (OS), (HR 1...

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

    Science.gov (United States)

    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 (Pthalidomide. 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.

  7. Thalidomide promotes leukocytosis in mice inoculated with 4T1 mammary carcinoma

    Directory of Open Access Journals (Sweden)

    Diego Carlos dos Reis

    2014-02-01

    Full Text Available The aim of this study was to evaluate the therapy effect of thalidomide in the 4T1 murine mammary carcinoma. 4T1 cell suspension was injected into the posterior left flank of all animals to obtain solid tumors. Five days after inoculation, the treatment group was orally administered 150 mg/kg of thalidomide for seven days. Tumors were measured every 48 hours until the end of treatment. Whole blood was collected for hematology analysis. Our results suggest that thalidomide therapy increase the number of circulating leukocytes in the 4T1 murine mammary carcinoma, and this response is accompanied by a decrease in tumor growth.

  8. A phase II study of thalidomide in patients with brain metastases from malignant melanoma

    DEFF Research Database (Denmark)

    Vestermark, Lene; Larsen, Susanne; Lindeløv, Birgit

    2008-01-01

    Introduction. Brain metastases develop in nearly half of the patients with advanced melanoma and in 15 to 20% of these patients CNS is the first site of relapse. Overall median survival is short, ranging from 2 to 4 months. Thalidomide has antiangiogenic and immunomodulatory effects. Results...... obtained in prior trials indicate that Thalidomide acts as a cytostatic agent in metastatic melanoma. We evaluated single agent antitumour activity and toxicity of Thalidomide in a phase II setting in patients with brain metastases associated with metastatic melanoma. Material and methods. Patients...

  9. Synthesis and evaluation of thalidomide and phthalimide esters as antitumor agents

    DEFF Research Database (Denmark)

    Zahran, Magdy A H; Abdin, Yasmin G.; Osman, Amany M A

    2014-01-01

    A series of thalidomide and phthalimide ester analogs were efficiently synthesized from N-chloromethylthalidomide, N-chloromethylphthalimide, and N-(2-bromoethyl)phthalimide derivatives with various biologically important carboxylic acids. The synthesized compounds were purified and characterized...

  10. Time to spare newly diagnosed non transplant eligible myeloma (ENDMM) from thalidomide

    DEFF Research Database (Denmark)

    Demarquette, H.; Guidez, S.; Jurczyszyn, A. J.

    2015-01-01

    Background. Thalidomide is one of the most prescribed regimens upfront in eNDMM, e.g. elderly myeloma, essentially as melphalan-prednisone-Thalidomide (MPT). Several options are offered at 1st and 2nd relapse to patients initially exposed to Thalidomide with either bortezomib or lenalidomide......-based therapy. On the other hand, the second most prescribed drug in elderly myeloma upfront is Bortezomib, primarily as Bortezomib-melphalan-prednisone (VMP), the 2nd standard of care upfront in Multiple Myeloma (MM) ineligible for transplantation. Interestingly, lenalidomide is the drug of choice at first...... upfront, and that were solely exposed to the 2 drugs, bortezomib-based regimen and lenalidomide-based therapy would have a lower survival than patients exposed to all 3 drugs, e.g. thalidomide, lenaldiomide and bortezomib. Method. A total of 145 patients were recruited in this multicentric study, 46...

  11. Shedding light on an old mystery: thalidomide suppresses survival pathways to induce limb defects.

    Science.gov (United States)

    Knobloch, Jürgen; Rüther, Ulrich

    2008-05-01

    Many hypotheses have been proposed to explain the molecular mechanism of thalidomide teratogenicity, in particular regarding to limb defects. Most experimental evidence in vivo has been provided for a model that suggests the generation of oxidative stress by thalidomide with subsequent downregulation of Wnt and Akt survival pathways. As a consequence apoptosis is induced during early embryonic limb development resulting in limb truncations. Here we summarize and discuss the relevant data supporting this hypothesis. We extend this model by presenting new data demonstrating an involvement of the transcription factors Tbx5 and Sall4 in thalidomide-induced molecular pathology. Finally, we discuss a possible participation of other stress-responsive and/or pro-apoptotic transcription factors in the mechanism of thalidomide teratogenicity.

  12. [Thalidomide: Drug of horror and last resort. A review. Part 1: Origin, molecular structure and first pattern of use.].

    Science.gov (United States)

    Jóhannesson, Thornorkell

    2003-10-01

    Thalidomide was originally a hypnotic, sedative and anxiolytic drug that was first used in 1955. It was considered to have little toxicity and have smooth activity. Thalidomide was in fact poorly studied both in animals and for therapeutic purposes. It was nevertheless agressively advertised, and inter alia for use in pregnancy, and accordingly it was a much used drug. During the year 1961 it became evident that intake of thalidomide in therapeutic doses could result in severe peripheral neuritis and, when taken early in pregnancy, in horrendous damage to the fetus. Thalidomide was thus shortly afterwards generally removed from the market and its use prohibited. Nevertheless, interest rose a few years later to use thalidomide on other indications than before. This is the topic of Part 2 of this review as well as discussion of studies pertinent to the mechanisms of action of thalidomide.

  13. Thalidomide and dexamethasone vs. bortezomib and dexamethasone for melphalan refractory myeloma

    DEFF Research Database (Denmark)

    Hjorth, Martin; Hjertner, Øyvind; Knudsen, Lene Meldgaard

    2012-01-01

    Thalidomide and bortezomib have been frequently used for second-line therapy in patients with myeloma relapsing after or refractory to initial melphalan-based treatment, but no randomized trials have been published comparing these two treatment alternatives.......Thalidomide and bortezomib have been frequently used for second-line therapy in patients with myeloma relapsing after or refractory to initial melphalan-based treatment, but no randomized trials have been published comparing these two treatment alternatives....

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

    Science.gov (United States)

    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.

  15. In vitro anti-proliferative and anti-angiogenic activities of thalidomide dithiocarbamate analogs.

    Science.gov (United States)

    El-Aarag, Bishoy Y A; Kasai, Tomonari; Zahran, Magdy A H; Zakhary, Nadia I; Shigehiro, Tsukasa; Sekhar, Sreeja C; Agwa, Hussein S; Mizutani, Akifumi; Murakami, Hiroshi; Kakuta, Hiroki; Seno, Masaharu

    2014-08-01

    Inhibition of angiogenesis is currently perceived as a promising strategy in the treatment of cancer. The anti-angiogenicity of thalidomide has inspired a second wave of research on this teratogenic drug. The present study aimed to investigate the anti-proliferative and anti-angiogenic activities of two thalidomide dithiocarbamate analogs by studying their anti-proliferative effects on human umbilical vein endothelial cells (HUVECs) and MDA-MB-231 human breast cancer cell lines. Their action on the expression levels of IL-6, IL-8, TNF-α, VEGF165, and MMP-2 was also assessed. Furthermore, their effect on angiogenesis was evaluated through wound healing, migration, tube formation, and nitric oxide (NO) assays. Results illustrated that the proliferation of HUVECs and MDA-MB-231 cells was not significantly affected by thalidomide at 6.25-100μM. Thalidomide failed to block angiogenesis at similar concentrations. By contrast, thalidomide dithiocarbamate analogs exhibited significant anti-proliferative action on HUVECs and MDA-MB-231 cells without causing cytotoxicity and also showed powerful anti-angiogenicity in wound healing, migration, tube formation, and NO assays. Thalidomide analogs 1 and 2 demonstrated more potent activity to suppress expression levels of IL-6, IL-8, TNF-α, VEGF165, and MMP-2 than thalidomide. Analog 1 consistently, showed the highest potency and efficacy in all the assays. Taken together, our results support further development and evaluation of novel thalidomide analogs as anti-tumor and anti-angiogenic agents. Copyright © 2014. Published by Elsevier B.V.

  16. Thalidomide induced early gene expression perturbations indicative of human embryopathy in mouse embryonic stem cells

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

    2015-08-15

    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 exposure 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.

  17. Thalidomide-induced limb abnormalities in a humanized CYP3A mouse model.

    Science.gov (United States)

    Kazuki, Yasuhiro; Akita, Masaharu; Kobayashi, Kaoru; Osaki, Mitsuhiko; Satoh, Daisuke; Ohta, Ryo; Abe, Satoshi; Takehara, Shoko; Kazuki, Kanako; Yamazaki, Hiroshi; Kamataki, Tetsuya; Oshimura, Mitsuo

    2016-02-23

    Thalidomide is a teratogen in humans but not in rodents. It causes multiple birth defects including malformations of limbs, ears, and other organs. However, the species-specific mechanism of thalidomide teratogenicity is not completely understood. Reproduction of the human teratogenicity of thalidomide in rodents has previously failed because of the lack of a model reflecting human drug metabolism. In addition, because the maternal metabolic effect cannot be eliminated, the migration of unchanged thalidomide to embryos is suppressed, and the metabolic activation is insufficient to develop teratogenicity. Previously, we generated transchromosomic mice containing a human cytochrome P450 (CYP) 3A cluster in which the endogenous mouse Cyp3a genes were deleted. Here, we determined whether human CYP3A or mouse Cyp3a enzyme expression was related to the species difference in a whole embryo culture system using humanized CYP3A mouse embryos. Thalidomide-treated embryos with the human CYP3A gene cluster showed limb abnormalities, and human CYP3A was expressed in the placenta, suggesting that human CYP3A in the placenta may contribute to the teratogenicity of thalidomide. These data suggest that the humanized CYP3A mouse is a useful model to predict embryonic toxicity in humans.

  18. Transcriptomic Analysis of Thalidomide Challenged Chick Embryo Suggests Possible Link between Impaired Vasculogenesis and Defective Organogenesis.

    Science.gov (United States)

    Veeriah, Vimal; Kumar, Pavitra; Sundaresan, Lakshmikirupa; Mafitha, Zeenath; Gupta, Ravi; Saran, Uttara; Manivannan, Jeganathan; Chatterjee, Suvro

    2017-10-16

    Since the conception of thalidomide as a teratogen, approximately 30 hypotheses have been put forward to explain the developmental toxicity of the molecule. However, no systems biology approach has been taken to understand the phenomena yet. The proposed work was aimed to explore the mechanism of thalidomide toxicity in developing chick embryo in the context of transcriptomics by using genome wide RNA sequencing data. In this study, we challenged the developing embryo at the stage of blood island formations (HH8), which is the most vulnerable stage for thalidomide-induced deformities. We observed that thalidomide affected the early vasculogenesis through interfering with the blood island formation extending the effect to organogenesis. The transcriptome analyses of the embryos collected on sixth day of incubation showed that liver, eye, and blood tissue associated genes were down regulated due to thalidomide treatment. The conserved gene coexpression module also indicated that the genes involved in lens development were heavily affected. Further, the Gene Ontology analysis explored that the pathways of eye development, retinol metabolism, and cartilage development were dampened, consistent with the observed deformities of various organs. The study concludes that thalidomide exerts its toxic teratogenic effects through interfering with early extra-embryonic vasculogenesis and ultimately gives an erroneous transcriptomic pattern to organogenesis.

  19. Thalidomide Promotes Morphine Efficacy and Prevents Morphine-Induced Tolerance in Rats with Diabetic Neuropathy.

    Science.gov (United States)

    Zhao, Jianhui; Wang, Hong; Song, Tieying; Yang, Yunliang; Gu, Kunfeng; Ma, Pengyu; Zhang, Zaiwang; Shen, Limin; Liu, Jiabao; Wang, Wenli

    2016-12-01

    Opioid analgesics have less efficacy in diabetic neuropathy treatment, and tolerance often occurs after chronic usage. Given that thalidomide can potentiate the morphine efficacy in diabetic neuropathy treatment, we investigated the effects of intrathecal administrations of thalidomide on morphine tolerance during the treatment of diabetic neuropathy. We found that intrathecal administrations of thalidomide (25 mg/kg/ml) potentiated the analgesic effects of morphine on mechanical hyperalgesia and prevented the development of morphine tolerance. While this treatment regimen did not alter the protein levels of μ-opioid receptor (MOR) in the spinal cord of diabetic rats, chronic morphine treatment robustly increased MOR binding density in the synaptic plasma membranes fraction, but decreased it in the microsomal fraction. Furthermore, thalidomide was able to reverse the distribution of MOR altered by chronic morphine treatment. Finally, STZ-induced diabetes promoted PKC activation and enhanced TNFα level in the spinal cord, which were attenuated by intrathecal administrations of thalidomide. Taken together, these results suggested that thalidomide may potentiate morphine efficacy on diabetic neuropathy and prevent the development of morphine tolerance by suppressing PKC activation and TNFα level in the spinal cord.

  20. Thalidomide: Still an important second-line treatment in refractory cutaneous lupus erythematosus?

    Science.gov (United States)

    Baret, Isabelle; De Haes, Petra

    2015-04-01

    Cutaneous lupus erythematosus (CLE) can be a severe disease, characterized by extensive, disfiguring lesions and a relapsing course. Thalidomide is known as an effective treatment for CLE, however, its use is restricted by its potential side-effects. Nevertheless, it remains a valuable option to consider. Therefore, it is important to report new clinical experiences. The data of 30 patients with refractory CLE, who were treated with thalidomide, were retrospectively analyzed. The response rate was categorized as complete, partial or no response. The relapse rate and the occurrence of side-effects were registered. Six patients prematurely discontinued treatment because of side-effects. The response rate was 100% in the remaining 24 patients, including 20 patients (83%) with complete response and 4 (27%) with partial response. Clinical relapse was frequent (73%) and occurred between 3 and 24 weeks after withdrawal of thalidomide. Nine patients (30%) developed peripheral neuropathy. In the majority, there was no complete resolution of the neuropathy-associated symptoms after stopping thalidomide. One patient developed a thrombosis in an artery stent. Because of high risk of polyneuropathy, low-dose thalidomide should be used and long-term therapy should be avoided. Therefore, it should be recommended to combine thalidomide with other treatments for CLE.

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

    Energy Technology Data Exchange (ETDEWEB)

    Scharpfenecker, Marion, E-mail: m.scharpfenecker@nki.nl [Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam (Netherlands); Floot, Ben [Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam (Netherlands); Russell, Nicola S. [Division of Radiotherapy, The Netherlands Cancer Institute, Amsterdam (Netherlands); Coppes, Rob P. [Departments of Radiation Oncology and Cell Biology, University Medical Centre Groningen, University of Groningen, Groningen (Netherlands); Stewart, Fiona A. [Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam (Netherlands)

    2014-07-01

    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, and 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.

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

    Directory of Open Access Journals (Sweden)

    Chunguang Chen

    Full Text Available 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.

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

    Science.gov (United States)

    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.

  4. Effects of immunosuppression induced by thalidomide and cyclosporine in heterotopic heart transplantation in rabbits.

    Science.gov (United States)

    Carvalho, J B V; Petroianu, A; Travolo, E; de Oliveira, B H; Duarte, A B B; Alberti, L R

    2007-06-01

    Because of its anti-inflammatory and immunodepressive effects, thalidomide has been used for the treatment of dermatologic diseases and of host-versus-graft reactions in patients undergoing bone marrow transplantation. We evaluated the immunosuppressive action of thalidomide alone or in combination with cyclosporine on the prevention of rejection of heterotopic cardiac allografts in rabbits. Fifty rabbits were used including 25 donors and 25 recipients. Recipient animals were divided into five groups (n = 5 each): group 1 (control), non-immunosuppressed animals; group II, animals immunosuppressed with cyclosporine (10 mg/kg per day); group III, immunosuppressed with thalidomide (100 mg/kg per day); group IV, immunosuppressed with cyclosporine (5.0 mg/kg per day); and group V, immunosuppressed with cyclosporine (5.0 mg/kg per day) in combination with thalidomide (50 mg/kg per day). The medications were administered through an orogastric catheter starting on the day before the transplant. The heart of the donor was implanted into the recipient's abdomen. The combination of thalidomide and cyclosporine showed the lowest histopathological rejection score (P cyclosporine was effective against rejection, significantly increasing survival (P < .01). Thalidomide may be considered to be an adjuvant immunosuppressant.

  5. The Curious Case of Thalidomide and the Absent Eugenic Clause in Canada's Amended Abortion Law of 1969.

    Science.gov (United States)

    Chisholm, Christine

    This essay traces the role of the drug thalidomide in the reform of Canadian abortion law during the late 1960s. Like elsewhere in the British Commonwealth, discussion of the "thalidomide disaster" of the early 1960s intensified leading up to the debates that culminated in the 1969 amendment to Canadian abortion law. Although thalidomide was a rallying point for advocates of eugenic abortion, a majority of Canadian MPs, unlike their British and Commonwealth counterparts, rejected this argument. Widespread public and political considerations of the thalidomide tragedy were thus unable to inspire support for a eugenic clause in Canada's new abortion law, in spite of the nation's infamous eugenic past.

  6. Thalidomide versus dexamethasone for the treatment of relapsed and/or refractory multiple myeloma: results from OPTIMUM, a randomized trial

    Science.gov (United States)

    Kropff, Martin; Baylon, Honorata Giongco; Hillengass, Jens; Robak, Tadeusz; Hajek, Roman; Liebisch, Peter; Goranov, Stefan; Hulin, Cyrille; Bladé, Joan; Caravita, Tommaso; Avet-Loiseau, Herve; Moehler, Thomas M.; Pattou, Claire; Lucy, Lela; Kueenburg, Elisabeth; Glasmacher, Axel; Zerbib, Robert; Facon, Thierry

    2012-01-01

    Background Thalidomide has potent antimyeloma activity, but no prospective, randomized controlled trial has evaluated thalidomide monotherapy in patients with relapsed/refractory multiple myeloma. Design and Methods We conducted an international, randomized, open-label, four-arm, phase III trial to compare three different doses of thalidomide (100, 200, or 400 mg/day) with standard dexamethasone in patients who had received one to three prior therapies. The primary end-point was time to progression. Results In the intent-to-treat population (N=499), the median time to progression was 6.1, 7.0, 7.6, and 9.1 months in patients treated with dexamethasone, and thalidomide 100, 200, and 400 mg/day, respectively; the difference between treatment groups was not statistically significant. In the per-protocol population (n=465), the median time to progression was 6.0, 7.0, 8.0, and 9.1 months, respectively. In patients who had received two or three prior therapies, thalidomide significantly prolonged the time to progression at all dose levels compared to the result achieved with dexamethasone. Response rates and median survival were similar in all treatment groups, but the median duration of response was significantly longer in all thalidomide groups than in the dexamethasone group. Adverse events reported in the thalidomide groups, such as fatigue, constipation and neuropathy, confirmed the known safety profile of thalidomide. Conclusions Although thalidomide was not superior to dexamethasone in this randomized trial, thalidomide monotherapy may be considered an effective salvage therapy option for patients with relapsed/refractory multiple myeloma, particularly those with a good prognosis and those who have received two or three prior therapies. The recommended starting dose of thalidomide monotherapy is 400 mg/day, which can be rapidly reduced for patients who do not tolerate this treatment. (Clinical trial registration number: NCT00452569) PMID:22133776

  7. Bortezomib and thalidomide maintenance after stem cell transplantation for multiple myeloma: a PETHEMA/GEM trial.

    Science.gov (United States)

    Rosiñol, L; Oriol, A; Teruel, A I; de la Guía, A L; Blanchard, MaJ; de la Rubia, J; Granell, M; Sampol, MaA; Palomera, L; González, Y; Etxebeste, MaA; Martínez-Martínez, R; Hernández, M T; de Arriba, F; Alegre, A; Cibeira, MaT; Mateos, MaV; Martínez-López, J; Lahuerta, J J; San Miguel, J; Bladé, J

    2017-09-01

    The phase III trial GEM05MENOS65 randomized 390 patients 65 years old or younger with newly diagnosed symptomatic multiple myeloma (MM) to receive induction with thalidomide/dexamethasone, bortezomib/thalidomide/dexamethasone and Vincristine, BCNU, melphalan, cyclophosphamide, prednisone/vincristine, BCNU, doxorubicin, dexamethasone bortezomib (VBMCP/VBAD/B) followed by autologous stem cell transplantation (ASCT) with MEL-200. After ASCT, a second randomization was performed to compare thalidomide/bortezomib (TV), thalidomide (T) and alfa-2b interferon (alfa2-IFN). Maintenance treatment consisted of TV (thalidomide 100 mg daily plus one cycle of intravenous bortezomib at 1.3 mg/m2 on days 1, 4, 8 and 11 every 3 months) versus T (100 mg daily) versus alfa2-IFN (3 MU three times per week) for up to 3 years. A total of 271 patients were randomized (TV: 91; T: 88; alfa2-IFN: 92). The complete response (CR) rate with maintenance was improved by 21% with TV, 11% with T and 17% with alfa2-IFN (P, not significant). After a median follow-up of 58.6 months, the progression-free survival (PFS) was significantly longer with TV compared with T and alfa2-IFN (50.6 vs 40.3 vs 32.5 months, P=0.03). Overall survival was not significantly different among the three arms. Grade 2-3 peripheral neuropathy was observed in 48.8%, 34.4% and 1% of patients treated with TV, T and alfa2-IFN, respectively. In conclusion, bortezomib and thalidomide maintenance resulted in a significantly longer PFS when compared with thalidomide or alfa2-IFN. (no. EUDRA 2005-001110-41).

  8. A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma.

    NARCIS (Netherlands)

    Lokhorst, H.M.; Holt, B. van der; Zweegman, S.; Vellenga, E.; Croockewit, S.; Oers, M.H. van; Borne, P. von dem; Wijermans, P.; Schaafsma, R.; Weerdt, O. de; Wittebol, S.; Delforge, M.; Berenschot, H.; Bos, G.M.; Jie, K.S.; Sinnige, H.; Marwijk-Kooy, M. van; Joosten, P.; Minnema, M.C.; Ammerlaan, R. van; Sonneveld, P.

    2010-01-01

    The phase 3 trial HOVON-50 was designed to evaluate the effect of thalidomide during induction treatment and as maintenance in patients with multiple myeloma who were transplant candidates. A total of 556 patients was randomly assigned to arm A: 3 cycles of vincristine, adriamycin, and

  9. A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma

    NARCIS (Netherlands)

    Lokhorst, Henk M.; van der Holt, Bronno; Zweegman, Sonja; Vellenga, Edo; Croockewit, Sandra; van Oers, Marinus H.; von dem Borne, Peter; Wijermans, Pierre; Schaafsma, Ron; de Weerdt, Okke; Wittebol, Shulamiet; Delforge, Michel; Berenschot, Henriëtte; Bos, Gerard M.; Jie, Kon-Siong G.; Sinnige, Harm; van Marwijk-Kooy, Marinus; Joosten, Peter; Minnema, Monique C.; van Ammerlaan, Rianne; Sonneveld, Pieter

    2010-01-01

    The phase 3 trial HOVON-50 was designed to evaluate the effect of thalidomide during induction treatment and as maintenance in patients with multiple myeloma who were transplant candidates. A total of 556 patients was randomly assigned to arm A: 3 cycles of vincristine, adriamycin, and

  10. A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma

    NARCIS (Netherlands)

    H.M. Lokhorst (Henk); B. van der Holt (Bronno); S. Zweegman (Sonja); E. Vellenga (Edo); S. Croockewit (Sandra); M.H.J. van Oers (Marinus); P.A. von dem Borne (P. A.); P.W. Wijermans (Pierre); R. Schaafsma (Ron); O. de Weerdt (Okke); S. Wittebol (Shulamit); M. Delforge (Michel); H. Berenschot (Henriëtte); G.M. Bos (Gerard); K.S-G. Jie; H. Sinnige (Harm); M. van Marwijk Kooy (Marinus); P. Joosten (Peter); M.C. Minnema (Monique); R.A.H.M. Ammerlaan (Rianne); P. Sonneveld (Pieter)

    2010-01-01

    textabstractThe phase 3 trial HOVON-50 was designed to evaluate the effect of thalidomide during induction treatment and as maintenance in patients with multiple myeloma who were transplant candidates. A total of 556 patients was randomly assigned to arm A: 3 cycles of vincristine, adriamycin, and

  11. A single oral dose of thalidomide enhances the capacity of lymphocytes to secrete gamma interferon in healthy humans

    NARCIS (Netherlands)

    Verbon, A.; Juffermans, N. P.; Speelman, P.; van Deventer, S. J.; ten Berge, I. J.; Guchelaar, H. J.; van der Poll, T.

    2000-01-01

    Thalidomide is increasingly being used as adjuvant therapy for patients with mycobacterial and human immunodeficiency virus (HIV) infections. The T-helper (Th)1 cytokine-Th2 cytokine balance critically determines the outcomes of these diseases. To obtain insight into the effect of thalidomide on the

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

    Science.gov (United States)

    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, e

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

    Science.gov (United States)

    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 thalidomide and LPS+etanercept treated groups compared to the LPS group (p 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).

  14. Follow-up of Thalidomide treatment in patients with Hereditary Haemorrhagic Telangiectasia.

    Science.gov (United States)

    Hosman, A; Westermann, C J J; Snijder, R; Disch, F; Mummery, C L; Mager, J J

    2015-12-01

    Patients with a hereditary vascular disorder called Rendu-Osler-Weber syndrome (Hereditary Haemorrhagic Telangiectasia, HHT) haemorrhage easily due to weak-walled vessels. Haemorrhage in lungs or brain can be fatal but patients suffer most from chronic and prolonged nosebleeds (epistaxis), the frequency and intensity of which increases with age. Several years ago, it was discovered serendipitously that the drug Thalidomide had beneficial effects on the disease symptoms in several of a small group of HHT patients: epistaxis and the incidence of anaemia were reduced and patients required fewer blood transfusions. In addition, they reported a better quality of life. However, Thalidomide has significant negative side effects, including neuropathy and fatigue. We followed up all HHT patients in the Netherlands who had been taking Thalidomide at the time the original study was completed to find out (i) how many had continued taking Thalidomide and for how long (ii) the nature and severity of any side-effects and (iii) whether side-effects had influenced their decision to continue taking Thalidomide. Only a minority of patients had continued taking the drug despite its beneficial effects on their symptoms and that the side effects were the primary reason to stop. Despite symptom reduction, alternative treatments are still necessary for epistaxis in HHT patients and a large-scale clinical trial is not justified although incidental use in the most severely affected patients can be considered.

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

    Science.gov (United States)

    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

    2017-05-01

    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 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 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.

  16. Thalidomide embryopathy: Follow-up of cases born between 1959 and 2010.

    Science.gov (United States)

    Kowalski, Thayne Woycinck; Sanseverino, Maria Teresa Vieira; Schuler-Faccini, Lavinia; Vianna, Fernanda Sales Luiz

    2015-09-01

    Thalidomide is a known teratogen and it is estimated that more than ten thousand babies were affected by thalidomide embryopathy (TE), which is characterized mainly by limb defects, but can involve many organs and systems. Most people with TE were only evaluated at birth and it is not well established if thalidomide exposure during embryonic development leads to later effects. We analyzed the clinical history of adults with TE to better understand this gap in the clinical findings of TE. Brazilian individuals with TE were invited to answer a clinical questionnaire which considered family history, social information, medical history, and current clinical and psychological health status. A clinical examination was also performed, including on the infant subjects to evaluate congenital anomalies. The characterization of the features was analyzed using descriptive statistics and Chi-square or Fisher's exact test. The congenital anomalies caused by thalidomide were reviewed in 28 Brazilian individuals, and the questionnaire was applied to the 23 adult subjects with TE (aged 19 to 55). Progressive deafness and dental loss were reported. From the comparison of TE individuals with the general Brazilian population, the early onset of cardiovascular diseases (p = 0.009) and a higher frequency of psychological disorders (p = 0.011) were observed. Although there is no sufficient evidence that thalidomide exposure caused or worsened the described events, this approach helps to better understand the TE phenotype, improves the clinical diagnosis, and can lead to adequate health support for these individuals. © 2015 Wiley Periodicals, Inc.

  17. Thalidomide induced early gene expression perturbations indicative of human embryopathy in mouse embryonic stem cells.

    Science.gov (United States)

    Gao, Xiugong; Sprando, Robert L; Yourick, Jeffrey J

    2015-08-15

    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 72h after exposure to 0.25mM 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. Published by Elsevier Inc.

  18. Superiority of the Triple Combination of Bortezomib-Thalidomide-Dexamethasone Over the Dual Combination of Thalidomide-Dexamethasone in Patients With Multiple Myeloma Progressing or Relapsing After Autologous Transplantation: The MMVAR/IFM 2005-04 Randomized Phase III Trial From the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

    NARCIS (Netherlands)

    Garderet, L.; Iacobelli, S.; Moreau, P.; Dib, M.; Lafon, I.; Niederwieser, D.; Masszi, T.; Fontan, J.; Michallet, M.; Gratwohl, A.; Milone, G.; Doyen, C.; Pegourie, B.; Hajek, R.; Casassus, P.; Kolb, B.; Chaleteix, C.; Hertenstein, B.; Onida, F.; Ludwig, H.; Ketterer, N.; Koenecke, C.; Os, M. van; Mohty, M.; Cakana, A.; Gorin, N.C.; Witte, T.J. de; Harousseau, J.L.; Morris, C.; Gahrton, G.

    2012-01-01

    PURPOSE This prospective multicenter phase III study compared the efficacy and safety of a triple combination (bortezomib-thalidomide-dexamethasone [VTD]) versus a dual combination (thalidomide-dexamethasone [TD]) in patients with multiple myeloma (MM) progressing or relapsing after autologous

  19. Treatment outcome of thalidomide based regimens in newly diagnosed and relapsed/refractory non-transplant multiple myeloma patients: a single center experience from Thailand

    Directory of Open Access Journals (Sweden)

    Aungchaisuksiri Pantep

    2010-01-01

    Full Text Available Abstract Background Thalidomide based regimen is an effective and well tolerated therapy in multiple myeloma (MM patients, however, there were a small number of studies written about the results of thalidomide therapy in non-transplant MM patients. We therefore conducted a retrospective study of 42 consecutive patients with newly diagnosed and relapsed/refractory MM treated with thalidomide- based induction regimens followed by thalidomide maintenance therapy. Results Induction regimens with thalidomide and dexamethasone, and the oral combination of melphalan, prednisolone and thalidomide were administrated in 22 and 16 patients, respectively. The remaining 4 patients received other thalidomide- containing regimens. Twenty-nine patients received thalidomide as a salvage regimen. Twenty-three out of 26 patients achieving complete remission (CR and very good partial remission (VGPR received thalidomide maintenance. Of the 41 evaluable patients, median time of treatment was 21 months (3- 45 months, ORR was 92.7% with a 63.4% CR/VGPR. With a median follow up of 23 months, 3-year- PFS and 3-year-OS were 58.6 and 72.6%, respectively. Median time to progression was 42 months. While 3-year-PFS and 3-year-OS in non-transplant patients receiving thalidomide maintenance therapy were 67 and 80%, respectively. Conclusions Prolonged thalidomide therapy enhanced survival rate and less frequently developed serious toxicity in non-transplant multiple myeloma patients.

  20. Magnetic resonance imaging for monitoring the effects of thalidomide on experimental human breast cancers

    Energy Technology Data Exchange (ETDEWEB)

    Cyran, Clemens C. [University of California San Francisco, Center for Pharmaceutical and Molecular Imaging, Department of Radiology, San Francisco, CA (United States); Ludwig-Maximilians-University, Department of Clinical Radiology, Klinikum Grosshadern, Munich (Germany); Sennino, Barbara; McDonald, Donald M. [University of California San Francisco, Comprehensive Cancer Center, Cardiovascular Research Institute, and Department of Anatomy, San Francisco, CA (United States); Chaopathomkul, Bundit; Fu, Yanjun; Rogut, Victor S.; Shames, David M.; Wendland, Michael F.; Brasch, Robert C. [University of California San Francisco, Center for Pharmaceutical and Molecular Imaging, Department of Radiology, San Francisco, CA (United States)

    2009-01-15

    Thalidomide, which inhibits angiogenesis in certain tumor types, reduced extravasation of a macromolecular contrast medium (MMCM) in a human breast cancer model as assayed by MMCM-enhanced dynamic magnetic resonance imaging (MRI) and fluorescence microscopy in the same tumors. After a 1-week, three-dose course of thalidomide, the mean MRI-assayed endothelial transfer coefficient, K{sup PS}, decreased significantly (p<0.05) from 19.4{+-}9.1 to 6.3{+-}9.1 {mu}l/min.100 cm{sup 3}. Correspondingly, microscopic measurements of extravasated MMCM, expressed as fractional area of streptavidin staining, were significantly (p<0.05) lower in thalidomide-treated tumors (18.6{+-}11.9%) than in control saline-treated tumors (50.2{+-}2.3%). On a tumor-by-tumor basis, post-treatment K{sup PS} values correlated significantly (r{sup 2}=0.55, p<0.05) with microscopic measures of MMCM extravasation. However, no significant differences were observed between saline- and thalidomide-treated tumors with respect to rate of growth, vascular richness, or amount of VEGF-containing cells. Because of its sensitivity to the detection of changes in vascular leakage in tumors, this MMCM-enhanced MRI assay could prove useful for monitoring the effects of thalidomide on an individual patient basis. The significant correlation between MRI and fluorescence microscopic measures of MMCM extravasation supports the utility of the non-invasive MRI approach for assessing the action of thalidomide on tumor blood vessels. (orig.)

  1. Epidemiological Surveillance of Birth Defects Compatible with Thalidomide Embryopathy in Brazil

    Science.gov (United States)

    Vianna, Fernanda Sales Luiz; Lopez-Camelo, Jorge S.; Leite, Júlio César Louguercio; Sanseverino, Maria Teresa Vieira; da Graça Dutra, Maria; 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

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

    Science.gov (United States)

    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.

  3. Epidemiological surveillance of birth defects compatible with thalidomide embryopathy in Brazil.

    Directory of Open Access Journals (Sweden)

    Fernanda Sales Luiz Vianna

    Full Text Available 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.

  4. Epidemiological surveillance of birth defects compatible with thalidomide embryopathy in Brazil.

    Science.gov (United States)

    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.

  5. Prurido braquiorradial tratado com talidomida Brachioradial pruritus treated with thalidomide

    Directory of Open Access Journals (Sweden)

    José Marcos Pereira

    2005-06-01

    Full Text Available Prurido braquiorradial é um tipo de prurido ou sensação de ardor intenso que acomete a região anterior do terço distal dos braços e terço proximal dos antebraços, correspondendo à região do músculo braquiorradial. A doença tem sido associada à radiação solar e também, cogitou-se, a lesões ortopédicas na coluna cervical. Uma das características da doença é a refratariedade ao tratamento. O autor apresenta duas pacientes com prurido braquiorradial tratadas com talidomida, com resultados excelentes.Brachioradial pruritus is a type of itching or a very intense burning sensation in the anterior distal third of arms and proximal third of forearms, corresponding to the brachioradial muscle region. The condition has been associated with solar radiation, and some authors related to orthopedic lesions in the cervical spine. The author presents two patients suffering from brachioradial pruritus who were treated with thalidomide and presented excellent results. This paper aims to suggest a new therapeutic option for this refractory disease.

  6. Evidence of mechanism in the evaluation of streptomycin and thalidomide.

    Science.gov (United States)

    Gillies, Donald

    2017-10-11

    This paper considers what evidence is needed to establish the effectiveness and safety of a drug therapy. The claim that A cures D is a particular case of a causal claim in medicine. So the paper begins with a general analysis of the evidence for causal claims in medicine. Such evidence is divided into two types: statistical evidence and evidence of mechanism. These are further divided into observational and interventional, producing a 2x2 classification. It is shown that historically there have different assessments of the importance of these different types of evidence. Evidence-based medicine (EBM) puts forward the thesis that claims of the form 'A cures D without harming the patient' can be established using only randomized controlled trials or RCTs. This thesis of EBM is criticized by considering two historical examples: streptomycin and thalidomide. Generalizing from these, it is claimed that the effectiveness and safety of a drug therapy can only be established by using both statistical evidence and evidence of mechanism. This is a specific instance of the Russo-Williamson thesis. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

  7. Effects of Thalidomide Combined with Interferon on Inhibiting Kasumi-1 Cell Proliferation.

    Science.gov (United States)

    Xu, Hao; Mi, Ruihua; Fan, Ruihua; Yin, Qingsong; Wei, Xudong

    2016-01-01

    Our previous clinical observations proved that the combination of thalidomide and interferon (IFN) had certain effects in relapsed or refractory AML. The aim of this study was to investigate the effects and its mechanism of thalidomide and IFN on inhibiting the proliferation of Kasumi-1 cells. Thalidomide, IFN and a combination of both drugs were used to treat Kasumi-1 cells. The inhibition of cell proliferation and the apoptosis rate were measured. Vascular endothelial growth factor levels and the expression of apoptosis-related proteins were detected by ELISA and Western blotting, respectively. Thalidomide and IFN could both inhibit Kasumi-1 cell proliferation in a dose-dependent manner. When Kasumi-1 cells were treated with thalidomide 350 μg/mL or IFN1400 U/mL for 48 h, the proliferation inhibition rates were (48.8 ± 4.64)% and (50.19 ± 2.59)% and the rates of apoptosis were (14.68 ± 2.61)% and (21.71 ± 0.71)%, respectively; when treated with a combination, the cell proliferation inhibition rate and apoptotic rate were statistically significantly higher than both the control group and the groups treated with a single drug. The ELISA assay revealed that both 350 μg/mL of thalidomide and 1400 U/mL of IFN could reduce the VEGF levels in cell culture supernatants; the two-drug combination group had a further decreased VEGF concentration. Forty-eighthour treatment of thalidomide 350 μg/mL and IFN 1400 U/mL could significantly decrease Bcl-2 expression and increase the expression levels of phosphor-P38, BAX, cytochrome c, and cleaved caspase-3, -8, and -9 as compared to the control group. The combination group exhibited significantly greater extents of reduction in Bcl-2 protein and increases in p-P38, BAX, and cytochrome c, and cleaved caspase-3, -8, and -9 protein expression as compared to the single drug groups. Thalidomide and IFN can synergistically inhibit Kasumi-1 cell proliferation, which is possibly achieved through the mitochondrial and death

  8. A Phase II Dose Titration Study of Thalidomide for Cancer-Associated Anorexia

    Science.gov (United States)

    Davis, Mellar; Lasheen, Wael; Walsh, Declan; Mahmoud, Fade; Bicanovsky, Leslie; Lagman, Ruth

    2013-01-01

    Context Sixty-five percent of people with advanced cancer suffer from loss of appetite. Several inflammatory cytokines appear to cause appetite loss in animal models. Thalidomide is an immunomodulatory drug that has been associated with improved appetite in those with HIV infections, and in cancer. Objectives We completed a two-stage Phase II dose titration study of thalidomide, the primary purpose of which was to assess appetite response to thalidomide in cancer-associated anorexia. Methods Individuals older than 18 years of age with active cancer, loss of appetite by numerical rating scale (NRS), life expectancy of at least four weeks, and Eastern Cooperative Oncology Group performance status of 0–3 were entered into the study. Pre-treatment screening included medical history, neurologic examination, and symptoms by NRS and categorical scale. Patients received 50 mg of thalidomide by mouth at bedtime for two weeks. Individuals who did not respond were dose escalated to 100 mg at night for two weeks. Assessment of appetite, early satiety, fatigue, insomnia, night sweats, pain, and quality of life occurred at two-week intervals. Toxicity also was assessed. The primary outcome was appetite response defined as a two-point reduction in the NRS, or one-point improvement in the categorical scale. Results Thirty-five patients entered the study; 33 completed 14 days of therapy and were analyzed for efficacy and toxicity. Sixty-four percent who completed at least two weeks of thalidomide had improved appetite. The categorical scale scores for appetite, insomnia and quality of life improved significantly. The 95% confidence intervals did not overlap. Five participants dropped out because of toxicity: two before two weeks and three later. Conclusion Thalidomide reduced multiple symptoms commonly associated with cancer-related anorexia and improved quality of life. Our findings confirmed and validated a previously published single arm trial. A recent randomized trial

  9. Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma

    DEFF Research Database (Denmark)

    Waage, Anders; Gimsing, Peter; Fayers, Peter

    2010-01-01

    In this double-blind, placebo-controlled study, 363 patients with untreated multiple myeloma were randomized to receive either melphalan-prednisone and thalidomide (MPT) or melphalan-prednisone and placebo (MP). The dose of melphalan was 0.25 mg/kg and prednisone was 100 mg given daily for 4 days...... every 6 weeks until plateau phase. The dose of thalidomide/placebo was escalated to 400 mg daily until plateau phase and thereafter reduced to 200 mg daily until progression. A total of 357 patients were analyzed. Partial response was 34% and 33%, and very good partial response or better was 23% and 7...

  10. Human Liver Microsomal Cytochrome P450 3A Enzymes Involved in Thalidomide 5-Hydroxylation and Formation of a Glutathione Conjugate

    Science.gov (United States)

    Chowdhury, Goutam; Murayama, Norie; Okada, Yusuke; Uno, Yasuhiro; Shimizu, Makiko; Shibata, Norio; Guengerich, F. Peter; Yamazaki, Hiroshi

    2013-01-01

    (R)-Thalidomide was oxidized to 5-hydroxythalidomide and 5’-hydroxythalidomide by NADPH-fortified liver microsomes from humans and monkeys. (R)-Thalidomide was hydroxylated more efficiently than (S)-thalidomide. Recombinant human P450s 3A4, 3A5, and 3A7 and monkey P450s 3A8 and 3A5 (co-expressed with NADPH-P450 reductase in bacterial membranes) also catalyzed (R)-thalidomide 5-hydroxylation. Purified human P450s 2C19, 3A4, and 3A5 mediated (R)-thalidomide 5-hydroxylation at similar rates in reconstituted systems. P450 2C19 showed a rather non-saturable substrate-velocity curve; however, P450s 3A4 and 3A5 showed sigmoidal curves. P450 also oxidized 5-hydroxythalidomide to an epoxide or dihydroxy compound. Liquid chromatography-mass spectrometry analysis revealed formation of a glutathione conjugate from (R)- and (S)-5-hydroxythalidomide, catalyzed by liver microsomal P450s 3A4 and 3A5 in the presence of glutathione (assigned as a conjugate of 5-hydroxythalidomide formed on the phenyl ring). These results indicate that human P450s 3A4 and 3A5 mediate thalidomide 5-hydroxylation and further oxidation leading to a glutathione conjugate, which may be of relevance in the pharmacological and toxicological actions of thalidomide. PMID:20443640

  11. The effect of thalidomide on ethanol-induced gastric mucosal damage in mice: involvement of inflammatory cytokines and nitric oxide.

    Science.gov (United States)

    Amirshahrokhi, Keyvan; Khalili, Ali-Reza

    2015-01-05

    Excessive ethanol ingestion causes gastric mucosal damage through the inflammatory and oxidative processes. The present study was aimed to evaluate the protective effect of thalidomide on ethanol-induced gastric mucosal damage in mice. The animals were pretreated with vehicle or thalidomide (30 or 60 mg/kg, orally), and one hour later, the gastric mucosal injury was induced by oral administration of acidified ethanol. The animals were euthanized one hour after ethanol ingestion, and gastric tissues were collected to biochemical analyzes. The gastric mucosal lesions were assessed by macroscopic and histopathological examinations. The results showed that treatment of mice with thalidomide prior to the administration of ethanol dose-dependently reduced the gastric ulcer index. Thalidomide pretreatment significantly reduced the levels of pro-inflammatory cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6], malondialdehyde (MDA) and myeloperoxidase (MPO) activity. In addition, thalidomide significantly inhibited ethanol-induced nitric oxide (NO) overproduction in gastric tissue. Histological observations showed that ethanol-induced gastric mucosal damage was attenuated by thalidomide pretreatment. It seems that thalidomide as an anti-inflammatory agent may have a protective effect against alcohol-induced mucosal damage by inhibition of neutrophil infiltration and reducing the production of nitric oxide and inflammatory cytokines in gastric tissue. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  14. Combination chemotherapy with cyclophosphamide, thalidomide and dexamethasone for patients with refractory, newly diagnosed or relapsed myeloma.

    Science.gov (United States)

    Sidra, Gamal; Williams, Cathy D; Russell, Nigel H; Zaman, Sonya; Myers, Bethan; Byrne, Jennifer L

    2006-06-01

    We evaluated the combination of thalidomide, pulsed dexamethasone and weekly cyclophosphamide (CTD) for the treatment of patients with newly diagnosed, relapsed or VAD-refractory multiple myeloma. We found that this combination was highly effective in inducing responses in all treatment groups with an overall response rate of 83.8%. CTD was well tolerated and did not impair stem cell mobilization.

  15. Bortezomib, melphalan, prednisone (VMP) versus melphalan, prednisone, thalidomide (MPT) in elderly newly diagnosed multiple myeloma patients

    DEFF Research Database (Denmark)

    Morabito, Fortunato; Bringhen, Sara; Larocca, Alessandra

    2014-01-01

    Novel agents in combination with melphalan and prednisone (MP) significantly improved progression-free survival (PFS) and overall survival (OS) in multiple myeloma (MM). Randomized trials comparing MP plus bortezomib (VMP) versus MP plus thalidomide (MPT) are lacking. Nine hundred and fifty-six e...

  16. [Therapy of recurrent exudative erythema multiforme. Effectiveness of thalidomide--report of a case].

    Science.gov (United States)

    Engeser, P; Klimm, H D

    1999-05-10

    The authors report on the efficacy of thalidomide used to treat recurrent erythema exsudativum multiforme associated with herpes simplex with massive involvement of the entire skin and also the nasal mucosa in a 73-year-old woman. Efficacy in terms of healing and the prevention of recurrence proved to be very good.

  17. O renascimento de um fármaco: talidomida The rebirth of a drug: thalidomide

    Directory of Open Access Journals (Sweden)

    Lídia Moreira Lima

    2001-10-01

    Full Text Available Thalidomide, first synthesized in 1953, was widely prescribed for morning sickness of pregnant women from 1957 to 1961, when it was found to be seriously teratogenic, having caused serious birth defect. Nowadays, a quarter of a century later, it appears that it may be a miracle drug for such diseases as leprosy, AIDS, cancer and tuberculosis.

  18. Thalidomide for Epistaxis in Patients with Hereditary Hemorrhagic Telangiectasia: A Preliminary Study.

    Science.gov (United States)

    Fang, Jia; Chen, Xiaomeng; Zhu, Bijun; Ye, Haibo; Zhang, Weitian; Guan, Jian; Su, Kaiming

    2017-08-01

    To evaluate the effectiveness of thalidomide for epistaxis in hereditary hemorrhagic telangiectasia (HHT), 7 HHT patients with recurrent epistaxis were treated with thalidomide at an initial dose of 50 mg/d, gradually increasing to 100 mg/d if needed. The Epistaxis Severity Score (ESS) was used to evaluate the treatment effects. Patients reported that epistaxis improved 1 to 3 weeks after starting thalidomide. The mean ESS before treatment, at the end of treatment, and 3 months after stopping treatment was 5.03 ± 2.05, 0.90 ± 0.84 ( P = .003), and 1.98 ± 1.33 ( P = .006), respectively. Four patients reported mild to moderate side effects, including drowsiness, dizziness, constipation, nausea, and peripheral neuropathy. Two patients stopped the treatment because of adverse effects. Those results showed that thalidomide may be a treatment choice for recurrent epistaxis in HHT patients, although the side effects should be considered. Further study should focus on guidelines for dosing and course and investigate how to reduce the adverse effects.

  19. Does low-molecular-weight heparin influence the antimyeloma effects of thalidomide?

    DEFF Research Database (Denmark)

    Beksac, Meral; Waage, Anders; Bringhen, Sara

    2015-01-01

    comparing melphalan and prednisolone with (MPT, n: 404) or without thalidomide (MP, n: 393) are analyzed for effects of LMWH. Forty percent (159/394) of the patients on MPT and 7.4% (29/390) in the MP arm received LMWH. RESULTS: Thalidomide improved response and progression-free survival (PFS). Regardless...... of thalidomide treatment, response rate was higher among those receiving LMWH vs. none vs. other anticoagulants (58.1 vs. 44.9 vs. 50.4%, p = 0.01). PFS was significantly longer (median 32 vs. 21 and 17 vs. 17 months, p = 0.004) only among international scoring system (ISS) I patients receiving MPT ± LMWH vs. MP...... ± LMWH. The group of MPT patients who also received LMWH had a better OS compared to those who did not [45 months, 95% confidence interval (CI) 27.7-62.3, vs. 32 months, 95% CI 26.1-37.9; p = 0.034]. When multivariate analysis was repeated in subgroups, thalidomide was no longer a significant factor...

  20. Identification of Thalidomide-Specific Transcriptomics and Proteomics Signatures during Differentiation of Human Embryonic Stem Cells

    Science.gov (United States)

    Meganathan, Kesavan; Jagtap, Smita; Wagh, Vilas; Winkler, Johannes; Gaspar, John Antonydas; Hildebrand, Diana; Trusch, Maria; Lehmann, Karola; Hescheler, Jürgen; Schlüter, Hartmut; Sachinidis, Agapios

    2012-01-01

    Embryonic development can be partially recapitulated in vitro by differentiating human embryonic stem cells (hESCs). Thalidomide is a developmental toxicant in vivo and acts in a species-dependent manner. Besides its therapeutic value, thalidomide also serves as a prototypical model to study teratogenecity. Although many in vivo and in vitro platforms have demonstrated its toxicity, only a few test systems accurately reflect human physiology. We used global gene expression and proteomics profiling (two dimensional electrophoresis (2DE) coupled with Tandem Mass spectrometry) to demonstrate hESC differentiation and thalidomide embryotoxicity/teratogenecity with clinically relevant dose(s). Proteome analysis showed loss of POU5F1 regulatory proteins PKM2 and RBM14 and an over expression of proteins involved in neuronal development (such as PAK2, PAFAH1B2 and PAFAH1B3) after 14 days of differentiation. The genomic and proteomic expression pattern demonstrated differential expression of limb, heart and embryonic development related transcription factors and biological processes. Moreover, this study uncovered novel possible mechanisms, such as the inhibition of RANBP1, that participate in the nucleocytoplasmic trafficking of proteins and inhibition of glutathione transferases (GSTA1, GSTA2), that protect the cell from secondary oxidative stress. As a proof of principle, we demonstrated that a combination of transcriptomics and proteomics, along with consistent differentiation of hESCs, enabled the detection of canonical and novel teratogenic intracellular mechanisms of thalidomide. PMID:22952932

  1. The Dihydroxy Metabolite of the Teratogen Thalidomide Causes Oxidative DNA Damage.

    Science.gov (United States)

    Wani, Tasaduq H; Chakrabarty, Anindita; Shibata, Norio; Yamazaki, Hiroshi; Guengerich, F Peter; Chowdhury, Goutam

    2017-08-21

    Thalidomide [α-(N-phthalimido)glutarimide] (1) is a sedative and antiemetic drug originally introduced into the clinic in the 1950s for the treatment of morning sickness. Although marketed as entirely safe, more than 10 000 babies were born with severe birth defects. Thalidomide was banned and subsequently approved for the treatment of multiple myeloma and complications associated with leprosy. Although known for more than 5 decades, the mechanism of teratogenicity remains to be conclusively understood. Various theories have been proposed in the literature including DNA damage and ROS and inhibition of angiogenesis and cereblon. All of the theories have their merits and limitations. Although the recently proposed cereblon theory has gained wide acceptance, it fails to explain the metabolism and low-dose requirement reported by a number of groups. Recently, we have provided convincing structural evidence in support of the presence of arene oxide and the quinone-reactive intermediates. However, the ability of these reactive intermediates to impart toxicity/teratogenicity needs investigation. Herein we report that the oxidative metabolite of thalidomide, dihydroxythalidomide, is responsible for generating ROS and causing DNA damage. We show, using cell lines, the formation of comet (DNA damage) and ROS. Using DNA-cleavage assays, we also show that catalase, radical scavengers, and desferal are capable of inhibiting DNA damage. A mechanism of teratogenicity is proposed that not only explains the DNA-damaging property but also the metabolism, low concentration, and species-specificity requirements of thalidomide.

  2. Efficacy of thalidomide in a girl with inflammatory calcinosis, a severe complication of juvenile dermatomyositis

    Directory of Open Access Journals (Sweden)

    Inayama Yoshiaki

    2010-02-01

    Full Text Available Abstract We report a 14-year-old girl with juvenile dermatomyositis (JDM complicated by severe inflammatory calcinosis successfully treated with thalidomide. She was diagnosed as JDM when she was 4 years old after a few months of increasing lethargy, muscle pain, muscle weakness, and rash. During three months, clinical manifestations and abnormal laboratory findings were effectively treated with oral prednisolone. However, calcinosis was recognized 18 months after disease onset. Generalized calcinosis rapidly progressed with high fever, multiple skin/subcutaneous inflammatory lesions, and increased level of CRP. Fifty mg/day (1.3 mg/kg day of oral thalidomide was given for the first four weeks, and then the dose was increased to 75 mg/day. Clinical manifestations subsided, and inflammatory markers had clearly improved. Frequent high fever and local severe pain with calcinosis were suppressed. The levels of FDP-E, IgG, and tryglyceride, which were all elevated before the thalidomide treatment, were gradually returned to the normal range. Over the 18 months of observation up to the present, she has had no inflammatory calcinosis, or needed any hospitalization, although established calcium deposits still remain. Her condition became painless, less extensive and less inflammatory with the CRP level below 3.08 mg/dL. Recent examination by whole-body 18F-FDG-PET-CT over the 15 months of thalidomide treatment demonstrated fewer hot spots around the subcutaneous calcified lesions.

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

    NARCIS (Netherlands)

    Scharpfenecker, Marion; Floot, Ben; Russell, Nicola S.; Coppes, Rob P.; Stewart, Fiona A.

    2014-01-01

    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

  4. What can we learn from the thalidomide experience: an ophthalmologic perspective

    Science.gov (United States)

    Miller, Marilyn T.; Strömland, Kerstin K.

    2013-01-01

    Purpose of review The thalidomide tragedy of the early 1960s resulted in a great number of studies and reports involving many specialties of medicine. Because of the estimated large number of affected children (5000+) worldwide exposed to this potent teratogen, and the many informative cases in which the exposure time was known, a teratogenic timetable was constructed relating affected structures to the time of exposure. This demonstrated that thalidomide had a teratogenic effect between approximately 20 to 36 days after fertilization. Recent findings We found that Duane syndrome and its variants were prominent in individuals who were exposed to thalidomide early in the sensitive period (days 20 to 26±). Other anomalies associated with this early effect were aberrant tearing, facial nerve palsy, ear malformations, and autism. Structural eye malformations were less frequent in this early phase, appearing slightly later in the sensitive period. Summary This study summarizes the ophthalmologic findings from a number of studies and compares them with respect to the implications of time of exposure. Because the timing of anomalies such as external ear and limb malformations are well established in the thalidomide literature, correlation with associated eye anomalies gives insight into the approximate timing of the causative teratogen exposure. PMID:21825994

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

    Science.gov (United States)

    2006-10-01

    Blurred vision 5 Diarrhea 4 Vasovagal episode/ bradycardia 1 1 1 Cardiac 4 Memory loss 3 Urinary frequency 3 Dyspnoea...York A, Gezer S, Venugopal P, Raza A. The clinical and biological effects of thalidomide in patients with myelodysplastic syndromes . Br J Haematol

  6. Phase II Study of Temozolomide and Thalidomide in Patients with Unresectable or Metastatic Leiomyosarcoma

    Directory of Open Access Journals (Sweden)

    Michelle S. Boyar

    2008-01-01

    Full Text Available We assessed the efficacy of combined temozolomide and thalidomide in patients with unresectable or metastatic leiomyosarcoma in a phase II single-institution trial. Twenty-four patients were enrolled. Temozolomide (150 mg/m2/day for 7 days every other week was administered with concomitant thalidomide (200 mg/day, and continued until unacceptable toxicity or disease progression. There were no complete responses and two (10% partial responses. Five patients (24% had stable disease for at least six months. Fourteen patients (67% progressed after a median of two-month treatment. The median overall survival (twenty-two assessable patients was 9.5 months [95% CI 7–28 months]. There were no treatment-related deaths or CTC grade 4 toxicities. Thirteen patients were dose-reduced or discontinued thalidomide due to toxicity. In conclusion, this combination of temozolomide and thalidomide provided disease stabilization in a subset of patients with advanced leiomyosarcoma. We hypothesize that temozolomide is the active agent in this regimen, and should be further studied.

  7. Phase II Study of Concomitant Thalidomide During Radiotherapy for Hepatocellular Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Ch' ang, Hui-Ju, E-mail: hjmc@nhri.org.tw [National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan (China); Department of Radiation Oncology, National Cheng Kung University Hospital, Tainan, Taiwan (China); Hsu, Chiun [Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan (China); Chen, Chien-Hung [Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan (China); Chang, Ya-Hui; Chang, Jeffrey S. [National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan (China); Chen, Li-Tzong [National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan (China); Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan (China)

    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 samples 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

  8. Myocardial infarction, symptomatic third degree atrioventricular block and pulmonary embolism caused by thalidomide: a case report.

    Science.gov (United States)

    Zhang, Shengyu; Yang, Jing; Jin, Xiaofeng; Zhang, Shuyang

    2015-12-18

    Thalidomide has been reported to cause numerous thromboembolic events. Deep vein thrombosis and pulmonary embolism are more common. It can also cause bradycardia and even total atrioventricular block. Rarely, it causes coronary artery spasm and even myocardial infarction. But almost simultaneous onset of myocardial infarction, third degree atrioventricular block and pulmonary embolism in one patient has not been reported so far. A 53-year old man presented because of chest pain, nausea and then syncope for several minutes. Previous medical history included neurodermitis for which thalidomide was given and hypercholesterolemia with simvastatin taking. The patient didn't exhibit any other established risk factors for coronary artery disease. Electrocardiography showed sinus rhythm with third degree atrioventricular block and complete right bundle branch block, and precordial leads ST segment elevation. The diagnosis of acute coronary syndrome was suspected, but further coronary angiography demonstrated no flow-limiting lesions in coronary arteries, and temporary pacemaker was implanted. After admission, low SpO2 and elevated D-dimer level was mentioned. Further computed tomography pulmonary angiography revealed pulmonary embolism. Thalidomide was thought to be the cause of hypercoagulability and coronary spasm, so it was ceased immediately. Therapeutic low molecule weight heparin was initiated and then switched to warfarin with appropriate INR, and nifedipine was described for coronary spasm. The patient's symptoms completely relived and SpO2 recovered, and atrioventricular block had disappeared during hospitalization with pacemaker removed. This is the very first case in which myocardial infarction, third degree atrioventricular block and pulmonary embolism almost simultaneously developed. We should be ware that anti-thrombotic prophylaxis, which needs further investigation for optimal drug and dosage, may be beneficial in thalidomide therapy. And it is also

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

    Science.gov (United States)

    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

  10. [Thalidomide therapy in relapsed diffuse large B-cell lymphoma in elderly patients. Three cases].

    Science.gov (United States)

    Wohner, Nikolett; Varga, Gergely; Szloboda, Péter; Farkas, Péter; Masszi, András; Horváth, Laura; Szombath, Gergely; Várkonyi, Judit; Benedek, Szabolcs; Masszi, Tamás

    2017-10-01

    Diffuse large B-cell lymphoma (DLBCL), a high-grade lymphoproliferative disease, is the most common lymphoma in adults, representing 31% of non-Hodgkin lymphomas (NHL). In elderly patients treatment is problematic because of the high toxicity of standard chemotherapy protocols, especially in relapsed cases, where high-dose chemotherapy and haematopoietic stem cell transplantation would be the best choice. More and more data is becoming available on alternative treatment of refractory/relapsed NHL, including studies on the positive effect of thalidomide and second generation IMiDs in DLBCL, which are already part of the standard treatment protocol in myeloma multiplex and myelodysplasia. The broadening use of IMiDs is due to their anti-angiogenetic, immunmodulatory and anti-inflammatory properties. In addition, a component of the E3-ubiquitin ligase complex, named cereblon, has been described in 2010 as the molecular effector of the thalidomide signal transduction pathway. We initiated thalidomide treatment in three elderly patients with relapsed DLBCL. In two cases, patients had CNS involvement, in the third case the patient had primary mediastinal disease. Patients received 100 mg thalidomide in combination with corticosteroids. Two patients showed an excellent response reaching complete remission on imaging; these patients are progression-free 12 and 20 months after the beginning of treatment. One patient with CNS involvement progressed and deceased despite therapy. According to the literature, IMiDs have significant activity in relapsed DLBCL. Our case-report presents promising results in an elderly patient population with aggressive relapsed NHL that usually has very poor outcome, as high-toxicity treatment cannot be given to these patients. Consequently, because of its efficiency, low-cost and low-toxicity, it is recommended to consider thalidomide therapy in elderly patients with high-grade DLBCL. Orv Hetil. 2017; 158(41): 1642-1648.

  11. Harvesting clues from genome wide transcriptome analysis for exploring thalidomide mediated anomalies in eye development of chick embryo: Nitric oxide rectifies the thalidomide mediated anomalies by swinging back the system to normal transcriptome pattern.

    Science.gov (United States)

    Kumar, Pavitra; Kasiviswanathan, Dharanibalan; Sundaresan, Lakshmikirupa; Kathirvel, Priyadarshan; Veeriah, Vimal; Dutta, Priya; Sankaranarayanan, Kavitha; Gupta, Ravi; Chatterjee, Suvro

    2016-02-01

    Thalidomide, the notorious teratogen is known to cause various developmental abnormalities, among which a range of eye deformations are very common. From the clinical point of view, it is necessary to pinpoint the mechanisms of teratogens that tune the gene expression. However, to our knowledge, the molecular basis of eye deformities under thalidomide treatmenthas not been reported so far. Present study focuses on the possible mechanism by which thalidomide affects eye development and the role of Nitric Oxide in recovering thalidomide-mediated anomalies of eye development using chick embryo and zebrafish models with transcriptome analysis. Transcriptome analysis showed that 403 genes were up-regulated and 223 genes were down-regulated significantly in thalidomide pre-treated embryos. 8% of the significantly modulated genes have been implicated in eye development including Pax6, OTX2, Dkk1 and Shh. A wide range of biological process and molecular function was affected by thalidomide exposure. Biological Processes including structural constituent of eye lens and Molecular functions such as visual perception and retinal metabolic process formed strong annotation clustersindicating the adverse effects of thalidomide on eye development and function. Here, we have discussed the whole embryo transcriptome with the expression of PAX6, SOX2, and CRYAAgenes from developing eyes. Our experimental data showing structural and functional aspects includingeye size, lens transparency and optic nerve activity and bioinformatics analyses of transcriptome suggest that NO could partially protect thalidomide treated embryos from its devastating effects on eye development and function. Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  12. Thalidomide treatment for patients with previously untreated multiple myeloma: a meta-analysis of randomized controlled trials.

    Science.gov (United States)

    Gao, Minjie; Kong, Yuanyuan; Wang, Houcai; Xie, Bingqian; Yang, Guang; Gao, Lu; Zhang, Yiwen; Zhan, Fenghuang; Dai, Bojie; Tao, Yi; Shi, Jumei

    2016-08-01

    The efficacy and safety of thalidomide as an initial treatment in myeloma patients who were unsuitable for autologous stem cell transplantation (ASCT), as induction treatment prior to ASCT, or as a maintenance treatment was unclear. The purpose of this study was to assess the benefits and risks of thalidomide for previously untreated myeloma patients. MEDLINE, EMBASE, and Cochrane Library were searched for randomized controlled trials (RCTs) of thalidomide used in either induction or maintenance therapy for previously untreated myeloma patients. Twenty-two RCTs enrolling 9098 patients were identified, including 15 RCTs of induction thalidomide, 6 RCTs of maintenance thalidomide, and 1 RCT of induction and maintenance thalidomide. Induction thalidomide improved overall response rate (ORR) (risk ratio (RR) 1.54, 95 % confidence interval (CI) 1.30-1.83), complete response rate (CRR) (RR 3.03, 95 % CI 1.91-4.80), progression-free survival (PFS) (hazard ratio (HR) 0.65, 95 % CI 0.56-0.76), and overall survival (OS) (HR 0.78, 95 % CI 0.67-0.91) in patients who were not allowed to receive ASCT. Induction thalidomide improved pre-ASCT ORR (RR 1.20, 95 % CI 1.11-1.30), pre-ASCT and post-ASCT CRR (RR 1.47, 95 % CI 1.12-1.93 and RR 1.23, 95 % CI 1.00-1.50, respectively), and PFS (HR 0.73, 95 % CI 0.59-0.91) in patients who were allowed to receive ASCT, but it did not improve post-ASCT ORR (RR 1.04, 95 % CI 0.99-1.09) and OS (HR 0.91, 95 % CI 0.79-1.05). Improved PFS and prolonged OS were observed (HR 0.61, 95 % CI 0.53-0.70 and HR 0.77, 95 % CI 0.62-0.95, respectively) when thalidomide was added to maintenance therapy. More patients experienced venous thromboembolism (VTE) of grade 3/4 when thalidomide was added to induction or maintenance therapy (HR 2.15, 95 % CI 1.58-2.92 and RR 1.96, 95 % CI 1.13-3.40, respectively). Induction thalidomide still increased the risk of VTE (RR 1.53, 95 % CI 1.12-2.08) after VTE prophylaxis was used. Induction thalidomide

  13. Renal-protective effect of thalidomide in streptozotocin-induced diabetic rats through anti-inflammatory pathway.

    Science.gov (United States)

    Zhang, Hongxia; Yang, Yanlan; Wang, Yanqin; Wang, Baodong; Li, Rongshan

    2018-01-01

    Diabetic nephropathy (DN) is a major microvascular complication in diabetes. An increasing body of evidence has shown that DN is related to chronic inflammation, kidney hypertrophy, and fibrosis. While thalidomide has been shown to have anti-inflammatory and antifibrotic effects, the effects of thalidomide on the pathogenesis of DN are unclear. This study was undertaken to explore whether thalidomide has renal-protective effects in diabetic rats. Male Sprague Dawley rats were injected intraperitoneally with 50 mg/kg streptozotocin to induce diabetes. Diabetic rats were treated with thalidomide (200 mg/kg/d) for 8 weeks, and then blood and urine were collected for measurement of renal function-related parameters. Histopathology, immunohistochemistry, enzyme-linked immunosorbent assay, and Western blot analyses were performed to assess renal proinflammatory cytokines, fibrotic protein, and related signaling pathways. Diabetic rats exhibited obvious renal structural and functional abnormalities, as well as renal inflammation and fibrosis. Compared with diabetic control rats, those treated with thalidomide showed significantly improved histological alterations and biomarkers of renal function, as well as reduced expression of renal inflammatory cytokines, including NF-κB and MCP-1. Furthermore, renal fibrotic proteins, such as TGF-β1, TβRII, TβRI, smad3, collagen IV, and fibronectin were also remarkably suppressed. Treatment with thalidomide markedly stimulated the phosphorylation of AMPKα. In this study, thalidomide suppressed the inflammatory and fibrotic processes in DN. These effects were partly mediated by the activation of AMPKα, and inhibition of the NF-κB/MCP-1 and TGF-β1/Smad signaling pathways. These results suggest that thalidomide may have therapeutic potential in diabetic renal injury through the anti-inflammatory pathway.

  14. Thalidomide Effects in Patients with Hereditary Hemorrhagic Telangiectasia During Therapeutic Treatment and in Fli-EGFP Transgenic Zebrafish Model.

    Science.gov (United States)

    Peng, Hong-Ling; Yi, Yi-Fang; Zhou, Shun-Ke; Xie, Si-Si; Zhang, Guang-Sen

    2015-11-20

    Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by recurrent epistaxis, mucocutaneous telangiectasia, and arteriovenous malformations. The efficacy of traditional treatments for HHT is very limited. The aim of this study was to investigate the therapeutic role of thalidomide in HHT patients and the effect in FLI-EGFP transgenic zebrafish model. HHT was diagnosed according to Shovlin criteria. Five HHT patients were treated with thalidomide (100 mg/d). The Epistaxis Severity Score (ESS), telangiectasia spots, and hepatic computed tomography angiography (CTA) were used to assess the clinical efficacy of thalidomide. The Fli-EGFP zebrafish model was investigated for the effect of thalidomide on angiogenesis. Dynamic real-time polymerase chain reaction assay, ELISA and Western blotting from patient's peripheral blood mononuclear cells and plasma were used to detect the expression of transforming growth factor beta 3 (TGF-β3) messenger RNA (mRNA) and vascular endothelial growth factor (VEGF) protein before and after 6 months of thalidomide treatment. The average ESS before and after thalidomide were 6.966 ± 3.093 and 1.799 ± 0.627, respectively (P = 0.009). The "telangiectatic spot" on the tongue almost vanished; CTA examination of case 2 indicated a smaller proximal hepatic artery and decreased or ceased hepatic artery collateral circulation. The Fli-EGFP zebrafish model manifested discontinuous vessel development and vascular occlusion (7 of 10 fishes), and the TGF-β3 mRNA expression of five patients was lower after thalidomide therapy. The plasma VEGF protein expression was down-regulated in HHT patients. Thalidomide reverses telangiectasia and controls nosebleeds by down-regulating the expression of TGF-β3 and VEGF in HHT patients. It also leads to vascular remodeling in the zebrafish model.

  15. Measurement of blood pressure in a thalidomide-impaired patient who required ovarian cystectomy: A case report.

    Science.gov (United States)

    Shiga, Yuka; Nojiri, Fumiyo; Yoshizawa, Atsuto; Shimbo, Takuro; Kawachi, Shoji

    2014-01-01

    Thalidomide was available for use over-the-counter between 1958 and 1962, and more than 300 thalidomide-impaired people have been confirmed in Japan. Currently, thalidomide-impaired people are nearing the age of 50 years and sometimes require medical treatment or surgery. However, a sphygmomanometer cannot be used to measure the blood pressure in some thalidomide-impaired people because of upper-limb shortening or hypoplastic defects. We encountered a patient with thalidomide-related upper limb defects who required abdominal ovarian cystectomy. The patient was a 49-year-old woman (146.5cm, 35.9kg) with thalidomide-related upper-limb defects, but no dysplasia of the lower limbs, who underwent abdominal ovarian cystectomy. During the surgery, the patient's arterial blood pressure was monitored in her lower limbs by both non-invasive and invasive methods, and almost the same variations of the blood pressure between the invasive and non-invasive measurements were observed. Usually, blood pressure measurements are performed in a non-invasive manner in the upper limbs, however, such measurement could not be performed in the present case. There are few reports of measurement of the blood pressure or surgery under anaesthesia in thalidomide-impaired patients, and we report here that it was useful to measure the blood pressure in the lower limbs in the current patient. Invasive arterial pressure measurements showed almost the same changes as the non-invasive pressure measurements, although the systolic blood pressure was 10-20mmHg lower than the noninvasively measured systolic blood pressure. Non-invasive blood pressure measurements in the lower limbs might be useful in thalidomide-impaired patients requiring blood pressure monitoring, but further studies are required to validate this method. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

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

    Science.gov (United States)

    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

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

    Directory of Open Access Journals (Sweden)

    Paiva Renata T

    2012-06-01

    Full Text Available Abstract 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.

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

    Science.gov (United States)

    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).

  19. [Inhibitory effect of thalidomide combined with interferon on the proliferation of Kasumi-1 cells].

    Science.gov (United States)

    Xu, Hao; Mi, Ruihua; Fan, Ruihua; Yin, Qingsong; Wang, Xiaojiao; Wei, Xudong

    2015-09-01

    To explore the inhibitory effect of thalidomide combined with interferon (IFN) on the human acute myeloid leukemia cell line Kasumi- 1 and its mechanism. The inhibitiory effect of Kasumi- 1 cells by thalidomide, interferon or combination was detected by CCK- 8 method, the apoptosis by flow cytometry, the expression of apoptosis related proteins by Western blot, vascular endothelial growth factor (VEGF) concentration in culture supernatant by ELISA. Thalidomide inhibited the proliferation of Kasumi- 1 in a dose- dependent manner from 50 μg/ml to 500 μg/ml with an IC₅₀ of (451.13 ± 6.92)μg/ml at 24 h and (362.50 ± 14.52)μg/ml at 48 h. IFN also demonstrated the inhibitory capacity in a dose-dependent manner from 500 U/ml to 5 000 U/ml, with an IC₅₀ of (2 209 ± 127) U/ml at 24 h and (1 393±63) U/ml at 48 h. The apoptosis rates of Kasumi-1 cells treated with thalidomide 350 μg/ml or IFN 1 400 U/ml for 48 h were (14.68 ± 2.61) % and (21.71 ± 0.71)%, respectively, significantly higher than control group (Pthalidomide group [(141.11 ± 3.70) ng/L and IFN group [(119.90 ± 2.00) ng/L (P thalidomide 350 μg/ml or IFN 1 400 U/ml for 48 h. When treated with the combination agents, the expression of Bcl-2 further decreased and p-P38, Bax, cytochrome C, cleaved-Caspase-3, 8, 9 further increased as compared with each single agent (P Thalidomide and IFN could synergistically inhibit the proliferation of Kasumi-1 cells probably through inducing apoptosis via the mitochondrial pathway, death receptor pathway and P38 MAPK pathway, as well as inhibiting VEGF secretion.

  20. Circularly permuted TRAIL plus thalidomide and dexamethasone versus thalidomide and dexamethasone for relapsed/refractory multiple myeloma: a phase 2 study.

    Science.gov (United States)

    Leng, Yun; Hou, Jian; Jin, Jie; Zhang, Mei; Ke, Xiaoyan; Jiang, Bin; Pan, Ling; Yang, Linhua; Zhou, Fang; Wang, Jianmin; Wang, Zhao; Liu, Li; Li, Wei; Shen, Zhixiang; Qiu, Lugui; Chang, Naibai; Li, Jianyong; Liu, Jing; Pang, Hongyan; Meng, Haitao; Wei, Peng; Jiang, Hua; Liu, Yan; Zheng, Xiangjun; Yang, Shifang; Chen, Wenming

    2017-06-01

    Circularly permuted TRAIL (CPT) has exhibited promising efficacy as a mono-therapy or in combination with thalidomide for patients with multiple myeloma (MM). In this phase 2 study, the safety and efficacy of CPT in combination with thalidomide and dexamethasone (CPT + TD) was evaluated in patients with pretreated relapsed/refractory MM (RRMM). Patients who received at least two previous therapies for MM were randomly assigned at a 2:1 ratio to receive treatment with CPT + TD or thalidomide and dexamethasone (TD). The primary endpoint was the overall response rate (ORR), and the secondary endpoints included progression-free survival (PFS), duration of response (DOR) and safety. Overall, 47 patients were assigned to the CPT + TD group, and 24 patients were recruited to the TD group. The ORR in the CPT + TD group was 38.3 vs. 25.0% in the TD group. The median PFS time was 6.7 months for the CPT + TD group and 3.1 months for the TD group. The median DORs for the CPT + TD and TD groups were 7.1 and 3.2 months, respectively. Most of the adverse effects (AEs) were grade 1 or 2. Serious AEs were reported in 19.7% of the patients. No treatment-related deaths were reported. CPT plus TD could serve as a new therapeutic strategy for patients with RRMM. A randomized, double-blind, placebo-controlled confirmatory study is currently under way.

  1. Iron content of skin before and after thalidomide treatment of lepra reaction. A preliminary report.

    Science.gov (United States)

    Sheskin, J; Gorodetsky, R; Weinreb, A; Loewinger, E

    1981-01-01

    THe concentration of copper, zinc and iron in the skin of patients suffering from lepra reaction was measured by diagnostic X-ray spectrometry (DXS) at the sites of the lesions before and after treatment with thalidomide. The results were compared with the levels of these elements in the skin of healthy individuals. No significant changes in the copper level of leprous skin were found. The zinc levels showed significant elevations in some lesions with no apparent trend. The iron level in the affected areas had highly elevated values in all cases of lepra reaction. However, in contrast to the fast clinical improvement which followed the treatment with thalidomide, the iron levels did not decrease for prolonged periods.

  2. Treatment of steroid dependant cases of recurrent lepra reaction with a combination of thalidomide and clofazimine.

    Science.gov (United States)

    Ramu, G; Girdhar, A

    1979-10-01

    22 Adult Male Lepromatous patients suffering from recurrent lepra reaction have been allotted to either a regimen of combined treatment with Clofazimine and Thalidomide alone. The initial dosage of either of the drugs was 300 mg daily administered in divided doses of 100 mg three times a day. The preliminary assessment of the ongoing study, indicates that the combined treatment controls the reactional state more rapidly than monotherapy with Thalidomide alone. Results of treatment as regards relief of neuritis and arthritis are particularly gratifying. Four month.ases relapsed into reactional status from 2 days to 15 days. 5 cases on the combined therapy relapsed from one to three months. Three other cases required six months and three cases 8 months treatment before clofazimine could be withdrawn. It would appear that a maintenance therapy of 6 months with flofazimine would be necessary for maintaining the control of reactional episodes while employing this combined therapy.

  3. Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma

    DEFF Research Database (Denmark)

    Waage, Anders; Gimsing, Peter; Fayers, Peter

    2010-01-01

    In this double-blind, placebo-controlled study, 363 patients with untreated multiple myeloma were randomized to receive either melphalan-prednisone and thalidomide (MPT) or melphalan-prednisone and placebo (MP). The dose of melphalan was 0.25 mg/kg and prednisone was 100 mg given daily for 4 days...... every 6 weeks until plateau phase. The dose of thalidomide/placebo was escalated to 400 mg daily until plateau phase and thereafter reduced to 200 mg daily until progression. A total of 357 patients were analyzed. Partial response was 34% and 33%, and very good partial response or better was 23% and 7...... was markedly increased in the MPT arm. Constipation, neuropathy, nonneuropathy neurologic toxicity, and skin reactions were significantly more frequent in the MPT arm. The number of thromboembolic events was equal in the 2 treatment arms. In conclusion, MPT had a significant antimyeloma effect, but this did...

  4. Mullerian agenesis associated with in-utero thalidomide exposure: A case report

    Directory of Open Access Journals (Sweden)

    Sarah Dotters-Katz

    2013-09-01

    Full Text Available Thalidomide is a well-known teratogen, which is experiencing resurgence as new uses are identified. Exposure is classically associated with limb deformities, such as: dysmelia, phocomelia, preaxial hypoplasia and polydactyly, in addition to visceral anomalies that have been documented as well. We report a case of a 38 year-old nulligravid female, who was previously evaluated for primary amenorrhea, and given the presumptive false diagnosis of an imperforate hymen. On magnetic resonance imaging (MRI exam, she was noted to have uterovaginal agenesis. The implications of thalidomide on women’s health extend beyond external birth defects. Although, most commonly associated with limb deformities, there may also be gynecologic implications of in utero exposure. As this medication is increasingly used for various medical conditions, obstetricians/gynecologists need to remain aware of this potential mullerian teratogenic effect.

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

    Science.gov (United States)

    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.

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

    OpenAIRE

    Lachmann, P.J.

    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 cos...

  7. Phase I trial of metastatic renal cell carcinoma with oral capecitabine and thalidomide

    Directory of Open Access Journals (Sweden)

    Brossart, Peter

    2009-06-01

    Full Text Available Background: The highly vascular nature of renal carcinoma cells suggests that inhibition of angiogenesis may be beneficial in this disease. Thalidomide has been described as inhibitor of the fibroblast growth factor (FGF and the vascular endothelial growth factor (VEGF. Therefore and in consideration of the promising response rates of the combination of IL-2, IFN-alpha and 5-FU [1] in metastatic renal cancer, we found it reasonable to test the combination of 5-FU and thalidomide. Thus, we conducted a phase I trial to determine safety, side effects and responses to such a treatment. Methods: Patients with metastasized renal cell cancer after nephrectomy and progress after IL-2 and interferon treatment, received oral 5-FU at a dose of 1250 mg/qm2 twice a day for two weeks, then after pausing a week, the oral application was restarted. In addition, oral thalidomide was applied constantly at a maximum dose of 400 mg/d. The combined therapy was given for three months. The primary endpoint was duration until disease progression, the secondary endpoint the response to treatment. Response was determined by CT scans three months after the end of treatment. Results: In total, 12 male patients participated in the trial and received the combined oral therapy. Concerning clinical response, one mixed response (8%, a stable disease in 4/12 patients (33% and progression was seen in 7 patients (58%. The survival from the start of the therapy showed a median of 21 months with three patients being alive. At present, the longest survival after the therapy is 51 months. Conclusions: The combination of oral 5-FU and thalidomide showed clinical response with tolerable side effects. Further studies will be required to assess the outcome of this treatment regimen.

  8. Pharmacovigilance of patients with multiple myeloma being treated with bortezomib and/or thalidomide

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    T.B.M. Castro

    2016-01-01

    Full Text Available In order to evaluate the main adverse effects of drug protocols using bortezomib and/or thalidomide for the treatment of multiple myeloma, we conducted a prospective study. Data were collected through interviews, clinical observation, and from hospital records. A total of 59 patients were included. There was a predominance of females, 36 (61% vs 23 (39% males, and of whites, 49 (83.1% vs 10 (16.9% blacks. Age ranged from 40 to 94 years, with a median of 65 years (SD=11.6. Regarding staging at diagnosis, 27 (45.7% patients were in stage III-A, with 12 (20.3% patients having serum creatinine ≥2 mg/dL. The main adverse effects in the bortezomib treatment group (n=40 were: neutropenia (42.5%, diarrhea (47.5%, and peripheral neuropathy in 60% of cases, with no difference between the iv (n=26 and sc (n=14 administration routes (P=0.343. In the group treated with thalidomide (n=19, 31.6% had neutropenia, 47.4% constipation, and 68.4% peripheral neuropathy. Neutropenia was associated with the use of alkylating agents (P=0.038. Of the 3 patients who received bortezomib in combination with thalidomide, only 1 presented peripheral neuropathy (33.3%. Peripheral neuropathy was the main adverse effect of the protocols that used bortezomib or thalidomide, with a higher risk of neutropenia in those using alkylating agents. Improving the identification of adverse effects is critical in multiple myeloma patient care, as the patient shows improvements during treatment, and requires a rational and safe use of medicines.

  9. Absence of significant adverse events following thalidomide administration in bitches diagnosed with mammary gland carcinomas.

    Science.gov (United States)

    de Campos, C B; Lavalle, G E; Fialho Ligório, S; Camargo Nunes, F; Carneiro, R A; Amorim, R L; Cassali, G D

    2016-11-19

    The aim of the study was to evaluate the incidence of adverse events (AEs) in female dogs diagnosed with advanced clinical stage mammary gland neoplasms following treatment with thalidomide. A prospective analysis of 29 female dogs treated with a high dose (HD) of 20 mg/kg/day of thalidomide for three months followed by a low dose (LD) of 10 mg/kg/day of thalidomide for three months was performed. All patients underwent physical examination, complete blood count, serum biochemistry profile, thoracic radiographs, and abdominal ultrasound analysis before the treatment and after the HD and LD. Clinical AEs were absent in 16/29 (55.17 per cent) patients following HD. An initial 3-5 day period of somnolence was described in 4/29 (13.79 per cent), prolonged somnolence in 5/29 (17.24 per cent), a short period of somnolence lasting only a few hours in 3/29 (10.34 per cent), and difficulty to rouse was described in 5/29 (17.24 per cent) cases. Two patients (6.89 per cent) presented with prolonged somnolence that interfered with activities of daily living, resulting in anticipation of the dose reduction to the proposed LD after 15 days of the HD treatment. Following dose reduction, AE improvement was observed in all patients. Albeit remaining within the reference ranges, erythrocytes, haematocrit, total leucocyte count, neutrophils, lymphocytes, monocytes and γ-glutamyltranspeptidase showed significant alteration associated to thalidomide treatment. British Veterinary Association.

  10. Identification of a thalidomide derivative that selectively targets tumorigenic liver progenitor cells and comparing its effects with lenalidomide and sorafenib.

    Science.gov (United States)

    Woo, Ken; Stewart, Scott G; Kong, Geraldine S; Finch-Edmondson, Megan L; Dwyer, Benjamin J; Yeung, Sing Y; Abraham, Lawrence J; Kampmann, Sven S; Diepeveen, Luke A; Passman, Adam M; Elsegood, Caryn L; Tirnitz-Parker, Janina E E; Callus, Bernard A; Olynyk, John K; Yeoh, George C T

    2016-09-14

    The availability of non-tumorigenic and tumorigenic liver progenitor cell (LPC) lines affords a method to screen putative anti-liver cancer agents to identify those that are selectively effective. To prove this principle we tested thalidomide and a range of its derivatives and compared them to lenalidomide and sorafenib, to assess their growth-inhibitory effects. Cell growth, the mitotic and apoptotic index of cell cultures were measured using the Cellavista instrument (SynenTec) using commercially available reagents. Neither lenalidomide nor thalidomide (100 μM) affected tumorigenic LPCs but killed their non-tumorigenic counterparts. Sorafenib arrested growth in both cell types. All but two derivatives of thalidomide were ineffective; of the two effective derivatives, one (thalidomide C1) specifically affected the tumorigenic cell line (10 μM). Mitotic and apoptotic analyses revealed that thalidomide C1 induced apoptotic cell death and not mitotic arrest. This study shows that screens incorporating non-tumorigenic and tumorigenic liver cell lines are a sound approach to identify agents that are effective and selective. A high throughput instrument such as the Cellavista affords robust and reproducible objective measurements with a large number of replicates that are reliable. These experiments show that neither lenalidomide nor thalidomide are potentially useful for anti-liver cancer therapy as they kill non-tumorigenic liver cells and not their tumorigenic counterparts. Sorafenib in contrast, is highly effective, but not selective. One tested thalidomide derivative has potential as an anti-tumor drug since it induced growth arrest; and importantly, it selectively induced apoptotic cell death only in tumorigenic liver progenitor cells. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  11. Thalidomide Increases Human Hepatic Cytochrome P450 3A Enzymes by Direct Activation of Pregnane X Receptor

    Science.gov (United States)

    Suemizu, Hiroshi; Guillouzo, Christiane Guguen; Shibata, Norio; Yajima, Kanako; Utoh, Masahiro; Shimizu, Makiko; Chesné, Christophe; Nakamura, Masato; Guengerich, F. Peter; Houtman, René; Yamazaki, Hiroshi

    2014-01-01

    Heterotropic cooperativity of human cytochrome P450 (P450) 3A4/3A5 by the teratogen thalidomide was recently demonstrated by H. Yamazaki et al. (2013) using the model substrate midazolam in various in vitro and in vivo models. Chimeric mice with humanized liver also displayed enhanced midazolam clearance upon pre treatment with orally administered thalidomide, presumably because of human P450 3A induction. In the current study, we further investigated the regulation of human hepatic drug metabolizing enzymes. Thalidomide enhanced levels of P450 3A4 and 2B6 mRNA, protein expression, and/or oxidation activity in human hepatocytes, indirectly suggesting activation of upstream transcription factors involved in detoxication, e.g. the nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR). A key event after ligand binding is an alteration of nuclear receptor conformation and recruitment of co regulator proteins that alter chromatin accessibility of target genes. To investigate direct engagement and functional alteration of PXR and CAR by thalidomide, we utilized a peptide microarray with 154 co regulator derived nuclear receptor interaction motifs and co regulator and nuclear receptor boxes, which serves as a sensor for nuclear receptor conformation and activity status as a function of ligand. Thalidomide and its human proximate metabolite 5 hydroxythalidomide displayed significant modulation of co regulator interaction with PXR and CAR ligand binding domains, similar to established agonists for these receptors. These results collectively suggest that thalidomide acts as a ligand for PXR and CAR and causes enzyme induction leading to increased P450 enzyme activity. The possibilities of drug interactions during thalidomide therapy in humans require further evaluation. PMID:24460184

  12. Improvement of Anaemia in Patients with Primary Myelofibrosis by Low-Dose Thalidomide and Prednisone.

    Science.gov (United States)

    Bělohlávková, Petra; Maisnar, Vladimír; Voglová, Jaroslava; Buchler, Tomáš; Žák, Pavel

    A combination of low-dose thalidomide and corticosteroids is a treatment option for anaemic patients with primary myelofibrosis (PMF) who are not eligible for allogeneic hematopoietic stem cell transplantation. We describe the outcomes of 13 patients with PMF treated with thalidomide 50 mg daily in combination with prednisone 0.5 mg/kg daily. Treatment responses were seen in 10/13 (77%) patients with a median onset of therapeutic effect at 4 weeks (range 3-7 weeks) after treatment initiation. Improvements of anaemia and thrombocytopenia and reduction in splenomegaly were observed in 70%, 38%, and 30% of patients, respectively. Four of six initially transfusion-dependent patients became transfusion independent following the therapy. The median duration of treatment response was 18 months (range 3-35 months). The treatment was well tolerated, with only one patient discontinuing therapy due to toxicity. Responders included both patients with and without JAK2 V617F, and included patients with both newly diagnosed and longstanding PMF. Our retrospective analysis confirmed that the therapy with low-doses thalidomide with prednisone in patients with PMF achieves significant response rate in anaemia with low treatment toxicity.

  13. Immunomodulatory treatment with thalidomide in experimental leptospirosis in Golden Syrian hamsters (Mesocricetus auratus).

    Science.gov (United States)

    Soares, Luciane Marieta; Macedo, Julio Oliveira; de Azevedo, Everton Cruz; Santos, Cleiton Silva; Sampaio, Marina de Queiroz; dos Santos, Andréia Carvalho; dos Reis, Mitermayer Galvão; Athanazio, Daniel Abensur

    2014-02-01

    The benefit of antibiotics in leptospirosis is limited when treatment is started four days after symptoms appear, and new adjuvant therapeutic options are urgently needed. Hamsters (Mesocricetus auratus) were infected by Leptospira interrogans strain L1-130, and groups were assigned based on no treatment (NONE), thalidomide only (TAL), ampicillin only (AMP) or both (AMP-TAL). Treatment was started two days after the onset of symptoms (experiment 1) and immediately after detection of the first death (experiment 2). Experiment 1: all hamsters from the groups AMP and AMP-TAL survived (n=8), while all hamsters from groups NONE (n=6) and TAL (n=8) died. The AMP and the AMP-TAL groups showed no renal or liver pathology and absent or very low leptospiral burden in target organs. Experiment 2: lethal outcome was observed in 6/6 hamsters in the NONE group, 8/8 in the TAL group, and 6/8 in both the AMP and AMP-TAL groups. Thalidomide showed no survival benefit when compared to hamsters treated with ampicillin alone. The TAL, AMP and AMP-TAL groups had very low tissue leptospiral counts. Thalidomide had minimal impact on survival in the late treatment of leptospirosis hamster model.

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

    Science.gov (United States)

    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

  15. Vascular endothelial growth factor (VEGF) gene polymorphisms may influence the efficacy of thalidomide in multiple myeloma

    DEFF Research Database (Denmark)

    Andersen, Niels Frost; Vogel, Ulla Birgitte; Klausen, Tobias W

    2012-01-01

    and prognosis. In this study, we evaluated the association between genetic variations in the VEGF gene in patients with multiple myeloma and time to treatment failure (TTF) after high-dose melphalan and stem cell support (HDT), overall survival (OS) and efficacy of the anti-angiogenic drug thalidomide....... Retrospectively, the SNPs -2,578C>A (rs699947), -460C>T (rs833061), +405G>C (rs2010963) and +936C>T (rs3025039) in the VEGF gene were examined in 348 patients with newly diagnosed multiple myeloma initially treated with HDT, where 176 patients were treated with thalidomide at relapse. None of the examined geno......- or haplotypes was associated with differences in TTF after initial therapy or OS. A possible relation between the haplotype -2,578A/-460C/+405G (ACG) and effect of thalidomide was seen. Patients with no copies of the haplotype ACG had a longer time to next treatment than patients with one or two copies...

  16. Thalidomide Embryopathy as Possible Cause of Anterior Sacral Meningocele: A Case Report.

    Science.gov (United States)

    Croci, Davide Marco; Dalolio, Martina; Schaeren, Stefan; Wasner, Morten G; Mariani, Luigi; Jost, Gregory F

    2017-10-16

    A 54-year-old male presented with a sudden burning sensation during urination and left flank pain. Apart from having congenital facial palsy and malformation of the inner right ear that was linked to thalidomide embryopathy, the patient has always been in good health. Urine examination showed the presence of a urinary tract infection. An abdominal ultrasound revealed a large cyst in the lower abdomen, which on MRI corresponded to a large anterior sacral meningocele (ASM) with sacral agenesis at S1/S2. After antibiotic treatment and the spontaneous passage of a kidney stone, the symptoms resolved. This suggests that the patient's acute symptoms were caused by the urolithiasis and not the ASM. Thalidomide is teratogenic between days 17 and 30 after conception. The neural tube closes between days 20 and 36, therefore, thalidomide embryopathy was the possible cause of ASM in this patient. Birth Defects Research 109:1390-1392, 2017.© 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  17. Thalidomide suppresses Up-regulation of human immunodeficiency virus coreceptors CXCR4 and CCR5 on CD4+ T cells in humans

    NARCIS (Netherlands)

    Juffermans, N. P.; Verbon, A.; Olszyna, D. P.; van Deventer, S. J.; Speelman, P.; van der Poll, T.

    2000-01-01

    Concurrent infection in patients with human immunodeficiency virus (HIV) infection increases the expression of HIV coreceptors CXCR4 and CCR5. Thalidomide has beneficial effects in a number of HIV-associated diseases. The effect of thalidomide on CXCR4 and CCR5 expression on CD4+ T cells was

  18. Thalidomide is Associated With Increased T Cell Activation and Inflammation in Antiretroviral-naive HIV-infected Individuals in a Randomised Clinical Trial of Efficacy and Safety

    Directory of Open Access Journals (Sweden)

    Tânia R.C. Vergara

    2017-09-01

    Conclusions: Short-term use of thalidomide led to an intense transient increase in T cell activation and inflammation, with a decrease in the CD4+ cell count without changes to the CD8+ cell count. We confirmed that thalidomide acts in vitro as a latency reversal agent and speculate that the in vivo results obtained were due to an increase in HIV replication.

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

    Science.gov (United States)

    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

  20. Renal-protective effect of thalidomide in streptozotocin-induced diabetic rats through anti-inflammatory pathway

    Directory of Open Access Journals (Sweden)

    Zhang H

    2018-01-01

    Full Text Available Hongxia Zhang,1 Yanlan Yang,2 Yanqin Wang,1 Baodong Wang,1 Rongshan Li1 1Department of Nephrology, 2Department of Endocrinology, Affiliated People’s Hospital of Shanxi Medical University, Shanxi Provincial People’s Hospital, Taiyuan, Shanxi, People’s Republic of China Background: Diabetic nephropathy (DN is a major microvascular complication in diabetes. An increasing body of evidence has shown that DN is related to chronic inflammation, kidney hypertrophy, and fibrosis. While thalidomide has been shown to have anti-inflammatory and antifibrotic effects, the effects of thalidomide on the pathogenesis of DN are unclear. This study was undertaken to explore whether thalidomide has renal-protective effects in diabetic rats.Methods: Male Sprague Dawley rats were injected intraperitoneally with 50 mg/kg streptozotocin to induce diabetes. Diabetic rats were treated with thalidomide (200 mg/kg/d for 8 weeks, and then blood and urine were collected for measurement of renal function-related parameters. Histopathology, immunohistochemistry, enzyme-linked immunosorbent assay, and Western blot analyses were performed to assess renal proinflammatory cytokines, fibrotic protein, and related signaling pathways.Results: Diabetic rats exhibited obvious renal structural and functional abnormalities, as well as renal inflammation and fibrosis. Compared with diabetic control rats, those treated with thalidomide showed significantly improved histological alterations and biomarkers of renal function, as well as reduced expression of renal inflammatory cytokines, including NF-κB and MCP-1. Furthermore, renal fibrotic proteins, such as TGF-β1, TβRII, TβRI, smad3, collagen IV, and fibronectin were also remarkably suppressed. Treatment with thalidomide markedly stimulated the phosphorylation of AMPKα.Conclusion: In this study, thalidomide suppressed the inflammatory and fibrotic processes in DN. These effects were partly mediated by the activation of AMPK

  1. Synthesis and evaluation of 4-[F-18]fluoro thalidomide for the in vivo studies of angiogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Kim, D. H.; Choi, Y. S.; Jeong, K. H.; Lee, K. H.; Choi, Y.; Kim, B. T. [Samsung Medical Center, Seoul (Korea, Republic of)

    2005-07-01

    Thalidomide has been recently rediscovered for its possible utility as an antitumor agent, although it was marketed as a sedative in the 1950s and later found to be a potent teratogen. In this study, therefore, F-18 labeled thalidomide was synthesized and evaluated for the in vivo studies of angiogenesis. 4-[F-18]Fluoro thalidomide ([F-18]1) was prepared by labeling of 4-trimethylammonium thalidomide triflate with TBA[F-18]F in DMSO (90 .deg. C, 10 min) and purified by HPLC. The triflate salt was prepared from 3-fluoro phthalic anhydride in 3 steps. [F-18]1 was incubated with HUVEC cells at 37 .deg. C for 15, 30, 60, and 120 min, respectively. Dynamic PET images of [F-18]1 was obtained in mice implanted with LLC cells. In vitro metabolism study of [F-18]1 was carried out using mouse, rabbit, or human liver microsomes in the presence of NADPH, and the metabolites obtained from the mouse liver microsomal incubation of 1 were analyzed using LC-MS. Radiochemical yield of [F-18]1 was 50-60%, and the specific activity was 42-120 GBq/imol. The HUVEC cell uptake of [F-18]1 increased with time (100% at 15 min and 241% at 120 min). PET images showed that the radioactivity was accumulated in the liver, the kidneys and the bladder of the mice, and brain uptake was shown from 40 min postinjection. However, there was low level of radioactivity uptake in tumor. [F-18]1 was not metabolized by mouse, rabbit, or human liver microsomes but was hydrolyzed significantly at physiological pH. The hydrolyzed product was further analyzed by LC-MS, showing a mass peak corresponding to that of 4-fluoro-N-(o-carboxybenzoyl)glutamic acid imide. This result suggests that [F-18]1 is easily hydrolyzed at physiological pH and thus may not be suitable for the in vivo studies of tumor angiogenesis at least in rodents, although it was reported that the hydrolysis product of thalidomide may be responsible for its angiogenesis activity in humans.

  2. A Mini-Review on Thalidomide: Chemistry, Mechanisms of Action, Therapeutic Potential and Anti-Angiogenic Properties in Multiple Myeloma.

    Science.gov (United States)

    Mercurio, Annalisa; Adriani, Giulia; Catalano, Alessia; Carocci, Alessia; Rao, Luigia; Lentini, Giovanni; Cavalluzzi, Maria M; Franchini, Carlo; Vacca, Angelo; Corbo, Filomena

    2017-01-01

    Thalidomide is a drug with interesting therapeutic properties but also with severe side effects which require a careful and monitored use. Potential immunomodulatory, antiinflammatory, anti-angiogenic and sedative properties make thalidomide a good candidate for the treatment of several diseases such as multiple myeloma. Through an increase in the degradation of TNFα-mRNA, thalidomide reduces the production of TNFα by monocytes and macrophages stimulated by lipopolysaccharide or by T lymphocytes induced by mitogenic stimuli. The decreased level of TNFα alters the mechanisms of intracellular transduction by preventing the activation of NF-kB and by decreasing the synthesis of proteins, in particular IL-6, involved in cell proliferation, inflammation, angiogenesis and protection from apoptosis. Furthermore, thalidomide affects VEGF levels by down-regulating its expression. Nowadays, new safer and less toxic drugs, analogs of thalidomide, are emerging as beneficial for a more targeted treatment of multiple myeloma and several other diseases such as Crohn';s disease, rheumatoid arthritis, sarcoidosis, erythema nodosum leprosum, graft-versus-host disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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

    Science.gov (United States)

    Stommel, Elijah W; Cohen, Jeffrey A; Fadul, Camilo E; Cogbill, Christopher H; Graber, David J; Kingman, Linda; Mackenzie, Todd; Channon Smith, Jacqueline Y; Harris, Brent T

    2009-01-01

    Neuroinflammation through the cytokine, tumor necrosis factor-alpha (TNF-alpha) 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-alpha 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-alpha inhibitor, thalidomide, does not appear to effectively modulate disease progression and can cause adverse effects.

  4. Effects of systemic Thalidomide and intracerebroventricular Etanercept and Infliximab administration in a Streptozotocin induced dementia model in rats.

    Science.gov (United States)

    Kübra Elçioğlu, H; Kabasakal, Levent; Tufan, Fatih; Elçioğlu, Ömer H; Solakoglu, Seyhun; Kotil, Tugba; Karan, Mehmet Akif

    2015-03-01

    Tumor necrosis factor-alpha (TNF-α) upregulation enhances amyloid β (Aβ) induced neurotoxicity in Alzheimer's disease (AD). Intracerebroventricular streptozotocin (STZ) administration causes pathological changes and cognitive deficits similar to those seen in AD by causing impairment of brain glucose and energy metabolism. Recent reports indicate a protective role of Thalidomide, Etanercept, and Infliximab, all of which have anti-TNF-α activity, against cognitive and neuropathological changes in experimental and clinical studies. We aimed to investigate the protective effects of Thalidomide, Etanercept, and Infliximab in a rat model of intracerebroventricular STZ-induced dementia. Sprague-Dawley rats (250-300g) were separated to sham (n=6) and STZ (n=24) groups. The STZ group was divided into four groups (STZ, STZ-thalidomide, STZ-etanercept, and STZ-infliximab). Morris's water maze (MWM) and passive avoidance (PA) tests were performed. At the end of the third week, brain tissues were obtained. Histopathological analysis, immunohistochemistry, and electron microscopic examinations were done. The improvement performance of the STZ group was significantly reduced in the MWM test (pthalidomide, STZ-etanercept, and STZ-infliximab groups had significantly better performance (pThalidomide, Etanercept, and Infliximab were associated with better PA reflexes compared to the STZ group (pThalidomide. Copyright © 2015 Elsevier GmbH. All rights reserved.

  5. Double-blind trial of the efficacy of pentoxifylline vs thalidomide for the treatment of type II reaction in leprosy

    Directory of Open Access Journals (Sweden)

    A.M. Sales

    2007-02-01

    Full Text Available Type II reaction in leprosy, or erythema nodosum leprosum (ENL, is often characterized by severe clinical symptoms together with nerve function impairment leading to permanent disabilities. Thalidomide has been shown to be a highly effective drug for the treatment of ENL. It is, however, contraindicated for women of childbearing age due to its teratogenicity. On the other hand, pentoxifylline, used to treat hypercoagulable states, is not teratogenic and, like thalidomide, can inhibit the synthesis of tumor necrosis factor-a and other cytokines. In the present randomized double-blind clinical study we compared the effectiveness of orally administered pentoxifylline vs thalidomide in treating type II reaction in 44 patients. Daily doses of 300 mg thalidomide or 1.2 g pentoxifylline were administered for 30 days to multibacillary leprosy patients undergoing type II reaction. Randomly chosen patients were included in the study before, during, and after specific multidrug therapy. Clinical evaluations were performed on the 1st, 7th, 14th, 21st, and 30th days of treatment and laboratory tests were carried out on the 1st and 30th days. As expected, overall, thalidomide proved to be more effective in the treatment of type II leprosy reaction. Nevertheless, continuous treatment with pentoxifylline was effective in relieving the clinical signs of ENL, especially limb edema and systemic symptoms, in 62.5% of the patients.

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

    Science.gov (United States)

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

    2016-03-23

    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.

  7. Clinical use and control of the dispensing of thalidomide in Brasilia-Federal District, Brazil, from 2001 to 2012

    Directory of Open Access Journals (Sweden)

    Francisco José Roma Paumgartten

    2013-11-01

    Full Text Available The use of thalidomide was never discontinued in Brazil where it is prescribed for leprosy type 2 reaction. Babies with birth defects compatible with the thalidomide embryopathy phenotype were born after 1965, an indication that control on drug dispensing and use failed in the country. The article reports data on thalidomide dispensing and clinical uses in the Federal District in 2011/12, when new rules were put into effect, and data on drug dispensing and use obtained ten years earlier. It was found that the number of patients making use of thalidomide declined from 819 in 2001 to 369 in 2011/12. Leprosy accounted for over 70% of prescriptions in both time periods analyzed in this study. In the same time interval, however, use for lupus erythematosus decreased from 13.7 to 4.9%, while that for multiple myeloma increased from 2.9 to 20.3% of all prescriptions. Thalidomide prescription for the remaining approved indications was far less frequent, and so was the use for off label indications that accounted for <1% of prescriptions in 2001 and 2011/12. Registration of prescribing doctors, patients and dispensing units at the state department of health, apparently rendered this control more effective and reliable.

  8. Simulation of Human Plasma Concentrations of Thalidomide and Primary 5-Hydroxylated Metabolites Explored with Pharmacokinetic Data in Humanized TK-NOG Mice.

    Science.gov (United States)

    Nishiyama, Sayako; Suemizu, Hiroshi; Shibata, Norio; Guengerich, F Peter; Yamazaki, Hiroshi

    2015-11-16

    Plasma concentrations of thalidomide and primary 5-hydroxylated metabolites including 5,6-dihydroxythalidomide and glutathione (GSH) conjugate(s) were investigated in chimeric mice with highly "humanized" liver cells harboring cytochrome P450 3A5*1. Following oral administration of thalidomide (100 mg/kg), plasma concentrations of GSH conjugate(s) of 5-hydroxythalidomide were higher in humanized mice than in controls. Simulation of human plasma concentrations of thalidomide were achieved with a simplified physiologically based pharmacokinetic model in accordance with reported thalidomide concentrations. The results indicate that the pharmacokinetics in humans of GSH conjugate and/or catechol primary 5-hydroxylated thalidomide contributing in vivo activation can be estimated for the first time.

  9. Effect of Thalidomide on Clinical Remission in Children and Adolescents with Ulcerative Colitis Refractory to Other Immunosuppressives: Pilot Randomized Clinical Trial.

    Science.gov (United States)

    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

    2015-08-01

    In a randomized controlled trial, thalidomide has shown to be effective in refractory Crohn's disease in children. This pilot study aimed at evaluating thalidomide in refractory pediatric ulcerative colitis (UC). Double-blind, placebo-controlled randomized clinical trial on thalidomide 1.5 to 2.5 mg/kg/day in children with active UC despite multiple immunosuppressive treatments. In an open-label extension, nonresponders to placebo received thalidomide for an additional 8 weeks; all responders were followed up for a minimum of 52 weeks. Twenty-six children with refractory UC were randomized to thalidomide or placebo. Clinical remission at week 8 was achieved by significantly more children treated with thalidomide {10/12 (83.3%) versus 2/11 (18.8%); risk ratio, 4.5 (95% confidence interval [CI], 1.2-16.4); P = 0.005; number needed to treat, 1.5}. Of the nonresponders to placebo who were switched to thalidomide, 8 of 11 (72.7%) subsequently reached remission at week 8 (risk ratio, 4.0 [95% CI, 1.1-14.7]; number needed to treat, 2.45; P = 0.01). Clinical remission in the thalidomide group was 135.0 weeks (95% CI, 32-238), compared with 8.0 weeks (95% CI, 2.4-13.6) in the placebo group (P thalidomide compared with placebo resulted in improved clinical remission at 8 weeks of treatment and in longer term maintenance of remission. These findings require replication in larger clinical studies evaluating both thalidomide efficacy and safety.

  10. Thalidomide dramatically improves the symptoms of early-onset sarcoidosis/Blau syndrome: its possible action and mechanism.

    Science.gov (United States)

    Yasui, Kozo; Yashiro, Masato; Tsuge, Mitsuru; Manki, Akira; Takemoto, Kei; Yamamoto, Michiko; Morishima, Tsuneo

    2010-01-01

    Early-onset sarcoidosis (EOS), which occurs in children younger than 5 years of age, is associated with granulomatous lesions and a sporadic genetic mutation of the nucleotide-binding oligomerization domain 2 that causes constitutive NF-kappaB activation. The symptoms of EOS can be uncontrollable, progressive, and associated with profound complications. However, appropriate therapy is still under investigation. The aim of this study was to assess the efficacy of thalidomide in patients with severe EOS, based on etiology supporting an initial role of NF-kappaB in activation of this disease. Thalidomide was given to 2 patients with EOS (a 16-year-old girl and an 8-year-old boy) at an initial dosage of 2 mg/kg/day, and the dosage was increased if necessary. To elucidate the mechanism of the drug, peripheral blood monocytes were isolated from the patients and stimulated with cytokines (macrophage colony-stimulating factor, tumor necrosis factor alpha, and interleukin-4), and their ability to form multinucleated giant cells (MGCs) and osteoclasts was measured. Both patients showed dramatic improvement of their clinical symptoms (alleviation of fever and optic nerve papillitis, achievement of a response according to the American College of Rheumatology Pediatric 50 and Pediatric 70 criteria) and laboratory findings. Monocytes from patients with EOS had a greater ability to survive and induce MGCs and osteoclasts than those from healthy control subjects. The formation of MGCs and osteoclasts was inhibited by the presence of thalidomide. The ability of thalidomide to improve clinical symptoms and laboratory findings in patients with EOS indicates a central role for NF-kappaB activity in this disorder. Inhibition of IKK might be a pharmacologic action by which thalidomide down-regulates NF-kappaB signaling. Thalidomide may be an effective medication in patients with severe complications of EOS, including ocular involvement.

  11. Relaxant and anti-inflammatory effect of two thalidomide analogs as PDE-4 inhibitors in pregnant rat uterus

    Science.gov (United States)

    Muñoz-Pérez, Víctor Manuel; Ponce-Monter, Héctor; Ortiz, Mario I.

    2017-01-01

    The aim of this study was to evaluate the relaxant and anti-inflammatory effects of two thalidomide analogs as phosphodiesterase-4 (PDE-4) inhibitors in pregnant rat uterus. Uteri from Wistar female rats were isolated at 19 day of pregnancy. Uterine samples were used in functional studies to evaluate the inhibitory effects of the thalidomide analogs, methyl 3-(4-nitrophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4NO2PDPMe) and methyl 3-(4-aminophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4APDPMe), on prostaglandin-F2α (PGF2α)-induced phasic, K+-induced tonic, and Ca2+-induced contractions. Accumulation of cAMP was quantified in uterine homogenates by ELISA. Anti-inflammatory effect was assessed by using ELISA for determination of the pro-inflammatory cytokines tumor necrosis factor-α (TNFα) and interleukin (IL)-1β, and anti-inflammatory IL-10, from uterine explants stimulated with lipopolysaccharide (LPS). Nifedipine, forskolin and rolipram were used as positive controls where required. Both thalidomide analogs induced a significant inhibition of the uterine contractions induced by the pharmaco- and electro-mechanic stimuli. Nifedipine and forskolin were more potent than the analogs to inhibit the uterine contractility, but these were more potent than rolipram, and 4APDPMe was equieffective to nifedipine. Thalidomide analogs increased uterine cAMP-levels in a concentration-dependent manner. The LPS-induced TNFα and IL-1β uterine secretion was diminished in a concentration-dependent fashion by both analogs, whereas IL-10 secretion was increased significantly. The thalidomide analogs induced utero-relaxant and anti-inflammatory effects, which were associated with the increased cAMP levels as PDE-4 inhibitors in the pregnant rat uterus. Such properties place these thalidomide analogs as potentially safe and effective tocolytic agents in a field that urgently needs improved pharmacological treatments, as in cases of preterm labor. PMID:28706457

  12. Thalidomide-based Regimens for Elderly and/or Transplant Ineligible Patients with Multiple Myeloma: A Meta-analysis.

    Science.gov (United States)

    Lyu, Wen-Wen; Zhao, Qing-Chun; Song, De-Hai; Zhang, Jin-Jie; Ding, Zhao-Xing; Li, Bao-Yuan; Wei, Chuan-Mei

    2016-02-05

    Thalidomide is an immunomodulatory and anti-angiogenic drug that has shown promise in patients with myeloma. Trials comparing efficacy of standard melphalan and prednisone (MP) therapy with MP plus thalidomide (MPT) in transplant-ineligible or elderly patients with multiple myeloma (MM) have provided conflicting evidence. This meta-analysis aimed to determine the efficacy and toxicity of thalidomide in previously untreated elderly patients with myeloma. Medline, the Cochrane Controlled Trials register, conference proceedings of the American Society of Hematology (1995-2014), the American Society of Clinical Oncology (1995-2014), and CBM, VIP, and CNKI databases were searched for randomized control trials with the use of the medical subject headings "MM " and "thalidomide ". Trials were assessed by two reviewers for eligibility. Meta-analysis was conducted using a fixed effects model. Sensitivity analysis was performed to test the robustness of the findings. Overall, seven trials were identified, covering a total of 1821 subjects. The summary hazard ratio (thalidomide vs. control) was 0.82 (95% confidence interval [CI]: 0.72-0.94) for overall survival (OS), and 0.65 (95% CI: 0.58-0.73) for progression-free survival, in favor of thalidomide treated group. The risk ratio of complete response with induction thalidomide was 3.48 (95% CI: 2.24-5.41). A higher rate of III/IV adverse events were observed in MPT arm compared with the MP arm. However, analysis of sub-groups administering anticoagulation as venous thromboembolism prophylaxis suggested no difference in relative risk of thrombotic events between two arms (RR = 1.47, 95% CI: 0.43-5.07, P = 0.54). Further analysis of trials on the treatment effects of MPT versus MP on adverse events-related mortality showed no statistical difference between two arms (RR = 1.24, 95% CI: [0.95-1.63], P = 0.120). Thalidomide appears to improve the OS of elderly and/or transplant-ineligible patients with MM when it is added to

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

    Science.gov (United States)

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

    2015-03-24

    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.

  14. Immunomodulatory intervention in sepsis by multidrug-resistant Pseudomonas aeruginosa with thalidomide: an experimental study

    Directory of Open Access Journals (Sweden)

    Perrea Despina

    2005-06-01

    Full Text Available Abstract Background Thalidomide is an inhibitor of tumour necrosis factor-alpha (TNFα that has been proven effective for the treatment of experimental sepsis by Escherichia coli. It was tested whether it might behave as an effective immunomodulator in experimental sepsis by multidrug-resistant (MDR Pseudomonas aeruginosa. Methods Sepsis was induced by the intraperitoneal injection of 1 × 108 cfu/kg inoculum of the test isolate in a total of 109 Wistar rats divided in three groups as follows: group A controls; group B administered seed oil 30 minutes before bacterial challenge; and group C administered 50 mg/kg of thalidomide diluted in seed oil 30 minutes before bacterial challenge. Blood was sampled for estimation of endotoxins (LPS, TNFα, interferon-gamma (IFNγ, nitric oxide (NO and malondialdehyde (MDA. LPS was measured by the QCL-1000 LAL assay, TNFα and IFNγ by ELISA, NO by a colorimetric assay and MDA by the thiobarbiturate assay. Results Mean (± SE survival of groups A, B and C were 18.60 ± 1.84, 12.60 ± 0.60 and 30.50 ± 6.62 hours (p of comparisons A to C equal to 0.043 and B to C equal to 0.002. Decreased TNFα and NO levels were found in sera of animals of group C compared to group A. Plasma levels of LPS, MDA and IFNγ did not differ between groups. Conclusion Intake of thalidomide considerably prolonged survival in experimental sepsis by MDR P.aeruginosa an effect probably attributed to decrease of serum TNFα.

  15. Anticancer effects of novel thalidomide analogs in A549 cells through inhibition of vascular endothelial growth factor and matrix metalloproteinase-2.

    Science.gov (United States)

    El-Aarag, Bishoy; Kasai, Tomonari; Masuda, Junko; Agwa, Hussein; Zahran, Magdy; Seno, Masaharu

    2017-01-01

    Lung cancer is one of the major causes of cancer-related mortality worldwide, and non-small-cell lung cancer is the most common form of lung cancer. Several studies had shown that thalidomide has potential for prevention and therapy of cancer. Therefore, the current study aimed to investigate the antitumor effects of two novel thalidomide analogs in human lung cancer A549 cells. The antiproliferative, antimigratory, and apoptotic effects in A549 cells induced by thalidomide analogs were examined. In addition, their effects on the expression of mRNAs encoding vascular endothelial growth factor165 (VEGF165) and matrix metalloproteinase-2 (MMP-2) were evaluated. Their influence on the tumor volume in nude mice was also determined. Results revealed that thalidomide analogs exhibited antiproliferative, antimigratory, and apoptotic activities with more pronounced effect than thalidomide drug. Furthermore, analogs 1 and 2 suppressed the expression levels of VEGF165 by 42% and 53.2% and those of MMP-2 by 45% and 52%, respectively. Thalidomide analogs 1 and 2 also reduced the tumor volume by 30.11% and 53.52%, respectively. Therefore, this study provides evidence that thalidomide analogs may serve as a new therapeutic option for treating lung cancer. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  16. Thalidomide can promote erythropoiesis by induction of STAT5 and repression of external pathway of apoptosis resulting in increased expression of GATA-1 transcription factor.

    Science.gov (United States)

    Grzasko, Norbert; Chocholska, Sylwia; Goracy, Aneta; Hus, Marek; Dmoszynska, Anna

    2015-12-01

    Thalidomide was shown to stimulate erythropoiesis and increase hemoglobin level in multiple myeloma patients, but way of such activity remains unclear. The aim of the study was to investigate the mechanisms of thalidomide stimulating effect on erythroid differentiation. Hematopoietic stem cells were isolated from bone marrow aspirates taken from myeloma patients and cultured with or without thalidomide. Then the generation of erythroid cells and the expression of STAT5, GATA-1, GATA-2, selected caspases and Bcl-2 family proteins in erythroid cells were assessed using flow cytometry and real-time PCR. The generation of erythroblasts was higher in thalidomide than in control cultures (63.9% vs. 55.8%, p thalidomide than in control cultures. The expression of STAT5 (cytometry 331.5 vs. 276.1, p = 0.015; PCR 24.3 vs. 21.1, p = 0.003) and GATA-1 (cytometry 259.7 vs. 232.0, p = 0.027; PCR 18.9 vs. 16.5, p = 0.003) was higher in thalidomide than in control cultures. Our results suggest that thalidomide enhances expression of STAT5 in response of erythroid cells to erythropoietin and as a result of caspase 3 suppression. Moreover it may exert inhibitory effect on an external pathway of caspases activation with consequent decreased degradation of GATA-1 transcription factor by downstream caspases. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  17. Recognition of the phenotype of thalidomide embryopathy in countries endemic for leprosy: new cases and review of the main dysmorphological findings.

    Science.gov (United States)

    Vianna, Fernanda S L; Schüler-Faccini, Lavínia; Leite, Julio César L; de Sousa, Silvia H C; da Costa, Lea Márcia M; Dias, Murilo F; Morelo, Elaine F; Doriqui, Maria Juliana R; Maximino, Claudia M; Sanseverino, Maria Teresa V

    2013-04-01

    Thalidomide is the best-known teratogen worldwide. It was first marketed as a sedative in the late 1950s, but the birth of ~10 000 children with birth defects resulted in the withdrawal of thalidomide from the market in 1962. Thalidomide embryopathy affects almost all organs but the main defects are concentrated in the limbs, eyes, ears, and heart. Shortly after the withdrawal of thalidomide from the market, its effectiveness in the treatment of erythema nodosum leprosum, an inflammatory condition resulting from leprosy, was reported and since the mid-1990s, the drug has been used widely in the treatment of cancers and autoimmune diseases, among other conditions. 40 000 new cases of leprosy are diagnosed every year in Brazil. Although there is a strict legislation for the prescription and use of thalidomide in Brazil, cases of thalidomide embryopathy have continued to be reported. Here, we present two new cases of thalidomide embryopathy identified in 2011 and review the major clinical findings in the literature that can aid the identification of the embryopathy.

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    Lachmann, P J

    2012-12-01

    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.

  20. Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma

    DEFF Research Database (Denmark)

    Zweegman, Sonja; van der Holt, Bronno; Mellqvist, Ulf-Henrik

    2016-01-01

    with thalidomide being replaced by lenalidomide (MPR-R). This multicenter, open-label, randomized phase 3 trial was undertaken by Dutch-Belgium Cooperative Trial Group for Hematology Oncology and the Nordic Myeloma Study Group (the HOVON87/NMSG18 trial). The primary end point was progression-free survival (PFS......). Response rates were similar, with at least a very good partial response of 47% and 45%, respectively. Hematologic toxicity was more pronounced with MPR-R, especially grades 3 and 4 neutropenia: 64% vs 27%. Neuropathy of at least grade 3 was significantly higher in the MPT-T arm: 16% vs 2% in MPR...

  1. Thalidomide and dexamethasone vs. bortezomib and dexamethasone for melphalan refractory myeloma: a randomized study.

    Science.gov (United States)

    Hjorth, Martin; Hjertner, Øyvind; Knudsen, Lene Meldgaard; Gulbrandsen, Nina; Holmberg, Erik; Pedersen, Per Trøllund; Andersen, Niels Frost; Andréasson, Björn; Billström, Rolf; Carlson, Kristina; Carlsson, Margaretha S; Flogegård, Max; Forsberg, Karin; Gimsing, Peter; Karlsson, Torbjörn; Linder, Olle; Nahi, Hareth; Othzén, Annika; Swedin, Agneta

    2012-06-01

    Thalidomide and bortezomib have been frequently used for second-line therapy in patients with myeloma relapsing after or refractory to initial melphalan-based treatment, but no randomized trials have been published comparing these two treatment alternatives. Thalidomide- and bortezomib-naïve patients with melphalan refractory myeloma were randomly assigned to low-dose thalidomide + dexamethasone (Thal-Dex) or bortezomib + dexamethasone (Bort-Dex). At progression on either therapy, the patients were offered crossover to the alternative drug combination. An estimated 300 patients would be needed for the trial to detect a 50% difference in median PFS between the treatment arms. After inclusion of 131 patients, the trial was prematurely closed because of low accrual. Sixty-seven patients were randomized to Thal-Dex and 64 to Bort-Dex. Progression-free survival was similar (median, 9.0 months for Thal-Dex and 7.2 for Bort-Dex). Response rate was similar (55% for Thal-Dex and 63% for Bort-Dex), but time to response was shorter (P Bort-Dex. Time-to-other treatment after crossover was similar (median, 13.2 months for Thal-Dex and 11.2 months for Bort-Dex), as was overall survival (22.8 months for Thal-Dex and 19.0 for Bort-Dex). Venous thromboembolism was seen in seven patients and cerebrovascular events in four patients in the Thal-Dex group. Severe neuropathy, reactivation of herpes virus infections, and mental depression were more frequently observed in the Bort-Dex group. In the quality-of-life analysis, no difference was noted for physical function, pain, and global quality of life. Fatigue and sleep disturbances were significantly more prevalent in the Bort-Dex group. Thalidomide (50-100 mg daily) in combination with dexamethasone seems to have an efficacy comparable with that of bortezomib and dexamethasone in melphalan refractory myeloma. However, the statistical strength of the results in this study is limited by the low number of included patients. © 2012 John

  2. Nasal powders of thalidomide for local treatment of nose bleeding in persons affected by hereditary hemorrhagic telangiectasia.

    Science.gov (United States)

    Colombo, G; Bortolotti, F; Chiapponi, V; Buttini, F; Sonvico, F; Invernizzi, R; Quaglia, F; Danesino, C; Pagella, F; Russo, P; Bettini, R; Colombo, P; Rossi, A

    2016-11-30

    In this work nasal powder formulations of thalidomide were designed and studied to be used by persons affected by hereditary hemorrhagic telangiectasia as a complementary anti-epistaxis therapy, with the goal of sustaining the effect obtained with thalidomide oral treatment after its discontinuation for adverse effects. Three nasal powders were prepared using as carriers β-CD or its more hydrophilic derivatives such as hydropropyl-β-CD and sulphobutylether-β-CD and tested with respect to technological and biopharmaceutical features after emission with active and passive nasal powder devices. For all formulated powders, improved dissolution rate was found compared to that of the raw material, making thalidomide promptly available in the nasal environment at a concentration favouring an accumulation in the mucosa. The very limited transmucosal transport measured in vitro suggests a low likelihood of significant systemic absorption. The topical action on bleeding could benefit from the poor absorption and from the fact that about 2-3% of the thalidomide applied on the nasal mucosa was accumulated within the tissue, particularly with the β-CD nasal powder. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

    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.

  4. Combined thalidomide and cyclophosphamide treatment for refractory or relapsed multiple myeloma patients : a prospective phase II study

    NARCIS (Netherlands)

    Hovenga, S; Daenen, SMGJ; de Wolf, JTM; van Imhoff, GW; Kluin-Nelemans, HC; Sluiter, WJ; Vellenga, E

    refractory multiple myeloma ( MM) with a response rate of 30-40% at doses of 200-800 mg but with considerable side effects. We questioned whether lower doses of thalidomide in combination with a daily dose of cyclophosphamide might be an effective regimen with fewer side effects. We included 38

  5. Thalidomide inhibits UVB-induced mouse keratinocyte apoptosis by both TNF-α-dependent and TNF-α-independent pathways

    NARCIS (Netherlands)

    Lu, K.Q.; Brenneman, S.; Burns Jr., R.; Vink, A.; Gaines, E.; Haake, A.; Gaspari, A.

    2003-01-01

    Background: Thalidomide is an anti-inflammatory pharmacologic agent that has been utilized as a therapy for a number of dermatologic diseases. Its anti-inflammatory properties have been attributed to its ability to antagonize tumor necrosis factor-alfa (TNF-α) production by monocytes. However, its

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

    Science.gov (United States)

    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.

  7. Thalidomide in systemic mastocytosis: results from an open-label, multicentre, phase II study.

    Science.gov (United States)

    Gruson, Bérengère; Lortholary, Olivier; Canioni, Danielle; Chandesris, Olivia; Lanternier, Fanny; Bruneau, Julie; Grosbois, Bernard; Livideanu, Cristina; Larroche, Claire; Durieu, Isabelle; Barete, Stéphane; Sevestre, Henri; Diouf, Momar; Chaby, Guillaume; Marolleau, Jean-Pierre; Dubreuil, Patrice; Hermine, Olivier; Damaj, Gandhi

    2013-05-01

    Mastocytosis can lead to organ failure as well as systemic symptoms that can be disabling, with considerable deterioration in quality of life. Beside symptomatic treatments, interferon-α and purine analogues have been shown to be effective but complete or long-term remission is rarely obtained with these drugs. We conducted a phase II, multicentre, study to investigate thalidomide in severely symptomatic indolent and aggressive systemic mastocytosis. Twenty patients were enrolled of whom 16 were analysed for response. The overall response rate was 56%. Responses were observed in the skin in 61% of patients with a significant decrease in the pruritus score. Mast cell mediator-related symptoms responded in 71% of cases and 25% of aggressive systemic mastocytosis patients had a response in terms of B/C findings (borderline/cytoreduction needed). Bone marrow mast cell infiltration decreased in five of the eight evaluable patients. There was no significant improvement in the AFIRMM (Association Française pour les Initiatives de Recherche sur le Mastocyte et Les Mastocytoses), Quality of Life or Hamilton scores. Grade 3-4 toxicities consisted of peripheral neuropathy (11%) and myelosuppression (neutropenia: 5%; thrombocytopenia: 11%). In conclusion, thalidomide might be useful in mastocytosis and in the treatment of mast cell-related symptoms. It might be considered in selected patients, taking into account the benefit/risk balance and the individual patient evaluation. © 2013 Blackwell Publishing Ltd.

  8. Significance of the antiangiogenic mechanisms of thalidomide in the therapy of diabetic retinopathy.

    Science.gov (United States)

    Behl, Tapan; Kaur, Ishneet; Goel, Heena; Kotwani, Anita

    2017-05-01

    Diabetic retinopathy is an ocular complication associated with the chronic endocrine disorder of diabetes mellitus. Angiogenesis is adjudged as a prime modulatory event in this complication. The formation of new blood vessels on the pre-existing vasculature gives rise to an abundance of anatomical and physiological alterations which ultimately results in vision loss. The drastic consequences of this complication prompt the obligation of developing effective therapies for its cure. The existing therapy mainly includes destructive techniques such as laser photocoagulation. Owing to the various drawbacks associated with this technique, there is a need to develop alternative therapies which could halt the progression of diabetic retinopathy without causing considerable damage to the retinal cells. One such possible alternative treatment being researched upon is the antiangiogenic therapy. Since angiogenesis is a critical event during the progression of this disorder, targeting this event may perhaps prove effective in its treatment. Amongst several antiangiogenic agents, thalidomide holds a reputable position due to its effectiveness in terminating angiogenesis during various pathological conditions. This review focuses on the diverse molecular mechanisms proposed to explain the antiangiogenic properties of thalidomide and their applicability in diabetic retinopathy. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Thalidomide in refractory bleeding due to gastrointestinal angiodysplasias Talidomida en la hemorragia recidivante por angiodisplasias gastrointestinales

    Directory of Open Access Journals (Sweden)

    Antonio Garrido

    2012-02-01

    Full Text Available Objectives: to assess the efficacy of thalidomide in the treatment of relapsed or refractory bleeding secondary to gastrointestinal angiodysplasia. Material and methods: we carried out a prospective study of 12 patients with bleeding due to gastrointestinal angiodysplasia refractory to conventional therapy who were treated with thalidomide. For each patient, we considered: age, sex, underlying disease, previous therapies, dose and duration of thalidomide treatment, evolution of haemoglobin levels and adverse effects of treatment. The data obtained were analysed using descriptive statistics with SPSS v. 16. Results: seven men and 5 women with a mean age of 77 years were included in the present study. Five had some underlying pathology and all of them had received prior endoscopic/octreotide treatment. The dose of thalidomide administered was 200 mg/24 h and the duration of the treatment four months, with the exception of two patients in whom treatment was discontinued because of adverse side effects. Mean haemoglobin concentration before onset of treatment was 6.5 g/dL, at two months it was 11.3 g/dL and at the end of treatment 12.1 g/dL. Conclusions: thalidomide is an effective treatment in gastrointestinal bleeding due to angiodysplasia, but it was withdrawn due to side effects in 16% of the patients included in our study.Objetivos: valorar la eficacia de talidomida en la hemorragia recidivante y refractaria por angiodisplasias gastrointestinales. Material y métodos: se realizó un estudio prospectivo de 12 pacientes con hemorragia por angiodisplasias refractarios a la terapia convencional, que recibieron tratamiento con talidomida. Se determinó en cada caso: edad, sexo, patología de base, tratamientos previos, dosis y duración del tratamiento con talidomida, evolución de los valores de hemoglobina y efectos secundarios del tratamiento. Los datos fueron procesados mediante estadística descriptiva con SPSS versión 16. Resultados: se

  10. Phase 3 trial of three thalidomide-containing regimens in patients with newly diagnosed multiple myeloma not transplant-eligible.

    Science.gov (United States)

    Hungria, V T M; Crusoé, E Q; Maiolino, A; Bittencourt, R; Fantl, D; Maciel, J F R; Pessoa de Magalhaes, R J; Almeida, M S S; Cury, P; Hisgashi, F; Peres, A L; Chiattone, C S

    2016-01-01

    The introduction of agents such as thalidomide, lenalidomide, and bortezomib has changed the management of patients with multiple myeloma who are not eligible for autologous transplantation, many of whom are elderly. We sought to compare three thalidomide-based oral regimens among such patients in Latin America. We randomized patients with newly diagnosed multiple myeloma with measurable disease to one of the following regimens: melphalan, prednisone, and thalidomide (MPT); cyclophosphamide, thalidomide, and dexamethasone (CTD); and thalidomide and dexamethasone (TD). The TD arm was closed prematurely and was analyzed only descriptively. The primary endpoint was the overall response rate (ORR), whereas progression-free survival (PFS) and overall survival (OS) were secondary endpoints. The accrual rate was slower than expected, and the study was terminated after 82 patients had been randomized. The ORRs were 67.9 % with MPT, 89.7 % with CTD, and 68.7 % with TD (p = 0.056 for the comparison between MPT and CTD). The median PFS was 24.1 months for MPT, 25.9 months for CTD, and 21.5 months for TD. There were no statistically significant differences in PFS or OS between MPT and CTD. In an unplanned logistic regression analysis, ORR was significantly associated with treatment with CTD (p = 0.046) and with performance status of 0 or 1 (p = 0.035). Based on the current results, no definitive recommendations can be made regarding the comparative merit of the regimens tested. Nevertheless and until the results of further studies become available, we recommend either CTD or MPT as suitable frontline regimens for patients with multiple myeloma who are not candidates to transplantation in settings where lenalidomide and bortezomib are not available.

  11. Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials

    DEFF Research Database (Denmark)

    Fayers, Peter M; Palumbo, Antonio; Hulin, Cyrille

    2011-01-01

    The role of thalidomide for previously untreated elderly patients with multiple myeloma remains unclear. Six randomized controlled trials, launched in or after 2000, compared melphalan and prednisone alone (MP) and with thalidomide (MPT). The effect on overall survival (OS) varied across trials. We...... carried out a meta-analysis of the 1685 individual patients in these trials. The primary endpoint was OS, and progression-free survival (PFS) and 1-year response rates were secondary endpoints. There was a highly significant benefit to OS from adding thalidomide to MP (hazard ratio = 0.83; 95% confidence...... interval 0.73-0.94, P = .004), representing increased median OS time of 6.6 months, from 32.7 months (MP) to 39.3 months (MPT). The thalidomide regimen was also associated with superior PFS (hazard ratio = 0.68, 95% confidence interval 0.61-0.76, P

  12. WHO co-ordinated short-term double-blind trial with thalidomide in the treatment of acute lepra reactions in male lepromatous patients.

    Science.gov (United States)

    Iyer, C G; Languillon, J; Ramanujam, K; Tarabini-Castellani, G; De las Aguas, J T; Bechelli, L M; Uemura, K; Martinez Dominguez, V; Sundaresan, T

    1971-01-01

    The treatment of lepra reactions constitutes one of the most serious problems in leprosy. For this reason, the first reports in 1965 of the favourable results obtained with thalidomide aroused considerable interest and led WHO, in 1967, to carry out a trial with the co-operation of four centres. A short-term double-blind trial was designed to study the effect of thalidomide, in comparison with acetylsalicylic acid, in the treatment of acute lepra reactions in male lepromatous patients. Acetylsalicylic acid was used instead of a placebo because of its antipyretic and analgesic activity. Because of the severe adverse reactions that may be caused by thalidomide, mainly the teratogenic effects, only males were included in the trial.The results of this short-term study seem to confirm previous reports of the efficacy of thalidomide and indicate that acetylsalicylic acid also seems to be helpful in the management of certain symptoms of lepra reactions.

  13. IgG antibody subclasses, tumor necrosis factor and IFN-gamma levels in patients with type II lepra reaction on thalidomide treatment.

    Science.gov (United States)

    Partida-Sanchez, S; Favila-Castillo, L; Pedraza-Sanchez, S; Gomez-Melgar, M; Saul, A; Estrada-Parra, S; Estrada-Garcia, I

    1998-05-01

    A group of 9 Mexican lepromatous leprosy patients was studied at the beginning of a type II reaction (erythema nodosum leprosum, ENL) and after 1 or 2 months of thalidomide treatment. ENL patients at the onset of the reaction had slightly higher amounts of anti-Mycobacterium leprae IgG1 and IgG2 antibodies, compared to similar lepromatous patients that did not develop ENL. Neither these antibody levels nor IgM and the other IgG subclasses were importantly modified after thalidomide treatment. Serum TNF was significantly higher in the patients that developed ENL compared to those that did not develop the reaction. TNF levels were slightly decreased after 1 month of thalidomide treatment and significantly decreased after 2 months of treatment. Serum IFN-gamma was significantly lower in patients at the onset of ENL and was increased after 1 and 2 months of thalidomide treatment.

  14. Randomized phase II adjuvant factorial study of dose-dense temozolomide alone and in combination with isotretinoin, celecoxib, and/or thalidomide for glioblastoma

    National Research Council Canada - National Science Library

    Penas-Prado, Marta; Hess, Kenneth R; Fisch, Michael J; Lagrone, Lore W; Groves, Morris D; Levin, Victor A; De Groot, John F; Puduvalli, Vinay K; Colman, Howard; Volas-Redd, Gena; Giglio, Pierre; Conrad, Charles A; Salacz, Michael E; Floyd, Justin D; Loghin, Monica E; Hsu, Sigmund H; Gonzalez, Javier; Chang, Eric L; Woo, Shiao Y; Mahajan, Anita; Aldape, Kenneth D; Yung, W K Alfred; Gilbert, Mark R

    2015-01-01

    ...) improves progression-free survival (PFS) for patients with newly diagnosed glioblastoma. A prior phase I trial established the safety of combining ddTMZ with isotretinoin, celecoxib, and/or thalidomide...

  15. Long-term treatment of thalidomide ameliorates amyloid-like pathology through inhibition of β-secretase in a mouse model of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Ping He

    Full Text Available Thalidomide is a tumor necrosis factor alpha (TNFα inhibitor which has been found to have abilities against tumor growth, angiogenesis and inflammation. Recently, it has been applied in clinic for the treatment of multiple myeloma as well as some inflammatory diseases. However, whether thalidomide has any therapeutic effects on neurodegenerative disorders, i.e. Alzheimer's disease (AD is not clear. AD is characterized by excessive amount of amyloid β peptides (Aβ, which results in a significant release of inflammatory factors, including TNFα in the brain. Studies have shown that inhibition of TNFα reduces amyloid-associated pathology, prevents neuron loss and improves cognition. Our recent report showed that genetic inhibition of TNFα/TNF receptor signal transduction down-regulates β amyloid cleavage enzyme 1 (BACE1 activity, reduces Aβ generation and improves learning and memory deficits. However, the mechanism of thalidomide involving in the mitigation of AD neuropathological features remains unclear. Here, we chronically administrated thalidomide on human APPswedish mutation transgenic (APP23 mice from 9 months old (an onset of Aβ deposits and early stage of AD-like changes to 12 months old. We found that, in addition of dramatic decrease in the activation of both astrocytes and microglia, thalidomide significantly reduces Aβ load and plaque formation. Furthermore, we found a significant decrease in BACE1 level and activity with long-term thalidomide application. Interestingly, these findings cannot be observed in the brains of 12-month-old APP23 mice with short-term treatment of thalidomide (3 days. These results suggest that chronic thalidomide administration is an alternative approach for AD prevention and therapeutics.

  16. Long-Term Treatment of Thalidomide Ameliorates Amyloid-Like Pathology through Inhibition of β-Secretase in a Mouse Model of Alzheimer’s Disease

    Science.gov (United States)

    He, Ping; Cheng, Xin; Staufenbiel, Matthias; Li, Rena; Shen, Yong

    2013-01-01

    Thalidomide is a tumor necrosis factor alpha (TNFα) inhibitor which has been found to have abilities against tumor growth, angiogenesis and inflammation. Recently, it has been applied in clinic for the treatment of multiple myeloma as well as some inflammatory diseases. However, whether thalidomide has any therapeutic effects on neurodegenerative disorders, i.e. Alzheimer’s disease (AD) is not clear. AD is characterized by excessive amount of amyloid β peptides (Aβ), which results in a significant release of inflammatory factors, including TNFα in the brain. Studies have shown that inhibition of TNFα reduces amyloid-associated pathology, prevents neuron loss and improves cognition. Our recent report showed that genetic inhibition of TNFα/TNF receptor signal transduction down-regulates β amyloid cleavage enzyme 1 (BACE1) activity, reduces Aβ generation and improves learning and memory deficits. However, the mechanism of thalidomide involving in the mitigation of AD neuropathological features remains unclear. Here, we chronically administrated thalidomide on human APPswedish mutation transgenic (APP23) mice from 9 months old (an onset of Aβ deposits and early stage of AD-like changes) to 12 months old. We found that, in addition of dramatic decrease in the activation of both astrocytes and microglia, thalidomide significantly reduces Aβ load and plaque formation. Furthermore, we found a significant decrease in BACE1 level and activity with long-term thalidomide application. Interestingly, these findings cannot be observed in the brains of 12-month-old APP23 mice with short-term treatment of thalidomide (3 days). These results suggest that chronic thalidomide administration is an alternative approach for AD prevention and therapeutics. PMID:23405115

  17. An unexpected case of venous and pulmonary thrombo-embolism in a patient treated with thalidomide for refractory erythema nodosum leprosum: a case report

    Directory of Open Access Journals (Sweden)

    Chamara Ratnayake

    2011-01-01

    Full Text Available Abstract Recent literature reports an increased incidence of venous thrombosis following thalidomide use in the treatment of diseases with disease-related thrombotic risks such as malignancy, as well as concomitant use with chemotherapy and/or systemic corticosteroids. We report a case of deep vein thrombosis (DVT and pulmonary embolism (PE following thalidomide use in a patient with erythema nodosum leprosum (ENL reaction who was concurrently treated with prednisolone, as well as a review of relevant literature.

  18. Anti-apoptotic, anti-oxidant, and anti-inflammatory effects of thalidomide on cerebral ischemia/reperfusion injury in rats.

    Science.gov (United States)

    Palencia, Guadalupe; Medrano, Juan Ángel Núñez-; Ortiz-Plata, Alma; Farfán, Dolores Jiménez; Sotelo, Julio; Sánchez, Aurora; Trejo-Solís, Cristina

    2015-04-15

    Thalidomide has shown protective effects in different models of ischemia/reperfusion damage. To elucidate the mechanisms of such protection, this study assessed the effects of thalidomide on the oxidative stress and inflammatory response induced by ischemia/reperfusion episodes in rats. Rats underwent middle cerebral artery occlusion (MCAO) for 2hours. All animals were sacrificed after different reperfusion times. Rats were administered either DMSO or thalidomide (20mg/kg (i.p.)) at different times before or during reperfusion: 1) 1h before reperfusion; the infarct area was measured 2h after reperfusion. 2) 10min before reperfusion and 80min after reperfusion; the infarct area was measured 24h after reperfusion; and 3) 10min before reperfusion and 1h, 24h, 48h, and 68h after reperfusion; the infarct area was measured 72h after reperfusion. Thalidomide reduced the infarct area 24h and 72h after MCAO, and decreased the neurological deficit in all groups with respect to controls. Thalidomide also lowered significantly the number of TUNEL-positive cells, levels of Bax, caspase-3, lipoperoxidation, and pro-inflammatory cytokines, and increased the levels of SOD1, Bcl-2 and pAkt. These results show that thalidomide has neuroprotective effects, apparently due to its anti-apoptotic, anti-oxidant, and anti-inflammatory effects. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. Development of thalidomide-loaded biodegradable devices and evaluation of the effect on inhibition of inflammation and angiogenesis after subcutaneous application.

    Science.gov (United States)

    Pereira, Bruno Gonçalves; Batista, Leandro Flores; de Souza, Pedro Alcântara Fonseca; da Silva, Gisele Rodrigues; Andrade, Silvia Passos; Serakides, Rogéria; da Nova Mussel, Wagner; Silva-Cunha, Armando; Fialho, Sílvia Ligório

    2015-04-01

    To develop thalidomide-loaded poly-lactide-co-glycolide implants and evaluate its in vivo release and biological activity against inflammation and angiogenesis after subcutaneous administration. Implants were prepared by the hot molding technique and characterized using stereomicroscopy, thermal analysis and X-ray diffraction. Swiss mice, divided in groups 1-3, received a subcutaneous implant containing 25% (w/w), 50% (w/w) or 75% (w/w) of thalidomide, respectively (n=6). The drug levels were determined during a 28-day study period. The toxicity associated with the implants was evaluated by light microscopy. The potential of the developed implant in the inhibition of inflammation and angiogenesis was evaluated in vivo using the sponge model. Thalidomide implant was developed and its characterization proved the stability of the drug and the polymer during preparation. Release profiles in vivo demonstrated an extended release of thalidomide from the implants during the 28 days. Histological evaluation did not show any sign of intense local inflammatory response to the presence of the implants in the subcutaneous pouch. The thalidomide implant reduced the number of vessels and N-acetyl-b-glucosaminidase (NAG) in vivo. The biodegradable implants delivered safe doses of thalidomide that were also effective to induce angiogenesis and inflammation regression. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  20. Talidomida, contextos históricos y éticos Thalidomide, historical and ethical contexts

    Directory of Open Access Journals (Sweden)

    José Ángel Chávez Viamontes

    2009-12-01

    Full Text Available A finales de la década del 50, en Europa, Australia, Japón y varios países africanos, la talidomida provocó más de 10 000 casos de defectos congénitos en hijos de madres que la consumieron durante el embarazo. En 1962, es retirada del mercado. Tres décadas después, se reivindica su prescripción en el manejo de enfermedades de pronóstico desfavorable. Sus propiedades antiangiogénicas e inmunorreguladoras la hacen diferente al fármaco de los años 50 en gran medida. A pesar de poseer las mismas propiedades farmacológicas y riesgos teratogénicos, la molécula talidomida tiene otras las indicaciones, dosis, campos de aplicación y condiciones legales de uso. Esta revisión tiene como objetivo reseñar los contextos históricos y éticos que condicionaron la proscripción de la talidomida a principios de los años 60, así como las actuales condiciones clínicas en que se usan o ensayan actualmente sus efectos terapéuticos.In Europe, Australia, Japan, and some African countries in the late 50's, Thalidomide caused more than 10 000 cases of congenital defects in children whose mothers consumed it during pregnancy. In 1962, it was withdrawn from market. Thirty years later, it is used for the management diseases with unfavorable prognosis. Its antiangiogenic and immunoregulatory characteristics distinguish it from the drug of 1950. Although containing the same pharmacological features and teratogenic risks, the molecule thalidomide does have other prescriptions, doses, application fields, and lawful conditions of use. This revision points out both the historical and ethical contexts, which conditioned the banning of Thalidomide in the early 60's, and the clinical conditions in which its therapeutic effects are used and studied today.

  1. A Brighter Side to Thalidomide: Its Potential Use in Immunological Disorders.

    Science.gov (United States)

    Millrine, David; Kishimoto, Tadamitsu

    2017-04-01

    Thalidomide and its derivatives are immunomodulatory drugs (IMiDs) known for their sedative, teratogenic, anti-angiogenic, and anti-inflammatory properties. Commonly used in the treatment of cancers such as multiple myeloma and myelodysplastic syndrome (MDS), IMiDs have also been used in the treatment of an inflammatory skin pathology associated with Hansen's disease/leprosy. They have also shown promise in the treatment of autoimmune disorders including systemic lupus erythmatosus (SLE) and inflammatory bowel disease (IBD). Recent structural and experimental observations have revolutionized our understanding of these properties by revealing the fundamental molecular events underpinning IMiD activity. We review these findings, their relevance to IMiD therapy in immunological disorders, and discuss how further research might unlock the vast clinical potential of these compounds. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Scleromyxedema with Subcutaneous Nodules: Successful Treatment with Thalidomide and Intravenous Immunoglobulin

    Directory of Open Access Journals (Sweden)

    M. Dolenc-Voljč

    2013-11-01

    Full Text Available Scleromyxedema is a rare cutaneous mucinosis, usually presenting with generalized papular eruption and sclerodermoid induration, monoclonal gammopathy and systemic manifestations. An atypical clinical presentation with cutaneous and subcutaneous nodules has been reported rarely. In recent years, intravenous immunoglobulin (IVIg appears to be the therapy of choice for scleromyxedema. Treatment experiences in atypical manifestations with mucinous nodules are limited to sporadic reports. We report the case of male patient with atypical scleromyxedema without underlying paraproteinemia, presenting with generalized papular and sclerodermoid skin eruption and multiple nodular mucinous lesions on the fingers and face as well as on the eyelids, and associated systemic symptoms. Complete regression of all cutaneous lesions and extracutaneous symptoms with sustained remission was achieved by combined treatment with thalidomide and IVIg.

  3. Severe Gastrointestinal Bleeding in a Patient With Subvalvular Aortic Stenosis Treated With Thalidomide and Octreotide

    DEFF Research Database (Denmark)

    Hvid-Jensen, Helene S; Poulsen, Steen H; Agnholt, Jørgen S

    2015-01-01

    Gastrointestinal bleeding (GB) due to angiodysplasias can cause severe, recurrent bleeding, especially in elderly patients. Angiodysplastic bleedings in the gastrointestinal tract have been associated with aortic stenosis and, more recently, hypertrophic obstructive cardiomyopathy, caused...... due to hypertrophic subvalvular obstructive cardiomyopathy. Endoscopic procedures with argon beaming were performed without effect on bleeding. The patient was treated with a combination of both thalidomide and octreotide. Within 3 months, the patient recovered from the anemia and was able to undergo...... to resolve bleeding, especially in patients with large numbers of angiodysplasias. In patients with aortic stenosis and GB, the main treatment is aortic valve replacement but the patients may be unfit to undergo surgery due to the complicating anemia. In this case story, we present a patient with severe, GB...

  4. Thalidomide attenuates the development and expression of antinociceptive tolerance to μ-opioid agonist morphine through l-arginine-iNOS and nitric oxide pathway.

    Science.gov (United States)

    Khan, Muhammad Imran; Ostadhadi, Sattar; Mumtaz, Faiza; Momeny, Majid; Moghaddaskho, Farima; Hassanipour, Mahsa; Ejtemaei-Mehr, Shahram; Dehpour, Ahmad Reza

    2017-01-01

    Morphine is a μ-opioid analgesic drug which is used in the treatment and management of chronic pain. However, due to development of antinociceptive tolerance its clinical use is limited. Thalidomide is an old glutamic acid derivative which recently reemerged because of its potential to counteract a number of disorders including neurodegenerative disorders. The potential underlying mechanisms and effects of thalidomide on morphine-induced antinociceptive tolerance is still elusive. Hence, the present study was designed to explore the effect of thalidomide on the development and expression of morphine antinociceptive tolerance targeting l-arginine-nitric oxide (NO) pathway in mice and T98G human glioblastoma cell line. When thalidomide was administered in a dose of 17.5mg/kg before each dose of morphine chronically for 5days it prevented the development of antinociceptive tolerance. Also, a single dose of thalidomide 20mg/kg attenuated the expression phase of antinociceptive tolerance. The protective effect of thalidomide was augmented in development phase when co-administration with NOS inhibitors like L-NAME (non- selective NOS inhibitor; 2mg/kg) or aminoguanidine (selective inducible NOS inhibitor; 50mg/kg). Also, the reversal effect of thalidomide in expression phase was potentiated when concomitantly administrated with L-NAME (5mg/kg) or aminoguanidine (100mg/kg). Co-administration of ODQ (a guanylyl cyclase inhibitor) 10mg/kg in developmental phase or 20mg/kg in expression phase also progressively increased the pain threshold. In addition, thalidomide (20μM) also significantly inhibited the overexpression of iNOS gene induced by morphine (2.5μM) in T98G cell line. Hence, our findings suggest that thalidomide has protective effect both in the development and expression phases of morphine antinociceptive tolerance. It is also evident that this effect of thalidomide is induced by the inhibition of NOS enzyme predominantly iNOS. Copyright © 2016 Elsevier Masson

  5. Polymorphisms in the endothelial nitric oxide synthase gene in thalidomide embryopathy.

    Science.gov (United States)

    Vianna, Fernanda Sales Luiz; Fraga, Lucas Rosa; Tovo-Rodrigues, Luciana; Tagliani-Ribeiro, Alice; Biondi, Flavia; Maximino, Claudia Marques; Sanseverino, Maria Teresa Vieira; Hutz, Mara Helena; Schuler-Faccini, Lavínia

    2013-11-30

    Thalidomide is one of the most potent teratogens known to humans. It is currently used for many clinical situations such as treatment of leprosy reactions and multiple myeloma. However, the teratogenic mechanisms by which it produces morphological defects still remain unclear. One of the hypotheses is the blockage of angiogenesis by reduction of nitric oxide (NO). In this study, we evaluated two functional polymorphisms of the endothelial nitric oxide synthase (eNOS) gene which is a constitutively expressed enzyme responsible for production of NO. The promoter -786T>C exon 7 (896G>T) polymorphisms were genotyped using real-time PCR for 28 individuals with thalidomide embryopathy (TE), 27 first-degree relatives of these individuals, and 68 individuals from the general population. Their allele, genotypic, and haplotypic frequencies were compared. A significant difference was observed in the -786T>C polymorphism genotypes (p=0.03) between the groups affected by TE and those unaffected (non-relatives). The TT genotype of the 896G>T polymorphism was observed in 10.7% of those affected and 2.9% of those unaffected, but the difference was not statistically significant (p=0.09). The haplotypic analysis indicated that the wild haplotype -786T/896G was distributed differently in the affected and unaffected groups (p=0.004). These results indicate that the individuals with TE have a higher frequency of alleles associated with lower expression of eNOS, indicating that this may be a genotype susceptible to TE. Copyright © 2013 Elsevier Inc. All rights reserved.

  6. Effectiveness of Risk Evaluation and Mitigation Strategies (REMS) for Lenalidomide and Thalidomide: Patient Comprehension and Knowledge Retention.

    Science.gov (United States)

    Brandenburg, Nancy A; Bwire, Robert; Freeman, John; Houn, Florence; Sheehan, Paul; Zeldis, Jerome B

    2017-04-01

    The effectiveness of patient education activities conducted within the lenalidomide and thalidomide risk evaluation and mitigation strategies (REMS) programs was evaluated by measuring understanding of serious risk and safe-use messages. Results from mandatory knowledge, attitude, and behavior surveys and voluntary patient surveys completed between June 2012 and June 2013 were analyzed, and responses to questions relating to compliance with birth control measures and understanding of safe-use messages are presented by patient risk category. In total, 73,645 patients were enrolled into the REMS programs for lenalidomide and thalidomide and completed mandatory surveys prior to medication dispense. Of these, 2790 (3.8%) completed an additional voluntary survey. Among voluntary survey participants, for all patient pregnancy risk categories, reported compliance with birth control requirements was above 90% when starting therapy and at follow-up. At the beginning of therapy, complete compliance was 96.3%; 3 months later it was 96.4%. Patient understanding of safe-use messages was very high in all pregnancy risk groups, notably for messages repeated at each physician visit. Overall, 98.2% of patients knew that lenalidomide and thalidomide could cause birth defects, which is part of the repeated educational messaging. In contrast, 87.1% recalled that unused product should be returned to their healthcare professional, which is not included in repeated messaging. The lenalidomide and thalidomide REMS programs enhance patient understanding of safe-use messages, resulting in high levels of compliance with the birth control precautions essential to prevent fetal exposure to these known and potential human teratogens. Overall compliance was maintained after 3 months of follow-up and throughout therapy.

  7. Discovering a new analogue of thalidomide which may be used as a potent modulator of TNF-alpha production.

    Science.gov (United States)

    Fernández Braña, Miguel; Acero, Nuria; Añorbe, Loreto; Muñoz Mingarro, Dolores; Llinares, Francisco; Domínguez, Gema

    2009-09-01

    A new series of imide derivatives related to thalidomide were synthesized and evaluated as modulators of TNF-alpha production. These derivatives enhance TNF-alpha production using human leukemia HL-60 cells induced with 12-O-tetradecanoylphorbol 13-acetate (TPA), while inhibiting TNF-alpha production induced with okadaic acid (OA) in the same cell line. The diphenylmaleimide derivative 2f, was found to be the most active product, producing a strong modulation of the cytokine level.

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

    Science.gov (United States)

    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.

  9. Induction of human cytochrome P450 3A enzymes in cultured placental cells by thalidomide and relevance to bioactivation and toxicity.

    Science.gov (United States)

    Murayama, Norie; Kazuki, Yasuhiro; Satoh, Daisuke; Arata, Kazuya; Harada, Tasuku; Shibata, Norio; Guengerich, F Peter; Yamazaki, Hiroshi

    2017-01-01

    Evidence has been presented for auto-induced human cytochrome P450 3A enzyme involvement in the teratogenicity and clinical outcome of thalidomide due to oxidation to 5-hydroxythalidomide and subsequent metabolic activation in livers. In this study, more relevant human placenta preparations and placental BeWo cells showed low but detectable P450 3A4/5 mRNA expression and drug oxidation activities. Human placental microsomal fractions from three subjects showed detectable midazolam 1´- and 4-hydroxylation and thalidomide 5-hydroxylation activities. Human placental BeWo cells, cultured in the recommended media, also indicated detectable midazolam 1´- and 4-hydroxylation and thalidomide 5-hydroxylation activities. To reduce any masking effects by endogenous hormones used in the recommended media, induction of P450 3A4/5 mRNA and oxidation activities were measured in placental BeWo cells cultured with a modified medium containing 5% charcoal-stripped fetal bovine serum. Thalidomide significantly induced P450 3A4/5, 2B6, and pregnane X receptor (PXR) mRNA levels 2 to 3-fold, but rifampicin only enhanced P450 3A5 and PXR mRNA under the modified media conditions. Under these modified conditions, thalidomide also significantly induced midazolam 1´-hydroxylation and thalidomide 5-hydroxylaion activities 3-fold but not bupropion hydroxylation activity. Taken together, activation of thalidomide to 5-hydroxythalidomide with autoinduction of P450 3A enzymes in human placentas, as well as livers, is suggested in vivo.

  10. Thalidomide enhanced the efficacy of CHOP chemotherapy in the treatment of diffuse large B cell lymphoma: A phase II study.

    Science.gov (United States)

    Ji, Dongmei; Li, Qiu; Cao, Junning; Guo, Ye; Lv, Fangfang; Liu, Xiaojian; Wang, Biyun; Wang, Leiping; Luo, Zhiguo; Chang, Jianhua; Wu, Xianghua; Hong, Xiaonan

    2016-05-31

    Cyclophosphamide, doxorubicin, vincristine, and prednisolone plus rituximab (R-CHOP) is the standard treatment for patients with diffuse large B cell lymphoma (DLBCL). However, rituximab cannot be popularly applied in a considerable number of patients with DLBCL because of economic reasons. To develop a new regimen to improve the outcome of these patients is extremely important. In our study, sixty five patients with DLBCL were randomly assigned to thalidomide plus CHOP group (n=32) or to CHOP alone group (n=33). Objective response rates (ORR) and complete remission rates (CRR) were 96.7% and 80.6% in T-CHOP group versus 78.9 % and 57.8 % in CHOP group, respectively (P thalidomide did not significantly increase the grade 3/4 toxicity of CHOP. We concluded that the addition of thalidomide to the CHOP regimen significantly improved the CRR and showed a trend of improving clinical outcome in patients with DLBCL, especially for patients with Bcl-2 positive and Bcl-6 negative B-cell phenotype, without increased toxicity.

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

    Science.gov (United States)

    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 (PThalidomide 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.

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

    Science.gov (United States)

    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

  13. Thalidomide is more efficient than sodium butyrate in enhancing GATA-1 and EKLF gene expression in erythroid progenitors derived from HSCs with β-globin gene mutation.

    Science.gov (United States)

    Jalali Far, Mohammad Ali; Dehghani Fard, Ali; Hajizamani, Saiedeh; Mossahebi-Mohammadi, Majid; Yaghooti, Hamid; Saki, Najmaldin

    2016-01-01

    Efficient induction of fetal hemoglobin (HbF) is considered as an effective therapeutic approach in beta thalassemia. HbF inducer agents can induce the expression of γ-globin gene and produce high levels of HbF via different epigenetic and molecular mechanisms. Thalidomide and sodium butyrate are known as HbF inducer drugs. CD133(+) stem cells were isolated from umbilical cord blood of a newborn with minor β-thalassemia in order to evaluate the effects of these two drugs on the in vitro expression of GATA-1 and EKLF genes as erythroid transcription factors. CD133(+) stem cells were expanded and differentiated into erythroid lineage and then treated with thalidomide and sodium butyrate and finally analyzed by quantitative real-time PCR. Statistical analysis was performed using student's t-test by SPSS software. Thalidomide and sodium butyrate increased GATA-1 and EKLF gene expression, compared to the non-treated control (P<0.05). Thalidomide was more efficient than sodium butyrate in augmenting expression of GATA-1 and EKLF genes. It seems that GATA-1 and EKLF have crucial roles in the efficient induction of HbF by thalidomide.

  14. Thalidomide represses inflammatory response and reduces radiculopathic pain by inhibiting IRAK-1 and NF-κB/p38/JNK signaling.

    Science.gov (United States)

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

    2016-01-15

    Intervertebral disc (IVD) disease, the most common cause of disc failure and low back pain, is characterized by age-related changes in the adult disc. In this study we aimed to analyze the potential of thalidomide for the treatment of IVD disease, through identifying and explaining its anti-inflammatory and anti-catabolic activity in both in vitro IVD cell culture and in vivo animal model. Inflammatory response was induced by IL-1β, then the activity and expression of inflammatory mediators and pathways were assessed in the presence or absence of thalidomide. The p38 inhibitor SB203580 was also used to investigate the involvement of the MAPK pathway in the observed effects. Moreover the analgesic properties of thalidomide were analyzed by the von Frey filament test in Sprague-Dawley rats. Our results indicated that thalidomide significantly inhibited the expression of pro-inflammatory mediators and matrix metalloproteinases in vitro, as well as radiculopathic pain in vivo, most probably by modulation of the activity of IRAK-1 and its downstream effectors p38, JNK and NF-κB. Our current study strongly supports the potential of thalidomide for the treatment of pain and inflammation in degenerative disc disease. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Bortezomib-thalidomide-based regimens improved clinical outcomes without increasing toxicity as induction treatment for untreated multiple myeloma: a meta-analysis of phase III randomized controlled trials.

    Science.gov (United States)

    Huang, Hejing; Zhou, Lili; Peng, Lihui; Fu, Weijun; Zhang, Chunyang; Hou, Jian

    2014-09-01

    Novel agents thalidomide and bortezomib have significantly improved myeloma treatment. However, it remains unclear whether patients will benefit more from the combination therapy of these two agents. Our meta-analysis aims to compare the efficiency, and more importantly, the safety of bortezomib-thalidomide-based (VT-based) versus bortezomib-based or thalidomide-based (V-based/T-based) regimens as induction therapy in patients with previously untreated myeloma. Overall, five phase III RCTs including 1765 patients were identified. Compared with V-based or T-based regimens, VT-based regimens significantly improved CR (OR=2.22, 95% CI [1.44, 3.43]), ORR (OR=2.19, 95% CI [1.51, 3.19]) as well as PFS (HR=0.69, 95% CI [0.54, 0.88]), but not OS (HR=1.04, 95% CI [0.91, 1.19]). Notably, most expected side effects of bortezomib or thalidomide were comparable in both groups, including hematologic (anemia, neutropenia, thrombocytopenia), nonhematologic (peripheral neuropathy, deep venous thrombosis, infections, gastrointestinal events) side effects and discontinuation during or after induction therapy. These results suggest that combination of thalidomide and bortezomib might be a better first-line choice for patients with untreated myeloma. Copyright © 2014 Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

    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

  17. Talidomida: indicações em Dermatologia Thalidomide: indications in Dermatology

    Directory of Open Access Journals (Sweden)

    Rubem David Azulay

    2004-10-01

    Full Text Available A talidomida, descoberta na Alemanha Oriental, em 1954, mostrou vários efeitos terapêuticos: antiemético, sedativo e hipnótico. De 1959 a 1961, foram descritas cerca de 12.000 crianças nascidas com defeitos teratogênicos. Seu uso foi, conseqüentemente, suspenso. Sheskin, entretanto, recomeçou a usar a droga e verificou efeito benéfico no eritema nodoso leprótico. A talidomida é derivada do ácido glutâmico. Sua eliminação urinária é mínima (1%. Tem ações: antiinflamatória, imunomoduladora e antiangiogênica. Tem sido usada, com certo êxito terapêutico, em algumas entidades mais adiante estudadas. O principal efeito adverso é teratogênico: alterações nos membros, orelhas, olhos e órgãos internos. Supõe-se que esses efeitos teratogênicos decorram da ação antiangiogênica. Outros efeitos adversos: cefaléia, secura da pele e da mucosa da boca, prurido, erupção cutânea, aumento de peso, hipotireoidismo, neutropenia, bradicardia ou taquicardia e hipotensão. Interage com outros fármacos: barbitúrico, clorpromazina, reserpina, álcool, acetaminofen, histamina, serotonina e prostaglandina.Thalidomide was discovered in East Germany in 1954. It presented with several therapeutic effects: antiemetic, sedative and hypnotic. From 1959 to 1961, roughly 12,000 children born with teratogenic defects were described. Its use was consequently halted. Sheskin started using the drug again and observed its beneficial effect on erythema nodosa leprosum. Thalidomide is derived from glutamic acid. Its urinary elimination is minimal (1%. It has the following actions: anti-inflammatory, immunomodulary and antiangiogenic. It has been used with a successful therapeutic outcome on some entities, which have been studied further. The main side effect is teratogenic: limb alterations, ears, eyes and internal organs. The teratogenic effects are assumed to result from antiangiogenic action. Other side effects are cephalea, dry skin and mouth

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

    Directory of Open Access Journals (Sweden)

    Alessia Nicotra

    Full Text Available 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.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.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.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.

  19. Thalidomide treatment modulates macrophage pro-inflammatory function and cytokine levels in Klebsiella pneumoniae B5055 induced pneumonia in BALB/c mice.

    Science.gov (United States)

    Kumar, Vijay; Harjai, Kusum; Chhibber, Sanjay

    2010-07-01

    Lung innate immune response plays an important role in the clearance of pathogens from lungs, however, profound activation of innate immune cells (alveolar macrophages or neutrophils) can lead to development of acute lung inflammation or injury by producing various pro-inflammatory molecules (IL-1, TNF-alpha and H2O2 etc.). Present study is designed to investigate the immunomodulatory action of thalidomide in Klebsiella pneumoniae B5055 induced acute lung infection in BALB/c mice. Acute lung inflammation was induced by intranasal instillation of K. pneumoniae B5055 into mice without any anaesthesia and treated with thalidomide (30 mg/kg/day/po) or normal saline orally using a treatment schedule shown to modulate pro-inflammatory innate immune response. Thalidomide treatment modulated pro-inflammatory function of alveolar macrophages by significantly (ppneumonia caused by gram negative bacterial infection. 2010 Elsevier B.V. All rights reserved.

  20. No influence of the polymorphisms CYP2C19 and CYP2D6 on the efficacy of cyclophosphamide, thalidomide, and bortezomib in patients with Multiple Myeloma

    DEFF Research Database (Denmark)

    Vangsted, A. J.; Soeby, K.; Klausen, T.W.

    2010-01-01

    Background: The response to treatment varies among patients with multiple myeloma and markers for prediction of treatment outcome are highly needed. Bioactivation of cyclophosphamide and thalidomide, and biodegradation of bortezomib, is dependent on cytochrome P450 metabolism. We explored....... The patients were genotyped for the non-functional alleles CYP2C19*2 and CYP2D6*3, *4, *5 (gene deletion), *6, and CYP2D6 gene duplication. Results: In patients who were treated with bortezomib and were carriers of one or two defective CYP2D6 alleles there was a trend towards a better time-to-next treatment....... We found no association between the number of functional CYP2C19 and CYP2D6 alleles and outcome of treatment with cyclophosphamide or thalidomide. Neither was the number of functional CYP2C19 and CYP2D6 alleles associated with neurological adverse reactions to thalidomide and bortezomib. Conclusion...

  1. Consequences of increased vascular permeability induced by treatment of mice with 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and thalidomide.

    Science.gov (United States)

    Chung, Francisco; Liu, Jenny; Ching, Lai-Ming; Baguley, Bruce C

    2008-03-01

    5,6-Dimethylxanthenone-4-acetic acid (DMXAA) (AS1404), a small-molecule vascular disrupting agent currently in clinical trial, increases vascular permeability and decreases blood flow in both murine and human tumours. DMXAA induces tumour necrosis factor (TNF) in mice and the effects on vascular permeability are hypothesised to result from both direct (DMXAA) and indirect (TNF) effects. Skin temperature decreases in mice treated with high doses of DMXAA, raising the question of whether host toxicity is mediated by the induction of increased vascular permeability in normal tissue. Thalidomide is an anti-inflammatory agent that potentiates the anti-tumour activity of DMXAA but decreases induction of TNF in plasma. We wished to determine how it potentiated the effects of DMXAA. Vascular permeability was measured in Colon 38 tumour and liver tissue by uptake of Evans Blue dye. Blood haematocrit and body temperature were also measured. Tumour vascular permeability was increased following administration of DMXAA (25 mg/kg i.p.), minimally affected following thalidomide (100 mg/kg i.p.) but strongly increased following co-administration of both drugs. In contrast, dye uptake into liver tissue was decreased following administration of DMXAA, thalidomide or both drugs. Administration of DMXAA at a potentially toxic dose (35 mg/kg i.p. or 50 mg/kg orally) was found to decrease body temperature and to increase the blood haematocrit, while administration of thalidomide alone (100 mg/kg i.p.) had no effect. Co-administration of thalidomide potentiated the effects of DMXAA on both body temperature and haematocrit but surprisingly did not increase toxicity. The results are consistent with the hypothesis that the host toxicity of high-dose DMXAA is mediated by effects on host vasculature. Co-administration of thalidomide increases the effective dose of DMXAA by reducing clearance but also, by inhibiting production of circulating TNF, reduces the host toxicity of DMXAA.

  2. Evaluation of low-dose thalidomide as induction and maintenance therapy in patients with multiple myeloma not eligible for stem cell transplantation.

    Science.gov (United States)

    Aznab, Mozaffar; Rezaei, Mansour; Navabi, Jafar; Moieni, Ali

    2017-04-01

    The role of thalidomide in induction and long-term maintenance therapy in patients with multiple myeloma not eligible for stem cell transplantation remains unclear. The aim of the present study was to evaluate the effect of low-dose thalidomide as induction therapy and as maintenance therapy for 24 months in patients with a complete remission after the induction chemotherapy and to monitor the survival and relapse rates. Between October 2005 and September 2013, 50 patients with multiple myeloma received six courses of Cyclophosphamide-Vincristine Adriamycin and Dexamethazone (c-VAD) and pamidronate, and thalidomide 100 mg daily during induction, then thalidomide 100 mg daily for 24 months as maintenance. The effects of thalidomide were assessed objectively and subjectively. Whenever necessary, electromyography and nerve capacity volume were performed monthly for 6 months, then once every 3 months until the end of treatment. Primary response was 96% (CR or very good PR in 48/50 patients). Fifteen out of the remaining 48 patients relapsed during the follow-up period. Nine out of the 15 patients who relapsed showed very good partial response to treatment and four patients showed partial response. Survival rate was 81% in these patients. The primary outcome measures showed a mean and median progression-free survival of 33 and 27 months, respectively, and a mean and median overall survival of 43 and 39 months, respectively. Low-dose thalidomide during induction therapy combined with conventional chemotherapy and a 2-year maintenance may be effective in preventing the relapse and improving the overall survival. © 2015 Wiley Publishing Asia Pty Ltd.

  3. Thromboembolic Events Associated with Thalidomide and Multimodality Therapy for Soft Tissue Sarcomas: Results of RTOG 0330

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    J. M. Kane

    2012-01-01

    Full Text Available Introduction. RTOG 0330 was developed to address the toxicity of RTOG 9514 and to add thalidomide (THAL to MAID chemoradiation for intermediate/high grade soft tissue sarcomas (STSs and to preoperative radiation (XRT for low-grade STS. Methods. Primary/locally recurrent extremity/trunk STS: ≥8 cm, intermediate/high grade (cohort A: >5 cm, low grade (cohort B. Cohort A: 3 cycles of neoadjuvant MAID, 2 cycles of interdigitated THAL (200 mg/day/concurrent 22 Gy XRT, resection, 12 months of adjuvant THAL. Cohort B: neoadjuvant THAL/concurrent 50 Gy XRT, resection, 6 months of adjuvant THAL. Planned accrual 44 patients. Results. 22 primary STS patients (cohort A/B 15/7. Cohort A/B: median age of 49/47 years; median tumor size 12.8/10 cm. 100% preoperative THAL/XRT and surgical resection. Three cycles of MAID were delivered in 93% cohort A. Positive margins: 27% cohort A/29% cohort B. Adjuvant THAL: 60% cohort A/57% cohort B. Grade 3/4 venous thromboembolic (VTE events: 40% cohort A (1 catheter thrombus and 5 DVT or PE versus 0% cohort B. RTOG 0330 closed early due to cohort A VTE risk and cohort B poor accrual. Conclusion. Neoadjuvant MAID with THAL/XRT was associated with increased VTE events not seen with THAL/XRT alone or in RTOG 9514 with neoadjuvant MAID/XRT.

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

    Science.gov (United States)

    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

    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. 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. 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

  5. Talidomida no Brasil: vigilância com responsabilidade compartilhada? Thalidomide in Brazil: monitoring with shared responsibility?

    Directory of Open Access Journals (Sweden)

    Maria Auxiliadora Oliveira

    1999-01-01

    Full Text Available Este trabalho analisa questões relacionadas ao processo de regulação e uso racional da talidomida no Brasil, mediante abordagem histórica, que percorre três momentos distintos. O primeiro segmento é composto por um rastreamento dos caminhos percorridos por esse polêmico medicamento, desde a fase inicial de sua síntese, mercadização e banimento, ocorridos na década de 50 e início dos anos 60, até os dias atuais, quando se encontra em curso um processo, aparentemente irreversível, de reabilitação da droga. Em seguida, relata-se a experiência brasileira com o uso da talidomida, enfatizando o trabalho desenvolvido pela ABPST e pelo Morhan nos campos jurídico, político e institucional. São apresentados e analisados os resultados de uma pesquisa de busca ativa dos casos, que compõem a chamada segunda geração dos portadores da síndrome da talidomida no Brasil. Finalizando, à luz das evidências clínicas e científicas da eficácia terapêutica da talidomida, do crescimento de movimentos sociais a favor e contra a liberação do uso da mesma e da proposta de regulamentação restritiva do Ministério da Saúde, discutem-se aspectos relacionados à implementação da política de regulação e uso racional da talidomida no Brasil.This paper discusses issues related to the regulation and rational use of thalidomide in Brazil, by means of a historical approach comprising three different stages. The first part is a historical review of the controversial drug since it was first synthesized, then marketed and subsequently banned during the 1950s and 60s, until the present, when an apparently irreversible process of rehabilitating the drug is under way. Brazilian experience with the use of thalidomide is described, emphasizing legal, political, and institutional work led by two social movements, the Brazilian Association of People with Thalidomide Syndrome (ABPST and the Movement for Reintegration of People with Hansen's Disease

  6. A randomized phase 3 trial of thalidomide and prednisone as maintenance therapy after ASCT in patients with MM with a quality-of-life assessment: the National Cancer Institute of Canada Clinicals Trials Group Myeloma 10 Trial

    Science.gov (United States)

    Trudel, Suzanne; Bahlis, Nizar J.; White, Darrell; Sabry, Waleed; Belch, Andrew; Reiman, Tony; Roy, Jean; Shustik, Chaim; Kovacs, Michael J.; Rubinger, Morel; Cantin, Guy; Song, Kevin; Tompkins, Kirsty A.; Marcellus, Deb C.; Lacy, Martha Q.; Sussman, Jonathan; Reece, Donna; Brundage, Michael; Harnett, Erica L.; Shepherd, Lois; Chapman, Judy-Anne W.; Meyer, Ralph M.

    2013-01-01

    We conducted a randomized, controlled trial comparing thalidomide-prednisone as maintenance therapy with observation in 332 patients who had undergone autologous stem cell transplantation with melphalan 200 mg/m2. The primary end point was overall survival (OS); secondary end points were myeloma-specific progression-free survival, progression-free survival, incidence of venous thromboembolism, and health-related quality of life (HRQoL). With a median follow-up of 4.1 years, no differences in OS between thalidomide-prednisone and observation were detected (respective 4-year estimates of 68% vs 60%, respectively; hazard ratio = 0.77; P = .18); thalidomide-prednisone was associated with superior myeloma-specific progression-free survival and progression-free survival (for both outcomes, the 4-year estimates were 32% vs 14%; hazard ratio = 0.56; P thalidomide-prednisone and 34.1 months in the observation group. Nine second malignancies were observed with thalidomide-prednisone versus 6 in the observation group. Those allocated to thalidomide-prednisone reported worse HRQoL with respect to cognitive function, dyspnea, constipation, thirst, leg swelling, numbness, dry mouth, and balance problems. We conclude that maintenance therapy with thalidomide-prednisone after autologous stem cell transplantation improves the duration of disease control, but is associated with worsening of patient-reported HRQoL and no detectable OS benefit. PMID:23297129

  7. Talidomida usada por pacientes com eritema nodoso hansênico Thalidomide used by patients with erythema nodosum leprosum

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    Maria do Socorro da Silva Valente

    2010-04-01

    Full Text Available INTRODUÇÃO: A talidomida é um fármaco utilizado atualmente no tratamento do eritema nodoso hansênico no Brasil. MÉTODOS: Estudo prospectivo para acompanhar a evolução clínica, registrar os eventos adversos e determinar as concentrações plasmáticas de talidomida em dose diária de 100mg/dia, em 20 pacientes com manifestações clínicas de eritema nodoso hansênico, divididos em dois grupos: após ou em curso da poliquimioterapia para hanseníase. RESULTADOS: Não foram observadas diferenças significativas nos grupos no decorrer do estudo, tanto na evolução clínica favorável dos pacientes, de 70% e 90%, quanto nos eventos adversos registrados que foram tontura e sonolência. Os teores plasmáticos de talidomida em D7 e D14 foram de 0,82±0,4μg/mL e 0,79±0,3μg/mL no grupo 1 e de 0,82±0,4 e 1,55±1,0 no grupo 2, respectivamente. CONCLUSÕES: Na amostra estudada, a poliquimioterapia não interferiu na evolução clínica, na incidência dos efeitos adversos e nos níveis plasmáticos de talidomida.INTRODUCTION: Thalidomide is a drug currently used in Brazil for treating erythema nodosum leprosum. METHODS: This was a prospective study to follow up clinical evolution, record adverse events and determine plasma thalidomide levels from a dose of 100 mg/day, among 20 patients with clinical manifestations of erythema nodosum leprosum, divided into two groups: during or after leprosy multidrug therapy. RESULTS: No significant differences between the groups were seen during the study, either in relation to favorable clinical evolution among the patients (70% and 90%, or in relation to the adverse events recorded, which were dizziness and somnolence. The plasma thalidomide levels on D7 and D14 were 0.82 ± 0.4μg/ml and 0.79 ± 0.3 μg/ml in group 1 and 0.82 ± 0.4 and 1.55 ± 1.0 in group 2, respectively. CONCLUSIONS: In this sample, the multidrug therapy had no effect on the clinical evolution, incidence of adverse events and plasma

  8. Low-dose thalidomide ameliorates cytopenias and splenomegaly in myelofibrosis with myeloid metaplasia: a phase II trial

    DEFF Research Database (Denmark)

    Marchetti, Monia; Barosi, Giovanni; Balestri, Francesca

    2004-01-01

    daily and increasing to 400 mg as tolerated. RESULTS: Half of the patients sustained daily doses more than 100 mg and the drop-out rate was 51% at 6 months: the drop-out rate was lower in patients with high baseline fatigue score. At efficacy analysis, anemia was ameliorated in 22% of the patients...... score occurred in 31% of patients and was associated with a significant reduction of fatigue. Disease severity amelioration was independently predicted by a high baseline myeloproliferative index (ie, large splenomegaly, thrombocytosis, or leukocytosis). CONCLUSION: Low-dose thalidomide displays...

  9. Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials

    DEFF Research Database (Denmark)

    Fayers, Peter M; Palumbo, Antonio; Hulin, Cyrille

    2011-01-01

    carried out a meta-analysis of the 1685 individual patients in these trials. The primary endpoint was OS, and progression-free survival (PFS) and 1-year response rates were secondary endpoints. There was a highly significant benefit to OS from adding thalidomide to MP (hazard ratio = 0.83; 95% confidence...

  10. Effects of Some Natural Immunomodulatory Compounds in Combination with Thalidomide on Survival Rate and Tumor Size in Fibrosarcoma-Bearing Mice

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    Reza Aghebati Maleki

    2014-10-01

    Full Text Available Purpose: Despite significant advances have been achieved in cancer therapy, response to conventional treatments like surgery, radiotherapy and chemotherapy varies among individuals. Immunotherapy is known to be an effective strategy for patients who are resistant to the currently available interventions. Methods: Ninety-six male Balb/c mice (aged 6-8 weeks were selected and divided into twelve groups of eight. Approximately, 1×106of WEHI-164 cells were injected to each mouse for tumor genesis. Five immunotherapy treatments were considered in this study, including Heat Shock Proteins (HSP, Bacillus Calmette-Guérin (BCG, Bifidobacterium, Immuno-Modulator Drug (IMOD and Thalidomide. After tumor formation, the groups were treated with one or more of these therapies. Tumor size and survival rate was regularly monitored. Results: Depending on the treatment group, tumor sizes were different. In some groups, combined treatments demonstrated more inhibitory effects on tumor growth rate. The mice in group (IMOD+ Thalidomide had the lowest survival rate but group (BCG+ HSP+ Thalidomide survived until the end of the experiment. Conclusion: The (HSP+ BCG+ Thalidomide group exhibited satisfactory outcomes and two third of the mice in this group went into complete remission. Some combination therapies in test groups had significant impacts on survival and tumor growth rate.

  11. Thalidomide for treatment of gastrointestinal bleedings due to angiodysplasia : a case report in acquired von Willebrand syndrome and review of the literature

    NARCIS (Netherlands)

    Engelen, E T; van Galen, K P M; Schutgens, R E G

    INTRODUCTION: Acquired von Willebrand syndrome is a rare bleeding disorder and treatment of the associated gastrointestinal (GI) bleeding due to angiodysplasia is challenging. AIM: The aim of this study was to present a new case on the successful use of thalidomide in a patient with acquired von

  12. Comparison of Thromboemboli Prophylactic Effect of Aspirin and Low Dose Warfarin in Standard Risk Multiple Myeloma Patients that Treated with Regimens Containing Thalidomide

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    Seyed Amir Dadkhahi

    2017-05-01

    Full Text Available Abstract Background: Most of the current regimens in the treatment of multiple myeloma include thalidomide. Thalidomide is a modulator of the immune system and according to several studies, its main complication is thromboembolism. The aim of this study is to compare the thromboemboli prophylactic effect of aspirin and low dose warfarin in standard risk multiple myeloma patients that treated with regimens containing thalidomide. Materials and Methods: In this double- blind clinical trial study, sixty-six patients with multiple myeloma under treatment with thalidomide-containing regimens with standard risk for thromboembolism who were admitted to Khansari hospital, entered the study according to inclusion and exclusion criteria. The incidence of thromboembolism in these patients was evaluated. Results: Five patients in the warfarin group and 2 patients in the aspirin group had thromboemboli. Chi square analyses showed no significant difference between groups (p=0.635. Conclusion: The results showed that both drugs are effective in preventing thromboembolism and can be used as a prophylactic treatment.

  13. Old Drug Scaffold, New Activity: Thalidomide-Correlated Compounds Exert Different Effects on Breast Cancer Cell Growth and Progression.

    Science.gov (United States)

    Iacopetta, Domenico; Carocci, Alessia; Sinicropi, Maria Stefania; Catalano, Alessia; Lentini, Giovanni; Ceramella, Jessica; Curcio, Rosita; Caroleo, Maria Cristina

    2017-03-07

    Thalidomide was first used for relief of morning sickness in pregnant women and then withdrawn from the market because of its dramatic effects on normal fetal development. Over the last decades, it has been used successfully for the treatment of several pathologies, including cancer. Many analogues with improved activity have been synthesized and tested. Herein we report some effects on the growth and progression of MCF-7 and MDA-MB-231 breast cancer cells by a small series of thalidomide-correlated compounds, which are very effective at inducing cancer cell death by triggering TNFα-mediated apoptosis. The most active compounds are able to drastically reduce the migration of breast cancer cells by regulation of the two major proteins involved in epithelial-mesenchymal transition (EMT): vimentin and E-cadherin. Moreover, these compounds diminish the intracellular biosynthesis of vascular endothelial growth factor (VEGF), which is primarily involved in the promotion of angiogenesis, sustaining tumor progression. The multiple features of these compounds that act on various key points of the tumorigenesis process make them good candidates for preclinical studies. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Efficacy and safety of bortezomib, thalidomide, and lenalidomide in multiple myeloma: An overview of systematic reviews with meta-analyses.

    Science.gov (United States)

    Aguiar, Patricia Melo; de Mendonça Lima, Tácio; Colleoni, Gisele Wally Braga; Storpirtis, Sílvia

    2017-05-01

    This overview summarizes evidence for the efficacy and safety of bortezomib, thalidomide, and lenalidomide in patients with multiple myeloma. We searched the Medline, Scopus, and LILACS databases through August 2016, including systematic reviews with meta-analyses of randomized controlled trials assessing the efficacy and/or safety of bortezomib, thalidomide, or lenalidomide in patients with multiple myeloma. Two authors performed study selection, data extraction, and quality assessment using AMSTAR and GRADE instruments. Twenty-nine studies satisfied the inclusion criteria. All three drugs significantly improved overall response and progression-free survival; however, only bortezomib showed significantly greater overall survival compared with the control arm (induction therapy, continuous therapy, or at any phase of treatment). The main concerns on adverse events were thrombosis/embolism events, peripheral neuropathy, and second primary malignancies. The most common problems detected in systematic reviews were non-registration of the study protocol and conflicts of interest not clearly acknowledged. Future research should adhere to quality assessment tools so that best evidence can be used in decision-making. Protocol PROSPERO registration number: CRD42016036062. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Long-term Results of Single-Agent Thalidomide as Initial Therapy for Asymptomatic (Smoldering or Indolent) Myeloma

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    Detweiler-Short, Kristen; Hayman, Suzanne; Gertz, Morie A.; Lacy, Martha Q.; Dispenzieri, Angela; Kumar, Shaji; Zeldenrust, Steven R.; Russell, Stephen J.; Lust, John A.; Kyle, Robert A.; Greipp, Philip R.; Witzig, Thomas E.; Rajkumar, S. Vincent

    2010-01-01

    We report the long-term follow-up results of a phase II trial of thalidomide for early stage multiple myeloma (MM). Patients were eligible if they had smoldering multiple myeloma (SMM) or indolent MM without need for immediate therapy. Thalidomide was initiated at a dose of 200 mg/day and adjusted as tolerated. Disease progression was defined using modified American Society of Hematology/Food and Drug Administration consensus panel criteria for SMM. Thirty-one patients were enrolled; 29 (19 SMM, 10 indolent MM) were eligible. The median age was 61 years. Median follow up of living patients was 10.2 years (range, 7.5–11.0 years). Ten patients (34%) had a partial response (PR) and nine had minimal response (MR) for an MR plus PR rate of 66%. The median time to progression (TTP) to symptomatic myeloma was 35 months. Median TTP was 61 months in those achieving PR, 39 months with MR, and 9 months among those failing to achieve either MR or PR, p=0.005. Median overall survival from diagnosis was 86 months; median survival from onset of symptomatic myeloma was 49 months. Grade 3–4 non-hematologic adverse events were noted in 55% of patients. Randomized trials are needed to determine the role of early therapy in SMM. PMID:20730790

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

    Science.gov (United States)

    Lv, Peng; Meng, Qingshun; Liu, Jie; Wang, Chuanfang

    2015-11-01

    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. 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. 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. 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.

  17. Pharmacokinetics of {sup 99m} Tc-thalidomide in BALB/c mice: comparison of endovenous and intraperitoneal administration; Farmacocinetica da talidomida marcada com tecnecio-99m em camundongos BALB/C: comparacao entre via endovenosa e intraperitoneal

    Energy Technology Data Exchange (ETDEWEB)

    Moreno, Silvana R.F.; Motta, Ana Paula R.; Cardoso, Rejane C.; Bernardo-Filho, Mario [Universidade do Estado, Rio de Janeiro, RJ (Brazil). Inst. de Biologia Roberto Alcantara Gomes. Dept. de Biofisica e Biometria

    1999-11-01

    Thalidomide is a teratogenic agent that is being used in the treatment of lung tuberculosis infection, HIV-1, lupus eritomatosus and host graft disease. This is due to its efficient immunosuppressive action. We have chosen the technetium-99 m, for the labeling of thalidomide for to test the possibility of the thalidomide as a radiopharmaceutical. Furthermore, we are studying the behaviour of this labeled drug through the biodistribution in mice (intraperitoneal and endovenous via). The percentage of radioactivity per gram was determined for each organ. So much the inoculation by intraperitoneal as endovenous via showed that kidney had the largest uptake of {sup 99m} Tc-thalidomide in each period of time tested. In the control animal, free {sup 99m} Tc was found in the stomach. (author) 13 refs., 8 tabs.; e-mail: bernardo at uerj.br

  18. Polymorphism of IL-10 receptor β affects the prognosis of multiple myeloma patients treated with thalidomide and/or bortezomib.

    Science.gov (United States)

    Kasamatsu, Tetsuhiro; Saitoh, Takayuki; Ino, Rumi; Gotoh, Nanami; Mitsui, Takeki; Shimizu, Hiroaki; Matsumoto, Morio; Sawamura, Morio; Yokohama, Akihiko; Handa, Hiroshi; Tsukamoto, Norifumi; Murakami, Hirokazu

    2017-12-01

    Interleukin-10 (IL-10) and IL-10 receptor (IL-10R) single nucleotide polymorphisms have been implicated in the pathogenesis of many cancers. We investigated the influence of IL-10 -592C/A, IL-10RA I224V, and IL-10RB K47E on the risk of developing multiple myeloma (MM) and the clinical features of MM. We extracted the genomic DNA from 128 MM patients and 202 healthy controls and used polymerase chain reaction-restriction fragment length polymorphism method to detect IL-10 promoter -592C/A (rs1800872), IL-10RA (rs2228055), and IL-10RB K47E (rs2834167) genotypes. Overall survival (OS) was defined as the interval from the date of diagnosis to the date of death or last clinical appointment. No statistically significant difference was observed in the genotype and allele frequencies of IL-10 -592C/A, IL-10RA I224V, and IL-10RB K47E between MM patients and healthy controls. IL-10RA II genotype was significantly associated with a hemoglobin level lower than that of IV and VV genotypes (mean ± standard deviation, 9.21 ± 2.46 vs 10.3 ± 2.33 g/dL; P = .021). IL-10 -592 AA genotype was significantly associated with OS better than that of CA and CC genotypes (median OS, 74.5 vs 46.3 months; P = .047). We observed significant differences in survival between patients treated with thalidomide and/or bortezomib and those treated with conventional treatments (median OS, 74.5 vs 38.2 months; P = .021). Therefore, we also examined the effect of IL-10 and IL-10R polymorphisms on the clinical variables and OS of patients treated with thalidomide and/or bortezomib. In addition, IL-10RB EE genotype was significantly associated with poorer survival than KK and KE genotypes (median OS, 46.3 vs 78.8 months; P = .015). Our findings indicate that IL-10 and IL-10R gene polymorphisms may not contribute to the susceptibility to MM but may be associated with the severity and prognosis of MM. In particular, IL-10RB K47E polymorphism may contribute to the poor prognosis of MM

  19. Poor Safety and Tolerability Hamper Reaching a Potentially Therapeutic Dose in the Use of Thalidomide for Alzheimer's Disease: Results from a Double-Blind, Placebo-Controlled Trial.

    Science.gov (United States)

    Decourt, Boris; Drumm-Gurnee, Denise; Wilson, Jeffrey; Jacobson, Sandra; Belden, Christine; Sirrel, Sherye; Ahmadi, Michael; Shill, Holly; Powell, Jessica; Walker, Aaron; Gonzales, Amanda; Macias, Mimi; Sabbagh, Marwan N

    2017-01-01

    To date there is no cure for Alzheimer's disease (AD). After amyloid beta immunotherapies have failed to meet primary endpoints of slowing cognitive decline in AD subjects, the inhibition of the beta-secretase BACE1 appears as a promising therapeutic approach. Pre-clinical data obtained in APP23 mice suggested that the anti-cancer drug thalidomide decreases brainBACE1 and Aβ levels. This prompted us to develop an NIH-supported Phase IIa clinical trial to test the potential of thalidomide for AD. We hypothesized that thalidomide can decrease or stabilize brain amyloid deposits, which would result in slower cognitive decline in drug- versus placebo-treated subjects. This was a 24-week, randomized, double-blind, placebo-controlled, parallel group study with escalating dose regimen of thalidomide with a target dose of 400mg daily in patients with mild to moderate AD. The primary outcome measures were tolerability and cognitive performance assessed by a battery of tests. A total of 185 subjects have been pre-screened, out of which25 were randomized. Mean age of the sample at baseline was 73.64 (±7.20) years; mean education was 14.24 (±2.3) years; mean MMSE score was 21.00 (±5.32); and mean GDS score was 2.76 (±2.28).Among the 25 participants, 14 (56%) terminated early due to adverse events, dramatically decreasing the power of the study. In addition, those who completed the study (44%) never reached the estimated therapeutic dose of 400 mg/day thalidomide because of reported adverse events. The cognitive data showed no difference between the treated and placebo groups at the end of the trial. This study demonstrates AD patients have poor tolerability for thalidomide, and are unable to reach a therapeutic dose felt to be sufficient to have effects on BACE1. Because of poor tolerability, this study failed to demonstrate a beneficial effect on cognition. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  20. Thalidomide-based induction regimens are as effective as bortezomib-based regimens in elderly patients with multiple myeloma with cereblon expression.

    Science.gov (United States)

    Jung, Sung-Hoon; Choi, Hyun-Jung; Shin, Myung-Geun; Lee, Seung-Shin; Hwang, Eu Chang; Jung, Tae-Young; Cho, Min-Seok; Yang, Deok-Hwan; Ahn, Jae-Sook; Kim, Yeo-Kyeoung; Kim, Hyeoung-Joon; Lee, Je-Jung

    2016-10-01

    Cereblon (CRBN) has been identified as a primary target of immunomodulatory drugs and is considered a biomarker for the prediction of outcomes after thalidomide- or lenalidomide-based treatments. In this study, we evaluated CRBN expression in bone marrow (BM) tissue at diagnosis and investigated the relationship between CRBN expression and treatment outcomes after thalidomide- or bortezomib-based front-line therapies in 89 elderly patients with multiple myeloma (MM). CRBN expression at the time of diagnosis was evaluated with immunohistochemical (IHC) staining for myeloma cells in paraffin wax-embedded BM tissue. CRBN-immunostained slides were scored by intensity and diffuseness, and a total score of >6 was defined as CRBN-positive (CRBN(+)). Thirty-eight patients (45.2 %) were CRBN(+). Among patients treated with thalidomide-based regimens, CRBN(+) patients showed a better treatment response than did CRBN-negative patients (35.0 vs. 11.8 % complete response rate, respectively; HR = 4.038, P = 0.137). During a median follow-up of 31.8 months, patients treated with bortezomib-based regimens had a longer time to progression (TTP) than did patients treated with thalidomide-based regimens (15.6 vs. 13.2 months, respectively; P = 0.047), but early mortality occurred frequently in patients treated with bortezomib-based regimens. Additionally, there was no significant difference in survival outcomes between thalidomide- and bortezomib-based regimens in CRBN(+) patients (median TTP, 13.8 vs. 15.6 months, respectively; P = 0.842 and median OS, 39.3 vs. 30.1 months, respectively; P = 0.074). These data suggest that thalidomide-based regimens are as effective as bortezomib-based regimens in elderly patients with MM who are CRBN(+). Thus, CRBN positivity, by IHC staining, may be useful in deciding appropriate treatment options in elderly patients with MM.

  1. Polyunsaturated fatty acids synergize with lipid droplet binding thalidomide analogs to induce oxidative stress in cancer cells

    Directory of Open Access Journals (Sweden)

    Madácsi Ramóna

    2010-06-01

    Full Text Available Abstract Background Cytoplasmic lipid-droplets are common inclusions of eukaryotic cells. Lipid-droplet binding thalidomide analogs (2,6-dialkylphenyl-4/5-amino-substituted-5,6,7-trifluorophthalimides with potent anticancer activities were synthesized. Results Cytotoxicity was detected in different cell lines including melanoma, leukemia, hepatocellular carcinoma, glioblastoma at micromolar concentrations. The synthesized analogs are non-toxic to adult animals up to 1 g/kg but are teratogenic to zebrafish embryos at micromolar concentrations with defects in the developing muscle. Treatment of tumor cells resulted in calcium release from the endoplasmic reticulum (ER, induction of reactive oxygen species (ROS, ER stress and cell death. Antioxidants could partially, while an intracellular calcium chelator almost completely diminish ROS production. Exogenous docosahexaenoic acid or eicosapentaenoic acid induced calcium release and ROS generation, and synergized with the analogs in vitro, while oleic acid had no such an effect. Gene expression analysis confirmed the induction of ER stress-mediated apoptosis pathway components, such as GADD153, ATF3, Luman/CREB3 and the ER-associated degradation-related HERPUD1 genes. Tumor suppressors, P53, LATS2 and ING3 were also up-regulated in various cell lines after drug treatment. Amino-phthalimides down-regulated the expression of CCL2, which is implicated in tumor metastasis and angiogenesis. Conclusions Because of the anticancer, anti-angiogenic action and the wide range of applicability of the immunomodulatory drugs, including thalidomide analogs, lipid droplet-binding members of this family could represent a new class of agents by affecting ER-membrane integrity and perturbations of ER homeostasis.

  2. Multicenter investigation of lifestyle-related diseases and visceral disorders in thalidomide embryopathy at around 50 years of age.

    Science.gov (United States)

    Shiga, Tomoko; Shimbo, Takuro; Yoshizawa, Atsuto

    2015-09-01

    In utero exposure to thalidomide causes a wide range of birth defects, including phocomelia, hearing loss and visceral disorders, known as thalidomide embryopathy (TE). Fifty years after the first report of TE, we conducted the first cross-sectional multicenter study to investigate the development of lifestyle-related diseases and identify risk factors for visceral disorders in subjects with TE. Seventy-six cases with TE (31 men, 45 women) underwent medical examinations between 2011 and 2014 to determine the types of TE-related anomalies (limbs, auditory organs, or visceral organs) and lifestyle-related diseases present. Logistic multiple regression analyses, adjusted for gender and age, were conducted between TE and lifestyle-related diseases and to evaluate association between block vertebra and gallbladder aplasia. Fatty liver (FL), nonalcoholic FL disease and dyslipidemia were detected in 52.6%, 35.0%, and 23.7% of subjects, respectively, with higher incidences among men. Dyslipidemia was detected in 40.0% of subjects with FL and was significantly associated with FL (odds ratio = 8.86; p = 0.008). Block vertebrae were detected in 44.4% of subjects with gallbladder aplasia, and this association was significant (odds ratio = 9.96; p = 0.006). Subjects with TE have also a risk for lifestyle-related disease as well as the general Japanese population. In addition, cervical spine radiography and magnetic resonance imaging are recommended to assess block vertebrae in subjects with TE with gallbladder aplasia who develop shoulder pain. © 2015 Wiley Periodicals, Inc.

  3. The thalidomide-binding domain of cereblon defines the CULT domain family and is a new member of the β-tent fold.

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    Andrei N Lupas

    2015-01-01

    Full Text Available Despite having caused one of the greatest medical catastrophies of the last century through its teratogenic side-effects, thalidomide continues to be an important agent in the treatment of leprosy and cancer. The protein cereblon, which forms an E3 ubiquitin ligase compex together with damaged DNA-binding protein 1 (DDB1 and cullin 4A, has been recently indentified as a primary target of thalidomide and its C-terminal part as responsible for binding thalidomide within a domain carrying several invariant cysteine and tryptophan residues. This domain, which we name CULT (cereblon domain of unknown activity, binding cellular ligands and thalidomide, is also found in a family of secreted proteins from animals and in a family of bacterial proteins occurring primarily in δ-proteobacteria. Its nearest relatives are yippee, a highly conserved eukaryotic protein of unknown function, and Mis18, a protein involved in the priming of centromeres for recruitment of CENP-A. Searches for distant homologs point to an evolutionary relationship of CULT, yippee, and Mis18 to proteins sharing a common fold, which consists of two four-stranded β-meanders packing at a roughly right angle and coordinating a zinc ion at their apex. A β-hairpin inserted into the first β-meander extends across the bottom of the structure towards the C-terminal edge of the second β-meander, with which it forms a cradle-shaped binding site that is topologically conserved in all members of this fold. We name this the β-tent fold for the striking arrangement of its constituent β-sheets. The fold has internal pseudosymmetry, raising the possibility that it arose by duplication of a subdomain-sized fragment.

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

    Science.gov (United States)

    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

  5. No influence of the polymorphisms CYP2C19 and CYP2D6 on the efficacy of cyclophosphamide, thalidomide, and bortezomib in patients with Multiple Myeloma

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    Vogel Ulla

    2010-08-01

    Full Text Available Abstract Background The response to treatment varies among patients with multiple myeloma and markers for prediction of treatment outcome are highly needed. Bioactivation of cyclophosphamide and thalidomide, and biodegradation of bortezomib, is dependent on cytochrome P450 metabolism. We explored the potential influence of different polymorphisms in the CYP enzymes on the outcome of treatment. Methods Data was analyzed from 348 patients undergoing high-dose treatment and stem cell support in Denmark in 1994 to 2004. Clinical information on relapse treatment in 243 individual patients was collected. The patients were genotyped for the non-functional alleles CYP2C19*2 and CYP2D6*3, *4, *5 (gene deletion, *6, and CYP2D6 gene duplication. Results In patients who were treated with bortezomib and were carriers of one or two defective CYP2D6 alleles there was a trend towards a better time-to-next treatment. We found no association between the number of functional CYP2C19 and CYP2D6 alleles and outcome of treatment with cyclophosphamide or thalidomide. Neither was the number of functional CYP2C19 and CYP2D6 alleles associated with neurological adverse reactions to thalidomide and bortezomib. Conclusion There was no association between functional CYP2C19 and CYP2D6 alleles and treatment outcome in multiple myeloma patients treated with cyclophosphamide, thalidomide or bortezomib. A larger number of patients treated with bortezomib are needed to determine the role of CYP2D6 alleles in treatment outcome.

  6. Synergistic Effect of Sodium Butyrate and Thalidomide in the Induction of Fetal Hemoglobin Expression in Erythroid Progenitors Derived from Cord Blood CD133 + Cells

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    Ali Dehghanifard

    2012-07-01

    Full Text Available Background: The use of drugs with the ability to induce production of fetal hemoglobin as a novel therapeutic approach in treating β-Hemoglobinopathies is considered. γ-globin gene expression inducer drugs including sodium butyrate and thalidomide can reduce additional α-globin chains accumulation in erythroid precursors. Materials and Methods: In this experimental study, MACS kit was used to isolate CD133+ cells of umbilical cord blood. Further, the effect of two drugs of thalidomide and sodium butyrate were separately and combined studied on the induction of quantitative expression of β-globin and γ-globin genes in erythroid precursor cells derived from CD133+ stem cells in-vitro. For this purpose, the technique SYBR green Real-time PCR was used.Results: Flow cytometry results showed that approximately 95% of purified cells were CD133+. Real-time PCR results also showed the increased levels of γ-globin mRNA in the cell groups treated with thalidomide, sodium butyrate and combination of drugs as 2.6 and 1.2 and 3.5 times respectively, and for β-globin gene, it is respectively 1.4 and 1.3 and 1.6 times compared with the control group (p<0.05.Conclusion: The study results showed that the mentioned drug combination can act as a pharmaceutical composition affecting the induction of fetal hemoglobin expression in erythroid precursor cells derived from CD133 + cells.

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

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    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.

  8. Novel thalidomide analogues, “me too” drugs and the Brazilian law / Novos análogos da talidomida, medicamentos “me too” e a lei brasileira

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    Francisco José Roma Paumgartten

    2013-08-01

    Full Text Available In Brazil, thalidomide has been used virtually without interruption since it was launched as a new and revolutionary sedative drug in 1956. After 1965, when its effi cacy to treat erythema nodosum leprosum (ENL was discovered, it was regarded as an essential drug because the prevalence of Hansen’s disease is high in the country. In the 1990s and thereafter myriad novel therapeutic uses for thalidomide (autoimmmune diseases, multiple myeloma, aphthous ulcers in AIDS, and others have emerged owing to its immunomodulatory and antiangiogenic activities. Owing to a marked teratogenicity, however, the prescription and dispensing of thalidomide to patients is strictly controlled in Brazil and elsewhere. Notwithstanding the stringent regulations, a number of post-1965 cases of thalidomide embryopathy have occurred in Brazil. In 2003, a federal law (Law 10.651/2003 prohibited the sale and dispensing of thalidomide in commercial pharmacies. The law, however, made no provision for teratogenic drug analogues such as lenalidomide and pomalidomide, which have been cleared for marketing in the USA, Europe and other countries. Although they are much more expensive than thalidomide, the clinical superiority of novel ana-logues over thalidomide in multiple myeloma and other conditions remains unproven. Therefore, so far novel analogues can be considered as thalidomide “me too” drugs. This author strongly recommends that an amendment to the current law prohibiting the sale and dispensing of thalid-omide in commercial pharmacies be extended to thalidomide analogues. Moreover, we consider that a demonstration of clinical superiority over thalidomide (through gold-standard comparative effi cacy trials should be an essential requirement for registration of any teratogenic analogue. ---------------------------No Brasil, a talidomida tem sido usada praticamente sem interrupção desde o seu lançamento como novo e revolucionário medicamento sedativo em 1956

  9. Thalidomide and pentoxifylline block the renal effects of supernatants of macrophages activated with Crotalus durissus cascavella venom

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    A.M.C. Martins

    2004-10-01

    Full Text Available Because thalidomide and pentoxifylline inhibit the synthesis and release of tumor necrosis factor-alpha (TNF-alpha, we determined the effect of these drugs on the renal damage induced by supernatants of macrophages activated with Crotalus durissus cascavella venom in order to identify the role of TNF-alpha in the process. Rat peritoneal macrophages were collected with RPMI medium and stimulated in vitro with C.d. cascavella venom (10 µg/ml in the absence and presence of thalidomide (15 µM or pentoxifylline (500 µM for 1 h and washed and kept in culture for 2 h. Supernatant (1 ml was tested on an isolated perfused rat kidney (N = 6 for each group. The first 30 min of each experiment were used as control. The supernatant was added to the perfusion system. All experiments lasted 120 min. The toxic effect of the preparation of venom-stimulated macrophages on renal parameters was determined. At 120 min, thalidomide (Thalid and pentoxifylline (Ptx inhibited (P < 0.05 the increase in perfusion pressure caused by the venom (control = 114.0 ± 1.3; venom = 137.1 ± 1.5; Thalid = 121.0 ± 2.5; Ptx = 121.4 ± 4.0 mmHg, renal vascular resistance (control = 4.5 ± 0.2; venom = 7.3 ± 0.6; Thalid = 4.5 ± 0.9; Ptx = 4.8 ± 0.6 mmHg/ml g-1 min-1, urinary flow (control = 0.23 ± 0.001; venom = 0.44 ± 0.01; Thalid = 0.22 ± 0.007; Ptx = 0.21 ± 0.009 ml g-1 min-1, glomerular filtration rate (control = 0.72 ± 0.06; venom = 1.91 ± 0.11; Thalid = 0.75 ± 0.04; Ptx = 0.77 ± 0.05 ml g-1 min-1 and the decrease in percent tubular sodium transport (control = 77.0 ± 0.9; venom = 73.9 ± 0.66; Thalid = 76.6 ± 1.1; Ptx = 81.8 ± 2.0%, percent tubular chloride transport (control = 77.1 ± 1.2; venom = 71.4 ± 1.1; Thalid = 77.6 ± 1.7; Ptx = 76.8 ± 1.2%, and percent tubular potassium transport (control = 72.7 ± 1.1; venom = 63.0 ± 1.1; Thalid = 72.6 ± 1.0; Ptx = 74.8 ± 1.0%, 30 min before and during the stimulation of macrophages with C.d. cascavella venom

  10. 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.

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    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.

  11. ¿Por qué se está usando otra vez la talidomida? Why is thalidomide back?

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    Emilio Sanín Pérez

    2004-02-01

    óxica ni en la Enfermedad crónica injerto contra huésped. Background: in 1998 the FDA approved the restricted commercialization of Thalidomide for the treatment of Erithema Nodosum Leprosum. Brazil and Mexico have also regulated its use. Because of the current use of this teratogenic drug in rheumatological, dermatological, infectious and neoplasic diseases, it is necessary to instruct General Practitioners and specialists on its most relevant topics, active principle, benefic and deleterious effects. We carried out a revision by reading and analyzing controlled clinical trials, randomized or not, case series and reviews about thalidomide and its potential uses, that appeared in Medline from January 1993 to December 2003, to draw indications and contraindications in light of the evidence found in them. Results: forty six randomized controlled studies were found and 22 (with at least 50 patients described were reviewed (complete articles and/or including design and end points measured – expressed abstracts, plus 10 reviews and 22 cases series. The analysis allowed us to inform potential or restricted and not indicated uses of thalidomide in humans, its pharmacokynetic principles which explain its benefic and deleterious effects, and recommendations to prevent teratogenesis. Conclusion: thalidomide is available, with restrictions, for the treatment of Erithema Nodosum Leprosum (first line and Multiple Myeloma (refractory to multiple chemotherapy. It appears to have beneficial effects in many other serious conditions refractory to first line treatments: AIDS, esophagus and prostate cancer and some severe dermatosis, rheumatological or not.

  12. Subcutaneous Administration of Bortezomib in Combination with Thalidomide and Dexamethasone for Treatment of Newly Diagnosed Multiple Myeloma Patients

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    Shenghao Wu

    2015-01-01

    Full Text Available Objective. To investigate the efficacy and safety of the treatment of the newly diagnosed multiple myeloma (MM patients with the therapy of subcutaneous (subQ administration of bortezomib and dexamethasone plus thalidomide (VTD regimen. Methods. A total of 60 newly diagnosed MM patients were analyzed. 30 patients received improved VTD regimen (improved VTD group with the subQ injection of bortezomib and the other 30 patients received conventional VTD regimen (VTD group.The efficacy and safety of two groups were analyzed retrospectively. Results. The overall remission (OR after eight cycles of treatment was 73.3% in the VTD group and 76.7% in the improved VTD group (P>0.05. No significant differences in time to 1-year estimate of overall survival (72% versus 75%, P=0.848 and progression-free survival (median 22 months versus 25 months; P=0.725 between two groups. The main toxicities related to therapy were leukopenia, neutropenia, thrombocytopenia, asthenia, fatigue, and renal and urinary disorders. Grade 3 and higher adverse events were significantly less common in the improved VTD group (50% than VTD group (80%, P=0.015. Conclusions. The improved VTD regimen by changing bortezomib from intravenous administration to subcutaneous injection has noninferior efficacy to standard VTD regimen, with an improved safety profile and reduced adverse events.

  13. Synthesis and evaluation of novel dapsone-thalidomide hybrids for the treatment of type 2 leprosy reactions.

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    Yamasaki, Paulo Renato; do Nascimento, Dejair Caetano; Chelucci, Rafael Consolin; de Faria Fernandes Belone, Andréa; Rosa, Patrícia Sammarco; Diório, Suzana Madeira; de Melo, Thais Regina Ferreira; Barbieri, Karina Pereira; Placeres, Marisa Campos Polési; Carlos, Iracilda Zepone; Chung, Man Chin; dos Santos, Jean Leandro

    2014-07-15

    We synthesized a series of novel dapsone-thalidomide hybrids (3a-i) by molecular hybridization and evaluated their potential for the treatment of type 2 leprosy reactions. All of the compounds had analgesic properties. Compounds 3c and 3h were the most active antinociceptive compounds and reduced acetic acid-induced abdominal constrictions by 49.8% and 39.1%, respectively. The hybrid compounds also reduced tumor necrosis factor-α levels in lipopolysaccharide-stimulated L929 cells. Compound 3i was the most active compound; at concentrations of 15.62 and 125 μM, compound 3i decreased tumor necrosis factor-α levels by 86.33% and 87.80%, respectively. In nude mice infected with Mycobacterium leprae in vivo, compound 3i did not reduce the number of bacilli compared with controls. Compound 3i did not have mutagenic effects in Salmonella typhimurium strains TA100 and TA102, with or without metabolic activation (S9 mixture). Our results indicate that compound 3i is a novel lead compound for the treatment of type 2 leprosy reactions. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Randomized phase II adjuvant factorial study of dose-dense temozolomide alone and in combination with isotretinoin, celecoxib, and/or thalidomide for glioblastoma.

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    Penas-Prado, Marta; Hess, Kenneth R; Fisch, Michael J; Lagrone, Lore W; Groves, Morris D; Levin, Victor A; De Groot, John F; Puduvalli, Vinay K; Colman, Howard; Volas-Redd, Gena; Giglio, Pierre; Conrad, Charles A; Salacz, Michael E; Floyd, Justin D; Loghin, Monica E; Hsu, Sigmund H; Gonzalez, Javier; Chang, Eric L; Woo, Shiao Y; Mahajan, Anita; Aldape, Kenneth D; Yung, W K Alfred; Gilbert, Mark R

    2015-02-01

    Chemoradiation, followed by adjuvant temozolomide, is the standard treatment for newly diagnosed glioblastoma. Adding other active agents may enhance treatment efficacy. The primary objective of this factorial phase II study was to determine if one of 3 potential chemotherapy agents added to dose-dense temozolomide (ddTMZ) improves progression-free survival (PFS) for patients with newly diagnosed glioblastoma. A prior phase I trial established the safety of combining ddTMZ with isotretinoin, celecoxib, and/or thalidomide. Adults with good performance status and no evidence of progression post chemoradiation were randomized into 8 arms: ddTMZ alone (7 days on/7 days off) or doublet, triplet, and quadruplet combinations with isotretinoin, celecoxib, and thalidomide. The study enrolled 155 participants with a median age of 53 years (range, 18-84 y). None of the agents demonstrated improved PFS when compared with arms not containing that specific agent. There was no difference in PFS for triplet compared with doublet regimens, although a trend for improved overall survival (OS) was seen (20.1 vs 17.0 months, P = .15). Compared with ddTMZ, the ddTMZ + isotretinoin doublet had worse PFS (10.5 vs 6.5 months, P = .043) and OS (21.2 vs 11.7 months, P = .037). Trends were also seen for worse outcomes with isotretinoin-containing regimens, but there was no impact with celecoxib or thalidomide combinations. Treatment was well tolerated with expected high rates of lymphopenia. The results do not establish a benefit for these combinations but indicate that adding isotretinoin to ddTMZ may be detrimental. This study demonstrated the feasibility and utility of the factorial design in efficiently testing drug combinations in newly diagnosed glioblastoma. NCT00112502. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  15. Therapeutic effect of transcatheter arterial chemoembolization combined with thalidomide or sorafenib in treatment of unresectable primary liver cancer: a comparative analysis

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    ZHENG Kang

    2016-05-01

    Full Text Available ObjectiveTo investigate the therapeutic effect and adverse effects of transcatheter arterial chemoembolization (TACE combined with thalidomide or sorafenib in the treatment of unresectable primary liver cancer. MethodsA total of 102 patients who underwent TACE combined with thalidomide or sorafenib in 215 Hospital of Nuclear Industry of Shaanxi Province from January 2012 to August 2013 were enrolled and divided into TACE-thalidomide group (49 patients and TACE-sorafenib group (53 patients. The short-term outcome, long-term outcome, changes in related indices, and adverse events were evaluated. The independent-samples t-test was applied for comparison of continuous data between groups, and the paired t-test was applied for comparison of continuous data within one group; the chi-square test was applied for comparison of categorical data between groups; the survival curve was used for survival analysis, and the log-rank test was applied for survival comparison. ResultsThe indices of short-term outcome, objective response rate and disease control rate, showed no significant differences between the two groups. The 2-year survival showed a significant difference between the two groups (χ2=4692, P=0.03. The log-rank test showed that overall survival time and median progression-free survival time showed significant differences between the two groups (χ2=8.267 and 6.896, P=0.004 and 0.009. After treatment, alpha-fetoprotein (AFP and gamma-glutamyl transpeptidase (GGT showed significant differences between the two groups (t=2.035 and 2.843, P=0.038 and 0.025. The incidence rates of nausea/vomiting, dizziness/headache, rash/desquamation, and increased blood pressure showed significant differences between the two groups (all P<0.05. ConclusionTACE combined with thalidomide has the same short-term therapeutic effect as TACE combined with sorafenib and can improve the patient′s long-term outcome and significantly reduce the levels of AFP and GGT, but

  16. Restraining tumor necrosis factor-alpha by thalidomide prevents the amyloid beta-induced impairment of recognition memory in mice.

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    Alkam, Tursun; Nitta, Atsumi; Mizoguchi, Hiroyuki; Saito, Kuniaki; Seshima, Mitsuru; Itoh, Akio; Yamada, Kiyofumi; Nabeshima, Toshitaka

    2008-05-16

    No effective remedy has currently been realized to prevent the cognitive impairments of Alzheimer's disease (AD). The interruption of the toxic pathways of amyloid beta peptide (Abeta) still remains promising for the treatment. The involvement of tumor necrosis factor-alpha (TNF-alpha) in the toxicity of Abeta(1-40) in recent reports provide a fresh target for the interruption. In the current study, we evaluated the feasibility of a strategy that target TNF-alpha to prevent the impairment of memory induced by Abeta. The i.c.v-injection of Abeta(25-35) increased the hippocampal mRNA expression of both TNF-alpha and inducible nitric oxide synthase (iNOS), of which the former was stronger. The knock-out of TNF-alpha (TNF-alpha (-/-)) in mouse prevented the increase of iNOS mRNA induced by Abeta(25-35). Not only the inhibition of iNOS activity but also TNF-alpha (-/-) prevented the nitration of proteins in the hippocampus and the impairment of recognition memory in mice induced by Abeta(25-35). Daily treatment with thalidomide (20 mg/kg), a preferential degrader of TNF-alpha mRNA, or i.c.v.-injection of an anti-TNF-alpha antibody (10 etag/mouse) prevented the nitration of proteins in the hippocampus and the impairment of recognition memory induced by Abeta(25-35) or Abeta(1-40) in mice. These results suggested the practicability of targeting TNF-alpha as a preventive strategy against Abeta-mediated cognitive impairments.

  17. Results of a phase II study of thalidomide and azacitidine in patients with clinically advanced myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and low blast count acute myeloid leukemia (AML).

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    Kenealy, Melita; Patton, Nigel; Filshie, Robin; Nicol, Andrew; Ho, Shir-Jing; Hertzberg, Mark; Mills, Tony; Prosser, Ian; Link, Emma; Cowan, Linda; Zannino, Diana; Seymour, John F

    2017-02-01

    Single agent azacitidine or immunomodulatory drugs are effective in myelodysplastic syndrome (MDS), with differing target mechanisms and toxicities. Objectives of this ALLG MDS3 study in clinically advanced MDS, AMML and low blast AML were to establish safety, response and quality of life of azacitidine and thalidomide. Patients received azacitidine (75mg/m2/d sc 7days every 28 days), and oral thalidomide up to 100mg/d for maximum 12months. Eighty patients registered; median age 68 years (range 42-82), 49% IPSS int2-high. With 36.5 months follow up, patients received median 9 cycles azacitidine, 6.1mths thalidomide. Nonhematologic toxicity grade 3+ in 85%, commonly infections. Overall response rate was 63%; 26% CR were unaffected by IPSS. Median response duration 26.3months; overall survival was 28.1months. This combination azacitidine and thalidomide in clinically advanced MDS, CMML and low-blast AML was tolerable without unexpected toxicity and encouraging responses support further investigation of combination approaches with hypomethylating agent and immunomodulatory drug.

  18. Degenerative Changes in the Cervical Spine Are More Common in Middle-Aged Individuals with Thalidomide Embryopathy than in Healthy Controls.

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    Shadi A Ghassemi Jahani

    Full Text Available Thalidomide was used as a sedative drug for pregnant women in the 1950-60:s and resulted in children born with thalidomide embryopathy (TE, including upper limb malformations. These may alter the motion pattern of the cervical spine by the use of head/shoulder and mouth grip.To compare degenerative changes in the cervical spine in TE individuals with healthy controls (CTR.Twenty-seven middle-aged TE individuals and 27 age- and gender-matched CTR were examined by cervical spine MRI. The presence of malformations, disc herniation(s, osteophytes, nerve and medullary compression and the degree of disc degeneration (DD were evaluated.Significantly higher degree of DD was seen in the TE group compared with the controls (p<0.001. Similar frequencies of disc herniation and disc space narrowing were observed in the two groups, but more foraminal narrowing was seen in the TE group (p = 0.002. DD was observed relatively frequently at all cervical levels in the TE group, however, mainly at the two lower levels in the CTR.Middle-aged individuals with TE have a higher frequency of degenerative changes in the cervical spine than controls, possibly caused by an altered load on the cervical spine.

  19. Degenerative Changes in the Cervical Spine Are More Common in Middle-Aged Individuals with Thalidomide Embryopathy than in Healthy Controls.

    Science.gov (United States)

    Ghassemi Jahani, Shadi A; Danielsson, Aina; Ab-Fawaz, Rana; Hebelka, Hanna; Danielson, Barbro; Brisby, Helena

    2016-01-01

    Thalidomide was used as a sedative drug for pregnant women in the 1950-60:s and resulted in children born with thalidomide embryopathy (TE), including upper limb malformations. These may alter the motion pattern of the cervical spine by the use of head/shoulder and mouth grip. To compare degenerative changes in the cervical spine in TE individuals with healthy controls (CTR). Twenty-seven middle-aged TE individuals and 27 age- and gender-matched CTR were examined by cervical spine MRI. The presence of malformations, disc herniation(s), osteophytes, nerve and medullary compression and the degree of disc degeneration (DD) were evaluated. Significantly higher degree of DD was seen in the TE group compared with the controls (p<0.001). Similar frequencies of disc herniation and disc space narrowing were observed in the two groups, but more foraminal narrowing was seen in the TE group (p = 0.002). DD was observed relatively frequently at all cervical levels in the TE group, however, mainly at the two lower levels in the CTR. Middle-aged individuals with TE have a higher frequency of degenerative changes in the cervical spine than controls, possibly caused by an altered load on the cervical spine.

  20. 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

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    Jing Lu

    2015-01-01

    Full Text Available 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.

  1. Efficacy and safety of thalidomide for the treatment of severe recurrent epistaxis in hereditary haemorrhagic telangiectasia: results of a non-randomised, single-centre, phase 2 study.

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    Invernizzi, Rosangela; Quaglia, Federica; Klersy, Catherine; Pagella, Fabio; Ornati, Federica; Chu, Francesco; Matti, Elina; Spinozzi, Giuseppe; Plumitallo, Sara; Grignani, Pierangela; Olivieri, Carla; Bastia, Raffaella; Bellistri, Francesca; Danesino, Cesare; Benazzo, Marco; Balduini, Carlo L

    2015-11-01

    Hereditary haemorrhagic telangiectasia is a genetic disease that leads to multiregional angiodysplasia. Severe recurrent epistaxis is the most common presentation, frequently leading to severe anaemia. Several therapeutic approaches have been investigated, but they are mostly palliative and have had variable results. We aimed to assess the efficacy of thalidomide for the reduction of epistaxis in patients with hereditary haemorrhagic telangiectasia that is refractory to standard therapy. We recruited patients aged 17 years or older with hereditary haemorrhagic telangiectasia who had severe recurrent epistaxis refractory to minimally invasive surgical procedures into an open-label, phase 2, non-randomised, single-centre study at IRCCS Policlinico San Matteo Foundation (Pavia, Italy). We gave patients thalidomide at a starting dose of 50 mg/day orally. If they had no response, we increased the thalidomide dose by 50 mg/day increments every 4 weeks, until a response was seen, up to a maximum dose of 200 mg/day. After patients had achieved a response, they continued treatment for 8-16 additional weeks. The primary endpoint was the efficacy of thalidomide measured as the percentage of patients who had reductions of at least one grade in the frequency, intensity, or duration of epistaxis. We followed up patients each month to assess epistaxis severity score and transfusion need, and any adverse events were reported. We included all patients who received any study drug and who participated in at least one post-baseline assessment in the primary efficacy population. The safety population consisted of all patients who received any dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01485224. Between Dec 1, 2011, and May 12, 2014, we enrolled 31 patients. Median follow-up was 15·9 months (IQR 10·1-22·3). Three (10%, 95% CI 2-26) patients had a complete response, with bleeding stopped, 28 (90%, 95% CI 74-98) patients had partial responses

  2. Effect of thalidomide on the healing of colonic anastomosis, in rats Efeito da talidomida na cicatrização de anastomoses colônicas em ratos

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    Samuel Gama Veneziano

    2008-01-01

    Full Text Available PURPOSE: Thalidomide, because of its anti-inflammatory properties, as re-emerged as an option for the treatment of Crohn's disease refractory to standard therapy. We studied the effect of thalidomide on the healing of colonic anastomosis. METHODS: Sixty male rats (Rattus norvegicus, were divided into 3 groups of 20 animals each, respectively receiving 0.5 or 1.0 mg/kg thalidomide by the oral route for 7 days, or saline solution (control. All animals were submitted to continuous end-to-end anastomosis with 6-0 Prolene sutures. After sacrifice the anastomoses were analyzed macroscopically and submitted to determination of hydroxyproline, to histology and to immunohistochemistry for metalloproteinase 1, metalloproteinase 1 inhibitor and vascular endothelial growth factor (VEGF. RESULTS: Statistical analysis of the data showed no significant difference in macroscopic aspect or hydroxyproline determination (p= 0.5403. In the immunohistochemical analysis, the following p values were obtained: p = 0.5817 for VEGF, p = 0.1854 for metalloproteinase 1, and p = 0.0023 for metalloproteinase 1 inhibitor, with this last value being considered statistically significant. CONCLUSION: We conclude that thalidomide influenced collagen maturation. There was a stronger action of metalloproteinases, possibly indicating a negative tendency for the healing process.OBJETIVO: Sabe-se que agentes farmacológicos podem influenciar no processo de cicatrização. A talidomida, devido às suas propriedades antiinflamatórias, tem ressurgido como uma opção no tratamento da doença de Cröhn refratária à terapêutica convencional. Neste trabalho, estudamos o efeito da talidomida na cicatrização de anastomoses colônicas no rato. MÉTODOS: Foram utilizados 60 animais Rattus norvegius, com peso médio de 300g. Organizou-se 3 grupos de 20 animais, sendo um grupo controle (AC, um grupo (BD, com administração de talidomida 0,5 mg/kg por 7 dias e um grupo (AD com administra

  3. Middle-aged individuals with thalidomide embryopathy have undergone few surgical limb procedures and demonstrate a high degree of physical independence.

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    Shadi A Ghassemi Jahani

    Full Text Available Thalidomide is known to have induced thalidomide embryopathy (TE in more than 10,000 live-born children worldwide between 1957-1962.The aim of this study was to investigate the need for orthopaedic surgery and limb orthosis in relation to function and physical independence in middle-aged individuals with TE.13 women/18 men with a mean age of 45.8 (SD 1.1 years were included. Information about limb surgery, the use of orthotic devices, jobs, accommodation, disability adjustments and personal assistants was collected. Physical function was measured by a modified general function score. The time needed for activities of daily living (ADL was collected. Individuals with proximal focal femoral deficiency, PFFD, and participants in need of home or work adaptations were compared with the rest of the group.31 surgical procedures had been performed in the extremities. Three individuals were in need of personal assistance and seven had disability-adjusted homes. 28 individuals were working and 24 reported participation in exercises. Those with PFFD had significantly lower function score and needed a significantly longer time for ADL in the morning (p = 0.001 and p = 0.032. The group in need of home or work adjustments had significantly lower function score and needed longer time for morning ADL (p = 0.012 and p = 0.009.Few orthopaedic procedures had been performed. The TE individuals except the ones with PFFD and those in the need of disability adjustments, were mostly active workers, reported good physical function and participated in exercises, despite limb malformations.

  4. Dynamic MRI of the bone marrow for monitoring multiple myeloma during treatment with thalidomide as monotherapy or in combination with CED chemotherapy; Dynamische MRT des Knochenmarks zum Monitoring des Multiplen Myeloms unter Thalidomid-Monotherapie oder Kombination mit CED-Chemotherapie

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    Wasser, K. [Deutsches Krebsforschungszentrum, Heidelberg (Germany). Abt. Onkologische Diagnostik und Therapie; Universitaetsklinikum Mannheim (Germany). Inst. fuer Klinische Radiologie; Moehler, T.; Neben, K.; Goldschmidt, H.; Hillengass, J. [Universitaetsklinikum Heidelberg (Germany). Medizinische Klinik und Poliklinik V; Nosas, S.; Heiss, J.; Kauczor, H.U.; Delorme, S. [Deutsches Krebsforschungszentrum, Heidelberg (Germany). Abt. Onkologische Diagnostik und Therapie; Dueber, C. [Universitaetsklinikum Mannheim (Germany). Inst. fuer Klinische Radiologie

    2004-09-01

    Purpose: To quantify changes of bone marrow microcirculation in multiple myeloma (MM) using contrast enhanced dynamic MRI (dMRI) during thalidomide as antiangiogenic monotherapy or in combination with chemotherapy (cyclophosphamide, etoposide, dexamethasone). Materials and Methods: The study includes 63 patients with refractory or relapsed MM, who underwent dMRI with high temporal resolution (T1w-turboFLASH) of the lumbar spine before and following treatment. The contrast uptake was quantified using a two compartment model with the output parameters amplitude and k{sub ep} (exchange rate constant). The evaluation considered the initial dMRI finding (pathological or non-pathological) and the clinical therapeutic response (response or no response). Results: During monotherapy with thalidomide (n=38), no significant changes of the dMRI parameters were found, even when considering the initial dMRI finding (positive n=22) and the therapeutic response (responder n=14). The combination with chemotherapy (n=25) had a significant reduction of k{sub ep} (p=0.01) in 18 patients with positive initial dMRI finding and therapeutic response. Reduction of the amplitude was seen in most cases, but in the end without any significance (p=0.09). (orig.)

  5. Single nucleotide polymorphisms in the promoter region of the IL1B gene influence outcome in multiple myeloma patients treated with high-dose chemotherapy independently of relapse treatment with thalidomide and bortezomib

    DEFF Research Database (Denmark)

    Vangsted, Annette J.; Klausen, Tobias W.; Abildgaard, Niels

    2011-01-01

    the impact on outcome of HDT, INF-α maintenance treatment, and treatment with thalidomide and bortezomib at relapse, in relation to the major identified functional polymorphisms in the promoter region of IL1B. The wild-type C-allele of IL1B C-3737T and non-carriage of the IL1B promoter haplotype TGT (−3737T...... carriers at both loci. No relation to genotype and outcome was found for relapse patients treated with thalidomide or bortezomib. Our results indicate that a subpopulation of myeloma patients carrying the wild-type C-allele of IL1B C-3737T and non-carriers of the promoter haplotype TGT (−3737T, −1464G...

  6. 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.

    Science.gov (United States)

    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.

  7. 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.

    Science.gov (United States)

    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.

  8. Talidomida: novas perspectivas para utilização como antiinflamatório, imunossupressor e antiangiogênico Thalidomide: new perspectives for its use as antiinflammatory, immunossupressive and antiangiogenic drug

    Directory of Open Access Journals (Sweden)

    Larissa de Godoy Borges

    2003-01-01

    Full Text Available Esta revisão tem como objetivo apresentar os novos usos da talidomida. O interesse por este fármaco é devido às suas propriedades antiinflamatórias, immunossupressoras, antiangiogênicas e até mesmo antivirais. Embora o seu mecanismo de ação seja desconhecido, resultados demonstram com sucesso o emprego deste fármaco no eritema nodoso leproso, mieloma múltiplo, doença enxerto-versus-hospedeiro e também como inibidor do vírus HIV e tratamento dos sintomas da Aids. O trabalho também mostra que apesar dos benefícios, a talidomida exige um controle muito rigoroso no que diz respeito à sua utilização e sua dispensação, devido às suas propriedades teratogênicas. Contudo, a talidomida constitui-se numa importante alternativa farmacêutica, sendo que o seu verdadeiro potencial ainda está sendo investigado.The new uses of thalidomide are reviewed. It has recently been used as antinflammatory, immunosuppressive, antiangiogenic, and antiviral agent. Although its mechanism of action is not yet understood, the advantage of its use in several diseases, such as erythema nodosum leprosum, multiple myeloma, and graft-versus-host-disease is evident. Owing to its teratogenic properties, the use of thalidomide must be very well controlled. However, thalidomide has become a very important alternative, with new applications being studied.

  9. Estudo comparativo dos efeitos da talidomida, da ciclosporina e do diclofenaco na sobrevida de aloenxertos cutâneos em coelho Assessment of immunossupresion induced by thalidomide, cyclosporine and diclofenac on skin allograft survival in rabbits

    Directory of Open Access Journals (Sweden)

    Diva Novy Barbosa Chaves

    2008-02-01

    effects of cyclosporine, as an immunosuppressor model, and thalidomide and dyclofenac as anti-inflammatory drugs on an experimental skin allograft research. METHODS: Forty-two rabbits were divided in the following groups (n=6: Group 1 - autografting control; Group 2 - allografting control; Group 3 - allografts under thalidomide effect (100 mg/kg/day; Group 4 - allografts under sodium dyclofenac effect (2 mg/kg/day; - Group 5 -allografts under cyclosporine effect (10 mg/kg/day; Group 6 - allografts under cyclosporine effect (5 mg/kg/day; Group 7- allografts under cyclosporine (5 mg/kg/day plus thalidomide (100 mg/kg/day effect. Drugs were given via orogastric tube since the day before transplantation and daily during the postoperative period. Circular total skin grafts of the ear were exchanged between California and White New Zealand rabbits. RESULTS: Cyclosporine 10 mg/kg/day increased allograft survival and this effect was comparable to the association of cyclosporine 5 mg/kg/day with thalidomide 100 mg/kg/day. Thalidomide as an isolated drug and dyclofenac had a minimum effect on the average survival of the skin allografts. The number of eosinophils around the necrotic skin was higher in the dyclofenac group and lower in the group receiving cyclosporine associated with thalidomide. CONCLUSION: This study showed that thalidomide may be an useful drug when associated with subtherapeutic doses of cyclosporine for treatment of skin allografts.

  10. Thalidomide Analogs in Brazil: Concern About Teratogenesis / Análogos da Talidomida no Brasil: Preocupação com a Teratogênese

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    Fernanda Sales Luiz Vianna

    2014-05-01

    Full Text Available It has been more than 50 years since thalidomide was withdrawn from the world market due to its teratogenic potential. However, its widespread use around the world resumed due to its immunomodulatory and anti-angiogenic properties. The drug established itself in new therapies, and interest continued with the emergence of more potent analogs, the most notable being lenalidomide and pomalidomide, which are not approved in Brazil. The question that arises after analog synthesis is: Do these drugs also have the same teratogenic potential? The answer to this question is based only on experimental studies because exposure to humans is not authorized and has not yet been descri-bed. Although thalidomide has been recognized as a powerful human teratogen for many years, its molecular mechanisms of teratogenesis remain to be fully explained. Efforts with animal models and human genetic studies have clarified some important pathways that are most likely involved in the teratogenic action of thalidomide. However, it has not yet been possible to identify the teratogenic domain of the molecule from the therapeutic ones. Moreover, there are species-specific differences that must be taken into consideration when teratogenicity is evaluated. -------------------------------------------------------------- Faz mais de 50 anos que a talidomida foi retirada do mercado mundial devido ao seu potencial teratogênico. Entretanto, seu uso disseminado em todo o mundo foi retomado devido às suas propriedades imunomodulatórias e antiangiogênicas. A droga foi utilizada em novas terapias e o interesse continuou com a emergência de análogos mais potentes, os mais notáveis deles sendo a lenalidomida e a pomalidomida, que não estão aprovados no Brasil. A questão que surge após a síntese dos análogos é: Estas drogas também têm o mesmo potencial teratogênico? A resposta a esta pergunta baseia-se apenas em estudos experimentais, pois a exposição a humanos não est

  11. Effects of the tumour necrosis factor-alpha inhibitors pentoxifylline and thalidomide in short-term experimental oral mucositis in hamsters.

    Science.gov (United States)

    Lima, V; Brito, G A C; Cunha, F Q; Rebouças, C G; Falcão, B A A; Augusto, R F; Souza, M L P; Leitão, B T; Ribeiro, R A

    2005-06-01

    Oral mucositis is a frequent side-effect of cancer therapy. A definitive method of prophylaxis or treatment is not yet available. As pentoxifylline (PTX) and thalidomide (TLD) have been shown to inhibit cytokine synthesis, we studied the effects of these cytokine inhibitors in an experimental oral mucositis model. Oral mucositis was induced in Golden hamsters by the administration of 5-fluorouracil (5-FU) followed by mechanical trauma of the cheek pouch. On days 4, 5, 10, 12, 14 and 16, lesions induced by 5-FU were examined macroscopically and microscopically, and the presence and intensity of hyperemia, erythema, edema, inflammatory cell infiltration, hemorrhagic areas, ulcers and abscesses were recorded. Saline (control), PTX (5, 15, 45 mg kg(-1)) or TLD (10, 30, 90 mg kg(-1)) were administered daily and animals were killed on day 10 for macroscopic and histological analysis and assay of myeloperoxidase (MPO) activity. Animals were weighed daily, and total and differential leukocyte counts were performed on peripheral blood. PTX and TLD were found to reduce the macroscopic and histological parameters of oral mucositis and MPO activity. PTX and TLD also reversed peripheral neutrophilia, but only PTX prevented weight loss. The results indicate a protective effect of PTX and TLD, suggesting an important role for tumour necrosis factor-alpha (TNF-alpha) in the pathophysiology of 5-FU induced-oral mucositis in hamsters. (c) Eur J Oral Sci, 2005

  12. Treatment of Light Chain Deposition Disease Using Bortezomib-Based Regimen Followed by Thalidomide-Based Regimen in a Saudi Male

    Directory of Open Access Journals (Sweden)

    Bappa Adamu

    2016-01-01

    Full Text Available Light chain deposition disease (LCDD is a rare illness with, as yet, no clear evidence-based guidelines for its treatment. To the best of our knowledge, LCDD has not been previously reported from Saudi Arabia. We present in this report, a 38-year-old Saudi male who presented with clinical features suggestive of hypertensive nephropathy but kidney biopsy later revealed the diagnosis of LCDD. His serum creatinine at presentation was 297 μmol/L which came down to 194 μmol/L on treatment with Bortezomib, Cyclophosphamide and Dexamethasone. His 24-hour protein excretion at presentation was 6 g/L which also came down to less than 1 g/day. He was later placed on Cyclophosphamide, Thalidomide, and Dexamethasone regimen because of persistent high titres of serum free light chains. He went into remission with undetectable serum free light chains and remained so for three years at the time of writing this report. We conclude that LCDD, though rare, does occur in Saudi population. The treatment of LCDD is challenging but the use of Bortezomib, a proteosome inhibitor, is promising. However, suboptimal response may require further treatment with other therapeutic options such as chemotherapy with alkylating agents or high-dose Melphalan with autologous stem cell transplant.

  13. Embryopathic effects of thalidomide and its hydrolysis products in rabbit embryo culture: evidence for a prostaglandin H synthase (PHS)-dependent, reactive oxygen species (ROS)-mediated mechanism.

    Science.gov (United States)

    Lee, Crystal J J; Gonçalves, Luisa L; Wells, Peter G

    2011-07-01

    Thalidomide (TD) causes birth defects in humans and rabbits via several potential mechanisms, including bioactivation by embryonic prostaglandin H synthase (PHS) enzymes to a reactive intermediate that enhances reactive oxygen species (ROS) formation. We show herein that TD in rabbit embryo culture produces relevant embryopathies, including decreases in head/brain development by 28% and limb bud growth by 71% (Pacid (PGMA) and 2-phthalimidoglutaric acid (PGA), were similarly embryopathic, attenuating otic vesicle (ear) and limb bud formation by up to 36 and 77%, respectively (Pacid (ETYA) or acetylsalicylic acid (ASA), or the free-radical spin trap phenylbutylnitrone (PBN), completely blocked embryonic 8-oxoG formation and/or embryopathies initiated by TD, PGMA, and PGA. This is the first demonstration of limb bud embryopathies initiated by TD, as well as its hydrolysis products, in a mammalian embryo culture model of a species susceptible to TD in vivo, indicating that all likely contribute to TD teratogenicity in vivo, in part through PHS-dependent, ROS-mediated mechanisms.

  14. Updated survivals and prognostic factor analysis in myeloma treated by a staged approach use of bortezomib/thalidomide/dexamethasone in transplant eligible patients

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    Chim Chor

    2010-11-01

    Full Text Available Abstract Background Bortezomib, an NFkB inhibitor, is an active agent for the treatment of myeloma (MM. We have reported a promising complete remission (CR rate for newly diagnosed myeloma patients treated by a staged approach, in which chemosensitive patients underwent autologous haematopoietic stem cell transplantation (auto-HSCT while less chemosensitive patients received salvage therapy with bortezomib/thalidomide/dexamethasone prior to auto-HSCT. Methods Herein, with an additional 13 months of follow-up, we reported the updated survivals, and examined potential prognostic factors impacting event-free (EFS and overall survival (OS. Results With a median follow-up of 30 months, the projected OS was 73% and EFS was 50.2%. Age, gender, clinical stage and DAPK methylation could not account for the differential chemosensitivity. Advanced ISS stage and DAPK methylation adversely impacted OS whereas oligoclonal reconstitution predicted superior EFS. Conclusions Our staged approach illustrated an economical use of expensive targeted agents while preserving a good CR rate and OS. The comparable survivals of chemosensitive and less chemosensitive patients suggested the staged approach might have abolished the adverse prognostic impact of suboptimal chemosensitivity. Finally, the adverse impact of DAPK methylation and favorable impact of oligoclonal reconstitution in myeloma warrants further study.

  15. Dynamic contrast-enhanced MRI for the evaluation of bone marrow microcirculation in hematologic malignancies before and during thalidomide therapy; Dynamische kontrastverstaerkte MRT zur Beurteilung der Knochenmarksmikrozirkulation bei malignen haematologischen Erkrankungen vor und waehrend einer Thalidomidtherapie

    Energy Technology Data Exchange (ETDEWEB)

    Scherer, A.; Wittsack, H.J.; Engelbrecht, V.; Moedder, U. [Duesseldorf Univ. (Germany). Inst. fuer Diagnostische Radiologie; Strupp, C.; Germing, U.; Gattermann, N.; Haas, R. [Duesseldorf Univ. (Germany). Klinik fuer Haematologie, Onkologie und klinische Immunologie; Willers, R. [Duesseldorf Univ. (Germany). Universitaetsrechenzentrum

    2002-03-01

    Purpose. The aim of the study was to measure microcirculation parameters by dynamic contrast-enhanced MRI (d-MRI) and to evaluate the anti-angiogentic effects during treatment with thalidomide in different hematologic malignancies. Methods. In 20 healthy normal persons, 20 patients with myelodysplastic syndromes (MDS), 10 patients with multiple myeloma (MM) and 10 with myelofibrosis (MF) a fast gradient echo sequence (Turbo fast low angle shot 2D) with a pump controlled bolus infusion of gadolinium-DTPA was performed before and in 18 of these after beginning (average of 4,3 months) of a thalidomide therapy. Two pharmacokinetic parameters - the amplitude and exchange-rate-constant - were calculated and a statistical comparison of these values between healthy persons and patients as well as a correlation with the clinical course was executed. Results. Compared with the normal controls the patients showed a higher amplitude (normal persons 14.4{+-}5.2, MDS 24.8{+-}8.1, MF 35.9{+-}4.3, MM 23.4{+-}3.6) and exchange-rate-constant (normal persons 0.124{+-}0.042, MDS 0.136{+-}0.036, MF 0.144{+-}0.068, MM 0.131{+-}0.034). In the d-MRI-follow-up examinations a signficant (p<0.005) reduction of the amplitude and exchange rate constant values was evident in 14 of 18 patients undergoing a thalidomide therapy. Clinically all of these patients showed a therapy responding with complete or partial diseases remission. Conclusions. In patients with hematologic malignancies significantly higher d-MRI-microcirculation parameters of the lumbar spine can be demonstrated than in normal persons. During anti-angiogenetic treatment with thalidomide a decrease of these values was observed in case of a responding to therapy. (orig.) [German] Fragestellung. Unser Ziel war die Beurteilung der Mikrovaskularisation und des antiangiogenetischen Effektes einer Thalidomidtherapie mittels dynamischer kontrastverstaerkter MRT (d-MRT) bei unterschiedlichen haematologischen Erkrankungen. Methodik. Bei 20

  16. Radiochemical quality control of phenobarbital, oxamniquine, amantadine and thalidomide molecules labelled with Technetium-99m; Controle de qualidade radioquimico das moleculas de fenobarbital, oxamniquine, amantadina e talidomida marcadas com tecnecio-99m

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    Oliveira, Marcia B.N. de; Correa, Rosane C.M.S.; Bernardo-Filho, Mario [Universidade do Estado, Rio de Janeiro, RJ (Brazil). Inst. de Biologia. Dept. de Biofisica e Biometria

    1996-07-01

    The quality control of radiopharmaceuticals is very important. When it is not carried out in can cause problems to the patient, as the necessity of the repetition of the examination and/or misinterpretation of the scintigraphic images. The chromatographic methods have good acceptance and can be used in paper, instant thin-layer chromatography and in gel. In this paper we show the chromatographic techniques applied to molecules labeled with technitium-99m (oxamniquine, phenobarbital, amantadine and thalidomide) used for research in our laboratory. (author)

  17. Agentes imunossupressores, talidomida e ácido valpróico nas síndromes mielodisplásicas Immunosuppressive agents, thalidomide and valproate acid in myelodysplastic syndromes

    Directory of Open Access Journals (Sweden)

    Elvira R. P. Velloso

    2006-09-01

    Full Text Available Agentes imunossupressores, como a globulina antitimocítica (GAL ou antilinfocítica (GAL e a ciclosporina A têm mostrado eficácia nas SMD, particularmente nos subtipos Anemias refratária (AR e nas SMD com fenótipo HLA-DR15, independente do grau de celularidade medular. Outras drogas disponíveis em nosso meio, de baixo custo, como a talidomida podem ser utilizada em pacientes refratários, e o ácido valpróico está sendo utilizado em ensaios clínicos. A quantificação da resposta a drogas deve utilizar os critérios de resposta do International Working Group (IWG. É proposto um fluxograma para uso de fatores de crescimento, agentes imunossupressores e talidomida em pacientes com SMD, de baixo risco, não candidatos a transplante de medula óssea (TMO.Patients with refractory anemia subtypes and HLA-DR15 with any degree of marrow cellularity have good responses to immunosuppressive agents, such as antithymocyte globulin, antilymphocyte globulin and cyclosporine A. Other cheaper drugs available in Brazil, including thalidomide may be useful in refractory patients. Valproate acid has started to be used in clinical trials. Response to treatment should be reported using the criteria proposed by the International Working Group. The use of growth factors, immunosuppressive agents and thalidomide in low risk patients with myelodysplastic syndromes who are not candidates for hematopoietic stem cell transplantation is suggested at the end of this publication.

  18. Underreporting of hemorrhagic and thrombotic complications of pharmaceuticals to the U.S. Food and Drug Administration: empirical findings for warfarin, clopidogrel, ticlopidine, and thalidomide from the Southern Network on Adverse Reactions (SONAR).

    Science.gov (United States)

    Moore, Thomas J; Bennett, Charles L

    2012-11-01

    The U.S. Food and Drug Administration's (FDA) Adverse Event Reporting System (AERS), familiarly known as "MedWatch," is the nation's primary tool for postmarket pharmaceutical safety surveillance. This system relies on adverse events voluntarily reported by health care providers and consumers either directly to the FDA or to drug manufacturers, which are required to prepare and forward the information to the agency. Little is known about how frequently adverse events are reported. Previous estimates range from 1 to 31% depending on the event, drug, and time period. We used published incidence studies to calculate reporting rates for hemorrhage, emergency hospitalization, and venous thromboembolism (VTE) associated with four drugs. We estimated annual reporting rates of 1.07% for 33,171 emergency hospitalizations of patients older than 65 years associated with warfarin, 0.9% for 13,363 hospitalizations of clopidogrel and ticlopidine, and 1.02% for an estimated 67,200 hemorrhage cases associated with warfarin. We also estimated a 9-year reporting rate of 2.3% for VTE associated with thalidomide. The incidence of these hematologic adverse drug events is high and reporting rates are low, and near the lower boundary of the 1 to 15% range seen for other events. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  19. Talidomida no tratamento do eritema nodoso hansênico: revisão sistemática dos ensaios clínicos e perspectivas de novas investigações Thalidomide in the treatment of erythema nodosum leprosum (ENL: systematic review of clinical trials and prospects of new investigations

    Directory of Open Access Journals (Sweden)

    Gerson Oliveira Penna

    2005-10-01

    Full Text Available FUNDAMENTOS: A hanseníase persiste como problema de saúde pública, e episódios de ENH são eventos agudos que ocorrem antes, durante e após PQT. Na última década, o uso da talidomida como agente imunomodulador foi expandido a outras doenças. OBJETIVOS: realizar revisão sistemática dos ensaios clínicos publicados sobre a eficácia e efeitos colaterais da talidomida no ENH. Descrever metodologia e resultados da triagem para recrutamento de ensaio clínico visando avaliar dose-resposta da talidomida seguida de desmame no ENH moderado e grave, realizado no Brasil. MÉTODOS: Analisaram-se ensaios publicados sobre talidomida no ENH. Foi delineado um ensaio clínico duplo-cego randomizado para avaliar dose de 100 thalid 300mg/dia de talidomida durante fase aguda de ENH, seguida de desmame da talidomida, thalid placebo. Para este ensaio clínico descreve-se metodologia e dados de recrutamento de pacientes, com ênfase na gravidade dos episódios de ENH. RESULTADOS: Os seis ensaios clínicos publicados nas décadas de 1960 e 1970 apontam para o benefício da talidomida no ENH, embora diferenças metodológicas dificultem a comparação. Na fase de recrutamento do ensaio brasileiro, dos 143 pacientes de ENH triados, 65% eram potencialmente elegíveis. A associação com neurite em 56,4% dos ENH moderados e graves exigiu co-intervenção com corticosteróide. CONCLUSÃO: O padrão de recrutamento dos pacientes evidenciou alta freqüência de neurite nos episódios de ENH. O esquema de talidomida isolada no ENH foi avaliado como infreqüente na prática clínica brasileira. O desafio atual é acumular evidências sobre a eficácia e efeitos colaterais da talidomida em associação com corticosteróides.BACKGROUND: Leprosy remains a public health problem. Episodes of erythema nodosum leprosum (ENL are acute events that occur before, during and after polychemotherapy. In the last decade, the use of thalidomide as an immunomodulating agent was

  20. Thalidomide with peginterferon alfa-2b and ribavirin in the treatment of non-responders genotype 1 chronic hepatitis C patients: proof of concept Talidomida, peginterferón alfa-2b y ribavirina en el tratamiento de pacientes no respondedores con hepatitis crónica C genotipo 1: estudio piloto

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    Benjamín Pardo-Yules

    2011-12-01

    Full Text Available Background: fewer than half of patients infected with hepatitis C virus (HCV achieve sustained viral clearance after peginterferon alfa/ribavirin (Peg-IFN/RBV therapy. Aims: thalidomide posses anti-inflammatory and immunomodulatory properties through inhibition of tumor necrosis factor and costimulatory effect on human CD8+ T cells. Methods: we started a prospective, open label trial of retreatment of very-difficult-to-treat genotype 1 chronic hepatitis C patients (CHC patients, who had failed to respond to the (Peg-IFN/RBV, with a triple therapy consisting in these same antivirals plus thalidomide 200 mg/day (the TRITAL study. Results: none of the eleven patients fulfilling the inclusion criteria and included in the trial reached complete early virological response or sustained virological response. Viral load decline after 12 weeks of triple therapy thalidomide-based retreatment did not differ from viral dynamics during the first course. The triple therapy was well tolerated and only one patient developed mild bilateral neuropathy. Conclusions: thalidomide addition to standard therapy is tolerated and did not increase the SVR rate in very-difficult-to-treat genotype 1 CHC patients. Different schedules are warranted to improve attempting retreatment of non responder CHC patients.Antecedentes: menos de la mitad de los pacientes con hepatitis C logra eliminar el virus de manera sostenida después de la terapia con peginterferón alfa y ribavirina (Peg-IFN/RBV. Objetivos: la talidomida posee propiedades antiinflamatorias e inmunomoduladoras a través de la inhibición del TNF-α y al efecto estimulador sobre las células T CD8+. Métodos: se inició un estudio prospectivo y abierto de re-tratamiento de pacientes con hepatitis crónica C genotipo 1, no respondedores al tratamiento con Peg-IFN/RBV, mediante triple terapia añadiendo a los mismos antivirales 200 mg/día de talidomida. Resultados: ninguno de los once pacientes que fueron incluidos en

  1. Histiocitose de células de Langerhans com acometimento vulvar e com resposta terapêutica à talidomida: relato de caso Langerhans cells histiocytosis with vulvar involvement and responding to thalidomide therapy: case report

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    Lana Bezerra Fernandes

    2011-08-01

    Full Text Available A histiocitose de células de Langerhans é representante de um raro grupo de síndromes histiocitárias, sendo caracterizada pela proliferação das células de Langerhans. Suas manifestações variam de lesão solitária a envolvimento multissistêmico, sendo o acometimento vulvar incomum. Segue-se o relato de caso refratário da doença limitada à pele, em mulher de 57 anos. A paciente apresentava história de pápulas eritematosas ulceradas em couro cabeludo, face, vulva, tronco e axila há seis anos. O diagnóstico da doença é difícil, sendo confirmado neste caso através de estudo imuno-histoquímico e se obteve resposta terapêutica e eficaz, com a administração de talidomidaLangerhans cell histiocytosis is a member of a group of rare histiocytic syndromes and is characterized for the proliferation of histiocytes called Langerhans'cells. Its manifestations vary from a solitary injury to systemic involvement, and vulvar lesions are uncommon. We describe a refractory case of cutaneous limited disease in a 57-year-old woman. She presented with a 6-year history of an erythematous papular eruption of the scalp, face, vulva, trunk and axillae. The diagnosis is difficult and in this case it was confirmed through immunohistochemical study and clinical improvement was achieved with thalidomide

  2. Treatment of chronic hepatitis C in non-responsive patients with pegylated interferon associated with ribavirin and thalidomide: report of six cases of total remission Tratamento de hepatite C crônica em pacientes não respondedores, com a associação interferon peguilado, ribavirina e talidomida: Relato de seis casos

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    Marcos Montani Caseiro

    2006-04-01

    Full Text Available Hepatitis C virus (HCV infection is an important public health issue worldwide. It is estimated that over 170 million people are infected with the virus. The present study reports six cases in which patients did not respond to combination therapy with pegylated interferon and ribavirin. However, after the addition of thalidomide to the therapy, the patients presented negative RNA PCR. The use of thalidomide combined with pegylated interferon and ribavirin for the treatment of hepatitis C is described here for the first time in the related literature.A infecção pelo vírus da Hepatite C (HCV representa um importante problema de saúde pública no mundo, estima-se que mais de 170 milhões de pessoas estejam infectadas. Relatamos o encontro de 6 pacientes não respondedores à associação de Interferon Peguilado e Ribavirina que negativaram seu PCRRNA após a associação com talidomida. Trata-se do primeiro relato desta associação no tratamento da hepatite C encontrado na literatura.

  3. Long-term thalidomide use in refractory cutaneous lesions of systemic lupus erythematosus Uso da talidomida por tempo prolongado no tratamento das lesões cutâneas refratárias do lúpus eritematoso sistêmico

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    E. I. Sato

    1998-12-01

    Full Text Available OBJECTIVE: To evaluate the efficacy of long-term thalidomide treatment in cutaneous lesions of systemic lupus erythematosus (SLE, not responsive to conventional therapy. PATIENTS AND METHODS: Were selected 18 SLE patients (ACR criteria with active cutaneous lesions not responsive to chloroquine, photoprotectors and low doses prednisone and who presented good response to thalidomide but relapsed after withdrawal of the drug. All female patients had no risk of pregnancy. Thalidomide was reintroduced and maintained at low dose (25-100mg/day for a minimum of 6 months. RESULTS: Eighteen patients (16 females with mean age of 34.2yo (16-57y.o. received thalidomide for 6-21 months (mean 8.5m. The mean dose of prednisone at beginning of study was 38.3 mg/d and at the end was 9.7mg/d (pOBJETIVO: Avaliar a eficácia do uso prolongado de talidomida no tratamento das lesões cutâneas do lúpus eritematoso sistêmico (LES refratárias ao tratamento convencional. PACIENTES E MÉTODOS: Foram avaliados 18 pacientes (16 mulheres com LES (critério do ACR com lesões cutâneas ativas não-responsivas ao uso de cloroquina, fotoprotetores e prednisona em doses baixas, que haviam apresentado boa resposta ao uso de talidomida, mas tiveram reativação das lesões após sua suspensão. Todas as pacientes femininas não tinham nenhum risco de gravidez. Talidomida foi reintroduzida e mantida em doses baixas (25-100mg/dia por no mínimo seis meses. RESULTADOS: Dezoito pacientes (16 mulheres, com média de idade de 34,2 anos, receberam talidomida por 6 a 21 meses, com média de 8,5 meses. A dose média de prednisona, no início do estudo, foi de 38,3mg/dia e, no final, de 9,7 mg/dia (p<0,05. Remissão completa das lesões cutâneas foram observadas em 13 pacientes (72% e remissão parcial em cinco (28%. Os efeitos colaterais observados foram: sonolência em oito, obstipação intestinal em cinco, oligúria transitória em um, parestesia em mãos com eletromiografia normal

  4. Mucormycosis and chromoblastomycosis occurring in a patient with leprosy type 2 reaction under prolonged corticosteroid and thalidomide therapy Mucormicose e cromoblastomicose em um paciente com reação hansênica tipo II sob terapia prolongada com corticosteróide e talidomida

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    Flávia Machado Alves Basílio

    2012-10-01

    Full Text Available Mucormycosis is an uncommon fungal infection caused by Mucorales. It frequently occurs in patients with neutropenia, diabetes, malignancy and on corticoid therapy. However, it is rare in patients with AIDS. Clinical disease can be manifested in several forms. The case reported illustrates the rare occurrence of chromoblastomycosis and mucormycosis in an immunosuppressed patient with multibacillary leprosy, under prolonged corticosteroid and thalidomide therapy to control leprosy type 2 reaction. Neutrophil dysfunction, thalidomide therapy and work activities are some of the risk factors in this case. Chromoblastomycosis was treated by surgical excision and mucormycosis with amphotericin B. Although the prognosis of mucormycosis is generally poor, in the reported case the patient recovered successfully. This case should alert dermatologists to possible opportunistic infections in immunosuppressed patients.Mucormicose é uma infecção fúngica incomum causada por Mucorales. Ocorre frequentemente em pacientes com neutropenia, diabetes, corticoterapia e condições malignas. Porém, é rara em pacientes com AIDS. A doença pode apresentar-se em diferentes formas. Este caso ilustra a rara ocorrência de mucormicose e cromoblastomicose em um paciente com hanseníase multibacilar, que estava sendo tratado com prednisona e talidomida devido a eritema nodoso (reação hansênica tipo II. Disfunção de neutrófilos, uso de talidomida e atividades profissionais são alguns fatores de risco neste caso. A cromoblastomicose foi tratada por excisão cirúrgica e a mucormicose com anfotericina B. Embora o prognóstico da mucormicose seja ruim, neste caso o tratamento foi bem sucedido. Este caso alerta dermatologistas para a possibilidade de infecções oportunistas em pacientes imunossuprimidos.

  5. Combinatorial antileukemic disruption of oxidative homeostasis and mitochondrial stability by the redox reactive thalidomide 2-(2,4-difluoro-phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49) and flavopiridol.

    Science.gov (United States)

    Ge, Yun; Byun, Jung S; De Luca, Paola; Gueron, Geraldine; Yabe, Idalia M; Sadiq-Ali, Sara G; Figg, William D; Quintero, Jesse; Haggerty, Cynthia M; Li, Quentin Q; De Siervi, Adriana; Gardner, Kevin

    2008-09-01

    2-(2,4-Difluoro-phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49) is a member of a recently identified class of redox-reactive thalidomide analogs that show selective killing of leukemic cells by increasing intracellular reactive oxygen species (ROS) and targeting multiple transcriptional pathways. Flavopiridol is a semisynthetic flavonoid that inhibits cyclin-dependent kinases and also shows selective lethality against leukemic cells. The purpose of this study is to explore the efficacy and mechanism of action of the combinatorial use of the redox-reactive thalidomide CPS49 and the cyclin-dependent kinase inhibitor flavopiridol as a selective antileukemic therapeutic strategy. In combination, CPS49 and flavopiridol were found to induce selective cytotoxicity associated with mitochondrial dysfunction and elevations of ROS in leukemic cells ranging from additive to synergistic activity at low micromolar concentrations. Highest synergy was observed at the level of ROS generation with a strong correlation between cell-specific cytotoxicity and reciprocal coupling of drug-induced ROS elevation with glutathione depletion. Examination of the transcriptional targeting of CPS49 and flavopiridol combinations reveals that the drugs act in concert to initiate a cell specific transcriptional program that manipulates nuclear factor-kappaB (NF-kappaB), E2F-1, and p73 activity to promote enhanced mitochondrial instability by simultaneously elevating the expression of the proapoptotic factors BAX, BAD, p73, and PUMA while depressing expression of the antiapoptotic genes MCL1, XIAP, BCL-xL, SURVIVIN, and MDM2. The coadministration of CPS49 and flavopiridol acts through coordinate targeting of transcriptional pathways that enforce selective mitochondrial dysfunction and ROS elevation and is therefore a promising new therapeutic combination that warrants further preclinical exploration.

  6. Thalidomide in Treating Patients With Myelodysplastic Syndrome

    Science.gov (United States)

    2013-01-23

    Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Refractory Anemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Refractory Anemia With Ringed Sideroblasts; Secondary Myelodysplastic Syndromes

  7. Talidomida e mieloma múltiplo: verificação dos efeitos terapêuticos através de parâmetros clínico e laboratoriais Thalidomide and multiple myeloma: therapy evaluation using clinical and laboratorial parameters

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    Rosane Bittencourt

    2004-12-01

    mechanisms that interfere in the physiopathogenesis and bone marrow microenvironment are turning control and regression of the malignant plasma cell clone into something achievable, which may change expectations related to this disease. The new idea of using an old drug, thalidomide, has shown to be effective in multiple myeloma. In 1997, using the known effects of immunomodulation and anti-angiogenesis of this drug, clinical trials were started in patients with unresponsive disease. Other therapeutic interventions in the bone marrow microenvironment and plasma cells have been added and proved to be efficacious, not only as a therapy for refractory patients, but also for induction and/or remission maintenance therapy. Thirty-five patients with multiple myeloma were treated with low-dose thalidomide (100 mg and followed up. Thirteen were on maintenance therapy after bone marrow transplantation, eleven started thalidomide after induction therapy, five after relapse, four were refractory to usual therapies and two had induction therapy with thalidomide. The study took place in the Hematology and Bone Marrow Transplantation service of the Hospital de Clínicas de Porto Alegre, from March 2001 to December 2003. Hemoglobin levels, serum or urine immunoglobulin peaks and bone marrow plasma cell counts were evaluated. These parameters were assessed before starting with the drug and after 3.6 and 12 months of usage. The immunoglobulin level was considered the gold standard to evaluate the response. The results showed that 100 mg was the tolerable dose for 51% of the patients. Sixty-five percent of those who used thalidomide for induction therapy showed a 25 to 50% improvement in immunoglobulin serum levels and 90% of the patients on maintenance therapy (13 after bone marrow transplantation, 11 after induction, sustained the same immunoglobulin levels of the initial plateau.

  8. The role of thalidomide as maintenance after autologous stem cell transplantation in multiple myeloma Papel da talidomida como manutenção após transplante autólogo de células-tronco hematopoéticas em mieloma múltiplo

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    Angelo Maiolino

    2009-08-01

    Full Text Available Major progress was obtained over the last ten years in the treatment of multiple myeloma (MM. High dose chemotherapy with autologous stem cell transplantation (ASCT and new drugs such as thalidomide, lenalidomide and bortezomib have completely changed the scenario of MM treatment. ASCT has become the mainstay of MM treatment for patients up to 65 years old. This strategy has been tested in randomized clinical trials which proved that ASCT can improve overall survival of MM patients. Unfortunately, the great majority of these patients will relapse in a few years after ASCT. Strategies of maintenance have been developed trying to improve the results of ASCT. Thalidomide has been tested in this setting in at least 4 randomized clinical trials with a significant impact on response rate, and event free and overall survival.l.Grandes progressos foram obtidos nos últimos anos no tratamento do mieloma múltiplo (MM. Quimioterapia em altas doses seguida de transplante autólogo de células-tronco hematopoéticas (TCTH e a utilização de novas drogas, como a talidomida, lenalidomida e bortezomibe, mudaram completamente o cenário de tratamento do MM. O TCTH tornou-se padrão na abordagem de pacientes com MM recém-diagnosticado e idade inferior a 65 anos. Esta estratégia foi testada em estudos multicêntricos e randomizados, que demonstraram uma vantagem em termos de sobrevida global para os pacientes submetidos a TCTH. Infelizmente, a grande maioria dos pacientes irá recair em poucos anos após o TCTH. Estratégias de manutenção ou consolidação foram então desenvolvidas com o intuito de melhorar estes resultados. A talidomida foi testada como manutenção em pelo menos quatro estudos randomizados, tendo sido demonstrado um impacto favorável em termos de taxa de resposta e prolongamento da sobrevida global.

  9. Thalidomide in Treating Patients With Recurrent or Persistent Endometrial Cancer

    Science.gov (United States)

    2013-01-23

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

  10. The effect of thalidomide on cachexia in upper gastrointestinal cancer

    OpenAIRE

    Green, Susi

    2015-01-01

    Progress made in the palliation of those with terminal cancers has allowed most symptoms to be controlled if not completely alleviated. For many in this situation now, the most overwhelming and unpleasant ongoing problems are related to the accompanying cachexia. Cachexia - (Greek,kakos-bad, hexis-condition) a wasting syndrome that causes weakness and a loss of weight, fat, and muscle(1) Cachexia has direct and tangible consequences such as reducing independence to a level where the pat...

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

    Science.gov (United States)

    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...

  12. Different aspects of thalidomide treatment and stem cell transplantation in multiple myeloma patients

    NARCIS (Netherlands)

    Marion, A.M.W. van

    2006-01-01

    Multiple myeloma (MM) is an haematological malignancy caused by an unrestrained proliferation of plasma cells (monoclonally differentiated B-cells), and part of the white blood cell count. This proliferation infiltrates the blood forming skeletal bone marrow, producing osteoclastic factors, causing

  13. Drug: D00754 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D00754 Drug Thalidomide (JAN/USP/INN); Thalomid (TN); Thaled (TN) C13H10N2O4 258.06... Other Antitumors D00754 Thalidomide (JAN/USP/INN) Anatomical Therapeutic Chemical (ATC) classification [BR:...ther immunosuppressants L04AX02 Thalidomide D00754 Thalidomide (JAN/USP/INN) USP ...drug classification [BR:br08302] Antineoplastics Antiangiogenic Agents Thalidomide D00754 Thalidomide (JAN/U...SP/INN) Antineoplastics [BR:br08308] Biologic response modifiers Nonspecific immunomodulation Thalidomide [ATC:L04AX02] D00754 Thalid

  14. Combined pegylated liposomal doxorubicin and bortezomib is highly effective in patients with recurrent or refractory multiple myeloma who received prior thalidomide/lenalidomide therapy

    NARCIS (Netherlands)

    P. Sonneveld (Pieter); R. Hajek (Roman); A. Nagler (Arnon); A. Spencer (Andrew); J. Bladé (Joan); T. Robak (Tadeusz); S.H. Zhuang (Sen); J-L. Harousseau (Jean-Luc); R.Z. Orlowski (Robert)

    2008-01-01

    textabstractBACKGROUND. Recently, the authors reported improved time to disease progression (TTP) with a combination of pegylated liposomal doxorubicin (PLD) and bortezomib compared with bortezomib alone in a phase 3 randomized trial in patients with recurrent/refractory multiple myeloma (MM). In

  15. Combined pegylated liposomal doxorubicin and bortezomib is highly effective in patients with recurrent or refractory multiple myeloma who received prior thalidomide/lenalidomide therapy.

    NARCIS (Netherlands)

    Sonneveld, P.; Hajek, R.; Nagler, A.; Spencer, A.; Blade, J.; Robak, T.; Zhuang, S.H.; Harousseau, J.L.; Orlowski, R.Z.

    2008-01-01

    BACKGROUND: Recently, the authors reported improved time to disease progression (TTP) with a combination of pegylated liposomal doxorubicin (PLD) and bortezomib compared with bortezomib alone in a phase 3 randomized trial in patients with recurrent/refractory multiple myeloma (MM). In the current

  16. Partial Response at Completion of Bortezomib-Thalidomide-Dexamethasone (VTd) Induction Regimen Upfront in Multiple Myeloma Does Not Preclude Response to VTd in Consolidation

    Science.gov (United States)

    Fouquet, Guillemette; Hebraud, Benjamin; Garciaz, Sylvain; Stoppa, Anne Marie; Roussel, Murielle; Caillot, Denis; Chrétien, Marie Lorraine; Arnulf, Bertrand; Szalat, Raphael; Garderet, Laurent; Benajiba, Lina; Pegourie, Brigitte; Regny, Caroline; Royer, Bruno; Caulier, Alexis; Touzeau, Cyrille; Tessoulin, Benoit; Fermand, Jean Paul; Facon, Thierry; Attal, Michel; Loiseau, Hervé Avet; Moreau, Philippe; Leleu, Xavier

    2014-01-01

    The impact of consolidation on response rates and PFS has recently been demonstrated after induction and autotransplantation upfront in Multiple Myeloma (MM). We further showed that patients in ≥VGPR following the intensification procedure benefited most from consolidation. Question remains as to the benefit of consolidation for patients in PR at completion of induction - feature of partial resistance to the induction regimen. We collected data from 54 newly diagnosed MM treated with VTd-auto-VTd regimen that reached only PR at completion of the induction procedure. Overall, 37 patients (68%) improved depth of response (≥VGPR) at completion of consolidation, including 35% that reached CR and 38% solely related to consolidation. Of patients that remained on PR or improved depth of response after ASCT, 26% and 38% further responded to consolidation, respectively. With a median follow-up of 36 months, improved depth of response translated into lower relapse rate compared with patients remaining in PR, 19% vs. 36%. This difference was more striking in patients that reached CR vs. others, 8% and 38%, respectively (p=0.039). The median TTP was prolonged in patients that improved depth of response after consolidation (p=0.012), with a 3-year TTP of 87% vs. 18% otherwise. In multivariate analysis, lack of improved depth of response to consolidation independently predicted shorten median TTP [OR=4.4, 95%CI=1-21; p=0.039], with elevated LDH and beta2m, and adverse FISH. This study shows that VTd consolidation should be recommended to patients solely on PR at completion of induction with VTd, feature of lower sensitivity to VTd. PMID:24665349

  17. The impact of polymorphisms in P-gp, DNA repair and folic acid metabolism genes in newly diagnosed multiple myeloma patients treated with thalidomide plus dexamethasone, with or without bortezomib

    OpenAIRE

    Lyzbicki, Barnaba

    2012-01-01

    The principle aim of this study was to investigate biological predictors of response and resistance to multiple myeloma treatment. Two hypothesis had been proposed as responsible of responsiveness: SNPs in DNA repair and Folate pathway, and P-gp dependent efflux. As a first objective, panel of SNPs in DNA repair and Folate pathway genes, were analyzed. It was a retrospective study in a group of 454, previously untreated, MM patients enrolled in a randomized phase III open-label study. Res...

  18. 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

    Science.gov (United States)

    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

  19. 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.

    Science.gov (United States)

    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.

  20. Thalidomide–A Notorious Sedative to a Wonder Anticancer Drug

    Science.gov (United States)

    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

  1. A systematic literature review and network meta-analysis of treatments for patients with untreated multiple myeloma not eligible for stem cell transplantation

    DEFF Research Database (Denmark)

    Weisel, Katja; Doyen, Chantal; Dimopoulos, Meletios

    2017-01-01

    In newly diagnosed multiple myeloma (MM), patients ineligible for front-line autologous stem cell transplantation (ASCT), melphalan and prednisone (MP) with thalidomide (MPT) or bortezomib (VMP) are standard first-line therapeutic options. Despite new treatment regimens incorporating bortezomib...

  2. Multiple Myeloma Treatment Strategies with Novel Agents in 2011: A European Perspective

    DEFF Research Database (Denmark)

    Ludwig, Heinz; Beksac, Meral; Bladé, Joan

    2011-01-01

    Abstract The arrival of the novel agents thalidomide, bortezomib, and lenalidomide has significantly changed our approach to the management of multiple myeloma and, importantly, patient outcomes have improved. These agents have been investigated intensively in different treatment settings...

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

    Directory of Open Access Journals (Sweden)

    Veronica Schmitz

    2016-08-01

    Full Text Available 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

  4. Treatment of newly diagnosed myeloma

    Science.gov (United States)

    Palumbo, A; Rajkumar, SV

    2014-01-01

    The introduction of thalidomide, bortezomib and lenalidomide has dramatically changed the treatment paradigm of multiple myeloma (MM). In patients eligible for autologous stem cell transplant (ASCT), combinations including thalidomide/dexamethasone (Thal/Dex) or bortezomib/dexamethasone (Bort/Dex) or lenalidomide/dexamethasone (Rev/Dex) have been introduced as induction regimens in patients eligible for ASCT. New induction regimens have significantly increased complete response rate before and after ASCT with a positive impact on progression-free survival. Maintenance therapy with thalidomide, under investigation with lenalidomide, may further prolong remission duration. In patients not eligible for ASCT, randomized studies have shown that melphalan, prednisone, thalidomide (MPT) and melphalan, prednisone and bortezomib (MPV) are both superior to melphalan and prednisone (MP), and are now considered standard of care. Ongoing trials will soon assess if MP plus lenalidomide may be considered an attractive option. More complex regimens combining thalidomide or bortezomib or lenalidomide with cyclophosphamide or doxorubicin have been also tested. In small cohorts of patients bortezomib or lenalidomide may overcome the poor prognosis induced by deletion 13 or translocation t(4;14) or deletion 17p13. If these data will be confirmed, a cytogenetically riskadapted strategy might become the most appropriate strategy. PMID:19005483

  5. Sustained complete remission in a patient with platinum-resistant ovarian yolk sac tumor.

    Science.gov (United States)

    Jeyakumar, A; Chalas, E; Hindenburg, A

    2001-09-01

    Yolk sac tumors of the ovary are generally very responsive to chemotherapy; however, they are difficult to manage in the setting of platinum resistance where treatment options are limited and outcomes are poorer. We present a 39-year-old woman who had a platinum-resistant yolk sac ovarian tumor. She achieved complete remission on an innovative regimen of docetaxel, gemcitabine, and thalidomide. The combination of docetaxel, gemcitabine, and thalidomide might be an active regimen for platinum-resistant ovarian nondysgerminomas and further investigation of this combination is warranted. Copyright 2001 Academic Press.

  6. Genetic variations in multiple myeloma II

    DEFF Research Database (Denmark)

    Vangsted, A.; Klausen, T.W.; Vogel, U.

    2012-01-01

    - and bortezomib-based therapy, maintenance treatment with interferon-α and in relation to therapy-related adverse effects caused by treatment. Candidate genes for prediction of effect of HDT include DNA repair genes, CYP genes and genes involved in inflammation and apoptosis such as IL1B and RAI. In thalidomide...... in function of the nervous system have been associated with VTE induced by thalidomide and with PN induced by bortezomib. SNP analysis is simple and can be performed, e.g., on blood and buccal cells. Further analysis of SNPs in clinical trials is needed, and collaboration between scientific groups...

  7. Case Report

    African Journals Online (AJOL)

    thalidomide, pentoxyphylline, infleximab, cyclosporine, methotrexate, and azathioprine [11, 12]. Conclusion. The possibility of isolated renal sarcoidosis should be considered in any case of impaired kidney function associated with unexplained hypercalcemia even in the absence of extra-renal systemic manifestations. The.

  8. The medical case report

    African Journals Online (AJOL)

    role in medical research and evidence-based medicine. A good example is the recognition of the link between giving thalidomide to pregnant women and malformations in their babies, which was triggered by a case report. Case reports have a role in pharmacovigilance and can contribute to the understanding of the clinical ...

  9. December 2017

    African Journals Online (AJOL)

    FOBUR

    Inflammation is common pathology associated with infections and other diseases process that lead to non specific sickness behaviours. Identification of .... inhibiting TNF alpha and have less side effects than. Thalidomide. Avipaxin. Avipaxin (HupA) is ... stress, depression and aging . Inappropriate stimulation of sympathetic ...

  10. Drug safety in pregnancy - monitoring congenital anomalies

    NARCIS (Netherlands)

    Morgan, Margery; De Jong-Van Den Berg, Lolkje T. W.; Jordan, Sue

    Aim 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. Background Since the thalidomide disaster, use of drugs in pregnancy has been carefully monitored

  11. Curcumin Enhances Bortezomib Treatment of Myeloma by Inhibiting ...

    African Journals Online (AJOL)

    Trop J Pharm Res, February 2015; 14(2): 228 stem cell transplantation, bortezomib combination programs, and thalidomide programs [4]. Bortezomib is the first proteasome inhibitor to be used in the clinic; it has shown remarkable success in the treatment of hematological malignancies and is regarded as one of the most ...

  12. A study on limb reduction defects in six European regions

    NARCIS (Netherlands)

    Stoll, C; Calzolari, E; Cornel, M; GarciaMinaur, S; Garne, E; Nevin, N

    1996-01-01

    Limb reduction defects (LRD) gained especial attention after the thalidomide tragedy in 1962, LRD are common congenital malformations which present as obvious congenital anomalies recognized at birth, Therefore it might be assumed that they are well documented, However classification of LRDs is

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

    Science.gov (United States)

    AbstractThalidomide 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...

  14. Pyoderma Gangranosum of the Penis

    Science.gov (United States)

    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

  15. Dual inhibition of DNMTs and EZH2 can overcome both intrinsic and acquired resistance of myeloma cells to IMiDs in a cereblon-independent manner

    DEFF Research Database (Denmark)

    Dimopoulos, Konstantinos; Søgaard Helbo, Alexandra; Fibiger Munch-Petersen, Helga

    2018-01-01

    Thalidomide and its derivatives, lenalidomide and pomalidomide (also known as IMiDs), have significantly changed the treatment landscape of multiple myeloma, and the recent discovery of cereblon (CRBN) as their direct biological target has led to a deeper understanding of their complex mechanism...

  16. Aktinsk prurigo

    DEFF Research Database (Denmark)

    Stockbridge, Eva Boné; Deleuran, Mette Søndergaard; Steiniche, Torben

    2008-01-01

    to the conclusion that the patient suffered from Actinic Prurigo. The disease was very severe and there was a lack of response to treatment with oral prednisolone, antihistamines and pentoxyfyllin. Therefore the patient was treated with Thalidomide 50 mg/25 mg daily (alternating). This resulted in the complete...

  17. Thalidomidbehandling af gastrointestinal angiodysplasi

    DEFF Research Database (Denmark)

    Bélard, Erika; Foss, Catherine H; Christensen, Lisbeth Ambrosius

    2009-01-01

    Patients with obscure recurrent intestinal bleeding refractory to standard treatment are a major clinical challenge. The bleeding is often a result of angiodysplasia. Most patients undergo numerous diagnostic and therapeutic procedures. In this article we present two cases with no response to sta...... to standard treatment, but who were successfully treated with Thalidomide. Udgivelsesdato: 2009-Nov...

  18. Multiple myeloma in Nigeria: An insight to the clinical, laboratory ...

    African Journals Online (AJOL)

    Clinical features at presentation were anemia (71.9%) and bone pains (78.1%), while pathological fractures were found in 69%, and nephropathy in 13.8%. The longest duration of survival of 288 and 252 weeks were recorded in patients on melphalan and prednisolone with or without thalidomide. Conclusion: Presence of ...

  19. Thalidomide‐induced teratogenesis: History and mechanisms

    Science.gov (United States)

    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

  20. Author Details

    African Journals Online (AJOL)

    Bunn, MR. Vol 20, No 4 (2008) - Articles Use of thalidomide in the management of three HIV seroreactive children with Kaposi's Sarcoma referred for palliative care. Abstract PDF. ISSN: 1995-7262. AJOL African Journals Online. HOW TO USE AJOL... for Researchers · for Librarians · for Authors · FAQ's · More about AJOL ...

  1. [Review: update on erythema nodosum leprosum].

    Science.gov (United States)

    Morand, J J; Badiane, C; Bobin, P

    2004-01-01

    Erythema nodosum leprosum (ENL) is an immunological reaction corresponding to vascularitis due to circulating immune complexes usually occurring during treatment of lepromatous leprosy. The precise mechanism underlying ENL are unclear but involvement of tumor necrosis factor alpha (TNFalpha) is suspected. Based on this suspicion pentoxifylline has been used instead of conventional treatments such as corticosteroids and thalidomide.

  2. CASE REPORT: Phocomelia Syndrome - A Case Report

    Directory of Open Access Journals (Sweden)

    Gayatri S. Chakre

    2012-07-01

    Full Text Available Phocomelia is an extremely rare malformation in which babies are born with limbs that look like flippers on a seal. Although various factors can cause phocomelia, the prominent roots came from the drug use of thalidomide and from genetic inheritance. Phocomelia is transmitted as an autosomal recessive trait with variable expressivity and malformation is linked to chromosome 8.

  3. Cytogenetic diagnosis of Roberts SC phocomelia syndrome: First ...

    African Journals Online (AJOL)

    Tahir M. Malla

    2015-07-14

    Jul 14, 2015 ... comelia [2]. These two syndromes had varying phenotypic expression and were later concluded as the same entity because of resemblance of thalidomide embryopathy with Robert's syndrome and were therefore termed as Roberts SC pho- comelia syndrome [3]. The gene responsible for the syndrome.

  4. Progressive non-infectious anterior vertebral fusion

    Energy Technology Data Exchange (ETDEWEB)

    Smith, J.R.G.; Martin, I.R.; Shaw, D.G.; Robinson, R.O.

    1986-11-01

    Four cases of progressive non-infectious anterior vertebral fusion are described. Three cases remain relatively asymptomatic, but one has developed spinal cord compression secondary to an acute angled kyphosis. The clinical, radiological, and pathological features are reviewed and some comparisons with the spinal changes in thalidomide embryopathy are made.

  5. The importance of a sub-region on chromosome 19q13.3 for prognosis of multiple myeloma patients after high-dose treatment and stem cell support: a linkage disequilibrium mapping in RAI and CD3EAP

    DEFF Research Database (Denmark)

    Vangsted, Annette J.; Klausen, Tobias Wirenfeldt; Gimsing, Peter

    2011-01-01

    with interferon-α (INF-α) as maintenance treatment, 177 patients treated with thalidomide, and 74 patients treated with bortezomib at relapse and address if the effects of polymorphisms in CD3EAP and RAI are modified by a functional polymorphism in NFКB1. By linkage disequilibrium mapping, we found that variant...

  6. The importance of a sub-region on chromosome 19q13.3 for prognosis of multiple myeloma patients after high-dose treatment and stem cell support: a linkage disequilibrium mapping in RAI and CD3EAP

    DEFF Research Database (Denmark)

    Vangsted, Annette Juul; Klausen, Tobias Wirenfeldt; Gimsing, Peter

    2011-01-01

    with interferon-a (INF-a) as maintenance treatment, 177 patients treated with thalidomide, and 74 patients treated with bortezomib at relapse and address if the effects of polymorphisms in CD3EAP and RAI are modified by a functional polymorphism in NF¿B1. By linkage disequilibrium mapping, we found that variant...

  7. Improved survival of multiple myeloma patients with late relapse after high-dose treatment and stem cell support, a population-based study of 348 patients in Denmark in 1994-2004*

    DEFF Research Database (Denmark)

    Vangsted, Annette Juul; Klausen, Tobias W; Andersen, Niels

    2010-01-01

    the introduction of thalidomide (1995-1999), before the introduction of bortezomib and lenalidomide (2000-2002) and when patients had access to all treatment modalities (2003-2008). RESULTS: Two hundred and forty-three patients suffered from relapse which required treatment. The median follow-up time was 91...

  8. Current multiple myeloma treatment strategies with novel agents

    DEFF Research Database (Denmark)

    Ludwig, Heinz; Beksac, Meral; Bladé, Joan

    2010-01-01

    The treatment of multiple myeloma (MM) has undergone significant developments in recent years. The availability of the novel agents thalidomide, bortezomib, and lenalidomide has expanded treatment options and has improved the outcome of patients with MM. Following the introduction of these agents...

  9. Nye medicinske behandlingsprincipper inden for haematologien

    DEFF Research Database (Denmark)

    Hasselbalch, H.C.; Birgens, H.; Dufva, I.H.

    2008-01-01

    in patients with chronic myelogeneous leukaemia who develop resistance to imatinib. Thalidomide, lenalidomide and bortezomib have all been shown to be highly effective in multiple myeloma, and JAK2-inhibitors have entered phase II studies of patients with JAK2-positive primary myelofibrosis and related...

  10. The human placenta--an alternative for studying foetal exposure

    DEFF Research Database (Denmark)

    Myren, Maja; Mose, Tina; Mathiesen, Line

    2007-01-01

    of the foetus (e.g. cigarette smoke) and development of the foetal organs (e.g. methylmercury and thalidomide). The scope of this review is to give insight to the placental anatomy, development and function. Furthermore, the compounds physical properties and the transfer mechanism across the placental barrier...

  11. Overall survival patterns in patients with multiple myeloma in the era of novel agents and the role of initial clinical presentation and comorbidities: A population-based study

    NARCIS (Netherlands)

    Oortgiesen, Berdien; Van Roon, Eric N.; Joosten, Peter; Kibbelaar, Robby; Storm, Huib; Hovenga, Sjoerd; Van Rees, Bas P.; Woolthuis, Gerhard; Veeger, Nic J. G. M.; Hoogendoorn, Mels

    2014-01-01

    Introduction Clinical trials have shown improved response rates, progression-free survival and overall survival (OS) in patients with multiple myeloma (MM) when using the novel agents thalidomide, lenalidomide and bortezomib. However, outcome data provided by population-based registries, reflecting

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

    Science.gov (United States)

    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

  13. Outcomes of autologous transplantation for multiple myeloma according to different induction regimens

    Directory of Open Access Journals (Sweden)

    Edvan de Queiroz Crusoe

    2014-01-01

    Full Text Available Background: Induction therapy followed by high-dose chemotherapy and autologous transplantation is the standard treatment for suitable patients with multiple myeloma. Objective: The aim of this study was to assess whether induction therapy with thalidomidecontaining regimens was associated with improved results compared to vincristine, doxorubicin, and dexamethasone, and whether cyclophosphamide, thalidomide, and dexamethasone were associated with better results than thalidomide and dexamethasone. Methods: The records of 152 patients who underwent autologous transplantation at this institution from August of 2004 to January of 2012 were reviewed, selecting those with at least partial response to a maximum of eight cycles of induction therapy and sufficient follow-up information for analysis. Results: This study included 89 patients; 44 were female, with a mean age of 55 years (there was a significant trend for increasing age over the years of the study.The median number of induction therapy cycles was four, again with a trend of increase over the years.At least a very good partial response to induction therapy was achieved more often in the cyclophosphamide, thalidomide, and dexamethasone group (61.1% and in the thalidomide and dexamethasone group (59.2% than in the vincristine, doxorubicin, and dexamethasone group (16.2%. The overall median progression-free survival was 34 months, with no statistically significant difference between the three groups. The overall median survival was not reached, and there was no significant difference between the three groups; the estimated five-year overall survival was 55%. Conclusion: Although the quality of responses appeared to be better with thalidomidecontaining regimens, these improvements did not translate into improved long-term outcomes. Given its track record, cyclophosphamide, thalidomide, and dexamethasone is currently considered the preferred regimen for first-line induction therapy in the

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

    Energy Technology Data Exchange (ETDEWEB)

    Ana J. Molinari; Romina F. Aromando; Maria E. Itoiz; Marcela A. Garabalino; Andrea Monti Hughes; Elisa M. Heber; Emiliano C. C. Pozzi; David W. Nigg; Veronica A. Trivillin; Amanda E. Schwint

    2012-07-01

    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 blood 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.

  15. Modulation of the toxicity of photons by non-conventional drugs

    Energy Technology Data Exchange (ETDEWEB)

    Bohm, L.; Theron, T.; Serafin, A.; Verheye, F. [Department of Radiation Oncology, Faculty of Medicine, University of Stellenbosch, (South Africa)

    1997-03-01

    The 3 drugs under investigation Pentoxifylline, Ouabain and Thalidomide are non-conventional in the sense that they have a low toxicity and do not damage DNA. Pentoxifylline reduces blood viscosity ad enhances peripheral blood flow. When combined with irradiation in a mouse rhabdomyosarcoma model we found markedly enhanced tumour growth delay and in cultured cells dose modifying factors for SF2 and alpha in the region of 1.2-1.7 (Strahlentherapie 1995;170:595-01). The drug also alters cell regulation by inhibiting the radiation induced G2/M block and suppressing control of DNA synthesis (Theron and Boehm, unpubl.). When Thalidomide was added in the absence of irradiation to the myelo-blastic cell line K-562 we found characteristic changes of cell morphology and cell surface markers suggesting differentiation and expression of a megacaryocytic lineage (Leukemia Research 1991;15:129-136). A summary of the current state of research is given. (authors)

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

    Science.gov (United States)

    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.

  17. The Effect of Glycolytic Modulation in Prostate Cancer

    Science.gov (United States)

    2009-11-01

    localization of the marker GFP-LC3 in auto - phagosome formation.ThelocalizationofGFP-LC3 is abrogatedbyBeclin1siRNA(all threelowerpanelsin3B...Abstracts in this Sub-Category: 1. Phase II trial of thalidomide (T), bevacizumab (Bv), and docetaxel (Doc) in patients (pts) with metastatic castration ...Prostate Cancer 2. Phase I study of docetaxel (Tax) and 153Sm repetitively administered for castrate metastatic prostate cancer (CMPC). Meeting

  18. April 2015 critical care case of the month: half-sided light house

    OpenAIRE

    Loftsgard T; Frost A; Evans D; Kolbet K

    2015-01-01

    No abstract available. Article truncated after 150 words. History of Present Illness: A 55 year old woman was transferred to the ICU from the general medicine ward for tachycardia and acute hypoxic respiratory distress. She has multiple myeloma and had received cycle one of bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide (VDT-PACE) and radiotherapy to T7 for a pathologic compression. She was admitted for pain control from mucositis.Past Medical H...

  19. Prenatal Effects of Exposure to High-Level Noise,

    Science.gov (United States)

    1982-03-01

    major variables: * The genotype of the species and perhaps of the individual; * The developmental stage ( gestational age) at which the ex- posure occurs...the best documented are maternal syphilis , maternal rubella, maternal toxoplasmosis, and maternal ingestion of thalidomide (see Bergsma, 1973, for...made measurements of one pregnant woman at 37 weeks of gestation . External sounds -- pure tones of 200, 500, 1000, 2000, and 4000 Hz -- were delivered

  20. Development of drug delivery systems for radionuclide therapy using a combination therapy

    Energy Technology Data Exchange (ETDEWEB)

    Kim, On Hee; Choi, Sun Ju [Korea Atomic Energy Research Institute, Taejon (Korea, Republic of)

    2005-07-01

    For the development of new controlled drug delivery systems, the application of combination therapy using angiogenesis inhibitor and tumor static agents has drawn great attention. This approach would be very beneficial for cancer treatment especially when a new drug deliver system utilizing biodegradable polymers is developed. Therefore, the present study for the combination therapy of angiogenesis inhibitor and chemotherapeutic agents was to carry out prior to the development of the novel drug delivery. In present study, the ability of inhibition on cell growth was investigated with treatment of anti-angiogenetic agent and anticancer agent. Thalidomide was used as an antivasculatory agents and Doxorubicine was treated as a chemotherapeutic agent. To demonstrate apoptotic process in in-vitro study, TUNEL assay was carried out. Also, the alteration of p53 level was examined by using western blotting. For the cell lines, NIH:OVCAR3, MKN45, SNU719, C6, L929, T98G, Hep3B and Calu6 were applied. Results showed that Thalidomide inhibited cell growth in tumor cell lines in a dose-dependent manner and Doxorubicin as well. A significant synergistic effect on the apoptotic was noticed in the combination treatment of Thalidomide and Doxorubicin compared to a single treatment of either drug. Therefore, it can be concluded that the mechanism of cytotoxicity was due to the enhancement of apoptosis in early cell death with combination treatment in tumor cell lines.

  1. Molecular Action of Lenalidomide in Lymphocytes and Hematologic Malignancies

    Directory of Open Access Journals (Sweden)

    Jessica M. McDaniel

    2012-01-01

    Full Text Available The immunomodulatory agent, lenalidomide, is a structural analogue of thalidomide approved by the US Food and Drug Administration for the treatment of myelodysplastic syndrome (MDS and multiple myeloma (MM. This agent is also currently under active investigation for the treatment of chronic lymphocytic leukemia (CLL and non-Hodgkin’s lymphoma (NHL, as well as in drug combinations for some solid tumors and mantle cell lymphoma (MCL. Although treatment with lenalidomide has translated into a significant extension in overall survival in MM and MDS and has superior safety and efficacy relative to thalidomide, the mechanism of action as it relates to immune modulation remains elusive. Based on preclinical models and clinical trials, lenalidomide, as well as other structural thalidomide derivatives, enhances the proliferative and functional capacity of T-lymphocytes and amplifies costimulatory signaling pathways that activate effector responses and suppress inflammation. This paper summarizes our current understanding of T- and natural killer (NK cell pathways that are modified by lenalidomide in hematopoietic neoplasms to inform future decisions about potential combination therapies.

  2. Standardization of a method to study angiogenesis in a mouse model

    Directory of Open Access Journals (Sweden)

    DAVID FEDER

    2013-01-01

    Full Text Available In the adult organism, angiogenesis is restricted to a few physiological conditions. On the other hand, uncontrolled angiogenesis have often been associated to angiogenesis-dependent pathologies. A variety of animal models have been described to provide more quantitative analysis of in vivo angiogenesis and to characterize pro- and antiangiogenic molecules. However, it is still necessary to establish a quantitative, reproducible and specific method for studies of angiogenesis factors and inhibitors. This work aimed to standardize a method for the study of angiogenesis and to investigate the effects of thalidomide on angiogenesis. Sponges of 0.5 x 0.5 x 0.5 cm were implanted in the back of mice groups, control and experimental (thalidomide 200 mg/K/day by gavage. After seven days, the sponges were removed. The dosage of hemoglobin in sponge and in circulation was performed and the ratio between the values was tested using nonparametric Mann-Whitney test. Results have shown that sponge-induced angiogenesis quantitated by ratio between hemoglobin content in serum and in sponge is a helpful model for in vivo studies on angiogenesis. Moreover, it was observed that sponge-induced angiogenesis can be suppressed by thalidomide, corroborating to the validity of the standardized method.

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

    Science.gov (United States)

    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.

  4. Immunomodulation of multiple myeloma.

    Science.gov (United States)

    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.

  5. Women's perception of risks of adverse fetal pregnancy outcomes: a large-scale multinational survey.

    Science.gov (United States)

    Petersen, Irene; McCrea, Rachel L; Lupattelli, Angela; Nordeng, Hedvig

    2015-06-01

    To determine pregnant women and new mothers' perception of risks in pregnancy. This was a large-scale multinational survey including 9113 pregnant women and new mothers from 18 countries in Europe, North America and Australia. Risk perception scores (0-10) for harmful effects to the fetus were derived for: (1) medicines (over-the-counter medicine and prescribed medicine), (2) food substances (eggs and blue veined cheese), (3) herbal substances (ginger and cranberries) (4) alcohol and tobacco, and (5) thalidomide. Overall, 80% (6453/8131) of women perceived the risk of giving birth to a child with a birth defect to be ≤ 5 of 100 births. The women rated cranberries and ginger least harmful (mean risk perception scores 1.1 and 1.5 of 10, respectively) and antidepressants, alcohol, smoking and thalidomide as most harmful (7.6, 8.6, 9.2 and 9.4 out of 10, respectively). The perception varied with age, level of education, pregnancy status, profession and geographical region. Noticeably, 70% had not heard about thalidomide, but of those who had (2692/9113), the risk perception scores were 0.4-0.5 points lower in women below 25 years compared to women aged 26-30 years. In general, women perceived the risks of giving birth to a child with birth defects low, but there were substantial disparities between women's perceived risks and the actual risks when it comes to over-the-counter agents against nausea and prescribed medication. The study revealed that few women knew of thalidomide, suggesting that the general awareness among women of the teratogenic effects of thalidomide is declining, but it has left a general scepticism about safety of medication in pregnancy. This may have some severe consequences if women are left without medical treatments in pregnancy. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  6. Treatment outcome and prognostic factor analysis in transplant-eligible Chinese myeloma patients receiving bortezomib-based induction regimens including the staged approach, PAD or VTD

    Directory of Open Access Journals (Sweden)

    Chim Chor

    2012-06-01

    Full Text Available Abstract Background We have reported promising outcomes using a staged approach, in which bortezomib/thalidomide/dexamethasone was used only in 14 patients with suboptimal response to VAD (vincristine/adriamycin/dexamethasone before autologous stem cell transplantation (ASCT. Here we compared the outcomes of the staged approach with frontline PAD (bortezomib/doxorubicin/dexamethasone or VTD (bortezomib/thalidomide/dexamethasone induction, and analysed prognostic factors for outcome. Patients and methods Ninety-one transplant-eligible Chinese patients received three induction regimens prior to ASCT [staged approach (N = 25, PAD (N = 31, VTD (N = 35]. and received thalidomide maintenance for 2 years post-ASCT. Results 43 (47.3% patients had International Staging System (ISS III disease. By an intention-to-treat analysis, the overall CR/nCR rate were 37.4% post-induction, and 62.6% post-ASCT. Five-year overall (OS and event-free (EFS survivals were 66% and 45.1%. There was no difference of the post-induction CR/nCR rate, EFS or OS between patients induced by these three regimens. Moreover, ISS III disease did not affect CR/nCR rates. Multivariate analysis showed that ISS and post-ASCT CR/nCR impacted OS while ISS and post-induction CR/nCR impacted EFS. Conclusions These three induction regimens produced comparable and favorable outcomes in myeloma. The unfavorable outcome of ISS stage III persisted despite upfront/early use of bortezomib. CR/nCR predicted favorable survivals.

  7. The hydrolysis of polyimides

    Science.gov (United States)

    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.

  8. Myelosuppression associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board.

    Science.gov (United States)

    Miceli, Teresa; Colson, Kathleen; Gavino, Maria; Lilleby, Kathy

    2008-06-01

    Novel therapies for multiple myeloma include the immunomodulatory drugs lenalidomide and thalidomide and the proteasome inhibitor bortezomib, which have increased response rates and survival times. However, the agents can cause myelosuppression, which, if not managed effectively, can be life threatening and interfere with optimal therapy and quality of life. The International Myeloma Foundation's Nurse Leadership Board developed a consensus statement that includes toxicity grading, strategies for monitoring and managing myelosuppression associated with novel therapies, and educational recommendations for patients and their caregivers. Although anemia, neutropenia, and thrombocytopenia are expected side effects of novel therapies for multiple myeloma, they are manageable with appropriate interventions and education.

  9. Peripheral neuropathy associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board.

    Science.gov (United States)

    Tariman, Joseph D; Love, Ginger; McCullagh, Emily; Sandifer, Stacey

    2008-06-01

    The novel therapies thalidomide and bortezomib can cause peripheral neuropathy, a challenging adverse event that can affect quality of life and compromise optimal treatment for patients with multiple myeloma. At baseline, patients should be evaluated for signs and symptoms of peripheral neuropathy with a neurotoxicity assessment tool and educated about the symptoms and the importance of reporting them. Signs, symptoms, and the ability to perform activities of daily living should be evaluated regularly so that appropriate interventions can be employed if necessary. Specific management strategies for peripheral neuropathy are based on the grade of severity and on signs and symptoms; strategies include dose and schedule modifications, pharmacologic interventions, nonpharmacologic approaches, and patient education.

  10. Gastrointestinal side effects associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board.

    Science.gov (United States)

    Smith, Lisa C; Bertolotti, Page; Curran, Kathleen; Jenkins, Bonnie

    2008-06-01

    The novel immunomodulatory drugs lenalidomide and thalidomide and the novel proteasome inhibitor bortezomib can cause gastrointestinal side effects, including constipation, diarrhea, nausea, and vomiting, which can have a deleterious effect on quality of life and interfere with optimal therapy. The International Myeloma Foundation's Nurse Leadership Board developed this consensus statement for the management of gastrointestinal side effects associated with novel therapies to be used by healthcare providers in any medical setting. It includes grading criteria and general recommendations for assessing and managing the side effects. Although constipation, diarrhea, nausea, and vomiting are expected side effects associated with novel therapies for multiple myeloma, they are manageable with appropriate medical interventions.

  11. Environmental contaminants as origins of disordered behavior

    Energy Technology Data Exchange (ETDEWEB)

    Weiss, B.

    1978-01-01

    Behavioral toxicology studies the behavioral effects of contaminants, such as heavy metals, in environmental and occupational settings. A classic example of metal poisoning with behavioral effects is Pink Disease, or acrodynia, due to mercurous chloride intoxication in children. Thalidomide is a more prominent example. Behavioral changes, unlike tangible consequences of pollution, are difficult to perceive as dangers and to correct. Other examples of environmental pollutants causing behavioral symptoms upon intoxication are polybrominated biphenyls, lead, mercury, methylmercury, and a variety of food additives. Sensitivity to food colors and flavors is suspected to be the cause of behavioral abnormalities in children now labeled as hyperactive or hyperkinetic. (ERB)

  12. Myeloma: making sense of a complex blood cancer.

    LENUS (Irish Health Repository)

    Kelly, Mary B

    2012-01-31

    Myeloma is a challenging blood cancer characterized by bone destruction, hypercalcaemia, renal insufficiency and anaemia. Although myeloma remains incurable, recent advancements in treatments have resulted in significant improvements in morbidity. The use of immunomodulatory drugs-thalidomide, lenalidomide, pomalidomide (in clinical trials)-and the proteasome inhibitor, bortezomib, in conjunction with conventional chemotherapy and supportive therapies, have resulted in a significant shift in approaches to treatment and an improvement in patients\\' quality of life. Nurses must remain up-to-date with current treatments for myeloma and their related side-effects. In addition, nurses play a key role in the coordination of a multidisciplinary approach to care for myeloma patients.

  13. Substâncias enantiomericamente puras (SEP: a questão dos fármacos quirais Pure enantiomeric substances: the question of chiral drugs

    Directory of Open Access Journals (Sweden)

    Eliezer J. Barreiro

    1997-12-01

    Full Text Available The thalidomide disaster, in the 60,s, is the most painful reminder of the importance of chirality for biological activity. After this episode, much attention has been devoted to study the correlations between toxicological and pharmacological properties and chirality. Actualy, to get a licence for a new chiral drug in EUA, European community and Japan, it is necessary to study the biological properties of each enatiomer independently. This article presents an overview about the importance of the chirality of organic compounds and its relationships with biological activity, asymmetric synthetic methodologies and market.

  14. Recurrent hemorrhagic pericardial effusion in a child due to diffuse lymphangiohemangiomatosis: a case report

    Directory of Open Access Journals (Sweden)

    Bakhshi Sameer

    2010-02-01

    Full Text Available Abstract Introduction Recurrent hemorrhagic pericardial effusion in children with no identifiable cause is a rare presentation. Case presentation We report the case of a 4-year-old Indian girl who presented with recurrent hemorrhagic pericardial effusion. Diffuse lymphangiomatosis was suspected when associated pulmonary involvement, soft tissue mediastinal mass, and lytic bone lesions were found. Pericardiectomy and lung biopsy confirmed the diagnosis of diffuse lymphangiohemangiomatosis. Partial clinical improvement occurred with thalidomide and low-dose radiotherapy, but our patient died from progressive respiratory failure. Conclusion Diffuse lymphangiohemangiomatosis should be considered in the differential diagnosis of hemorrhagic pericardial effusion of unclear cause.

  15. Biological Activity of Lenalidomide and Its Underlying Therapeutic Effects in Multiple Myeloma

    Directory of Open Access Journals (Sweden)

    Roberta Martiniani

    2012-01-01

    Full Text Available Lenalidomide is a synthetic compound derived by modifying the chemical structure of thalidomide. It belongs to the second generation of immunomodulatory drugs (IMiDs and possesses pleiotropic properties. Even if lenalidomide has been shown to be active in the treatment of several hematologic malignancies, this review article is mostly focalized on its mode of action in multiple myeloma. The present paper is about the direct and indirect antitumor effects of lenalidomide on malignant plasmacells, bone marrow microenvironment, bone resorption and host’s immune response. The molecular mechanisms and targets of lenalidomide remain largely unknown, but recent evidence shows cereblon (CRBN as a possible mediator of its therapeutical effects.

  16. Monoclonal gammopathy associated membranous glomerulonephritis: A rare entity

    Directory of Open Access Journals (Sweden)

    K K Gowda

    2015-01-01

    Full Text Available A 40-year-old male presented with nephrotic syndrome. Light microscopic analysis of the renal biopsy showed thickening of the glomerular capillary wall. Immunofluorescence examination revealed granular deposition of monoclonal immunoglobulin (Ig G3-kappa and complement C3 along the glomerular basement membrane. Electron microscopy showed subepithelial electron dense deposits, thus confirming membranous glomerulonephritis (MGN with monoclonal gammopathy. MGN with monoclonal gammopathy is an extremely rare but distinctive entity. This patient was treated with a combination of bortezomib, thalidomide and dexamethasone and showed partial remission of his nephrotic state and dysproteinemia.

  17. [Research Advance in Light Chain Escape of Multiple Myeloma -Review].

    Science.gov (United States)

    Huang, Qian-Chuan; Ding, Jin-Ya

    2017-12-01

    More than 80% of patients with MM is present as intact monoclonal immunoglobulin (Ig). Usually, the patients with intact immunoglobulin MM (IIMM) show parallel fluctuations of their intact Ig and FLCs or BJP. In the era of novel agents, including thalidomide, lenalidomide and bortezomib, the natural disease development and classic relapse patterns have been changed, the relapse was characterized by an increase in sFLC or BJP without a corresponding increase in paraprotein level, a phenomenon termed "light chain escape", indicates a worse outcome in patients with MM. This review focuses on the mechanism, clinical significance and early diagnosis of light chain escape.

  18. Therapeutic advancements in multiple myeloma

    Directory of Open Access Journals (Sweden)

    Alessandro eGozzetti

    2014-09-01

    Full Text Available Multiple myeloma survival has significantly improved in latest years, due to a broad spectrum of novel agents available for treatment. The introduction of thalidomide, bortezomib and lenalidomide together with autologous stem cell transplantation has dramatically prolonged complete remissions rate, progression free survivals resulting ultimately in prolonged survivals in myeloma patients. Moreover, novel strategies of treatment such as consolidation and maintenance are being used to implement responses. A number of new drugs such as carfilzomib and pomalidomide are already in clinical practice, and new kids on the block are entering, making the future of myeloma patients brighter.

  19. Historical perspective and advances in the treatment of multiple myeloma

    Directory of Open Access Journals (Sweden)

    Amir Harandi

    2011-12-01

    Full Text Available Corticosteroids and melphalan were used for decades to treat multiple myeloma. Combination chemotherapy has been extensively studied with similar overall survival rates to melphalan and prednisone. In the last decade, the development of new agents has progressed significantly. Thalidomide and its newer derivatives lenalidomide, bortezomib, and pegylated liposomal doxorubicin have drastically revolutionized treatment approaches. As a result, numerous clinical trials have yielded exciting treatment strategies resulting in therapeutic advances, and improved responses and overall survival of patients. This review summarizes the international uniform response criteria for multiple myeloma and gives a historical perspective on previous therapies with updates on the newest available treatments.

  20. Interferon-alpha in the treatment of multiple myeloma

    DEFF Research Database (Denmark)

    Khoo, T.L.; Joshua, D.; Gibson, J.

    2011-01-01

    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......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 hematological malignancy multiple myeloma. Interferon has been used...... of multiple myeloma or will interferon be resigned to the history books remains to be seen....

  1. Lenalidomide for the treatment of relapsed and refractory multiple myeloma

    Science.gov (United States)

    van de Donk, Niels WCJ; Görgün, Güllü; Groen, Richard WJ; Jakubikova, Jana; Mitsiades, Constantine S; Hideshima, Teru; Laubach, Jacob; Nijhof, Inger S; Raymakers, Reinier A; Lokhorst, Henk M; Richardson, Paul G; Anderson, Kenneth C

    2012-01-01

    Lenalidomide is an amino-substituted derivative of thalidomide with direct antiproliferative and cytotoxic effects on the myeloma tumor cell, as well as antiangiogenic activity and immunomodulatory effects. Together with the introduction of bortezomib and thalidomide, lenalidomide has significantly improved the survival of patients with relapsed and refractory myeloma. The most common adverse events associated with lenalidomide include fatigue, skin rash, thrombocytopenia, and neutropenia. In addition, when lenalidomide is combined with dexamethasone or other conventional cytotoxic agents, there is an increase in the incidence of venous thromboembolic events. There is now evidence that continued treatment with lenalidomide has a significant impact on survival by improving the depth and duration of response. This highlights the value of adverse event management and appropriate dose adjustments to prevent toxicity, and of allowing continued treatment until disease progression. In this review, we will discuss the different lenalidomide-based treatment regimens for patients with relapsed/refractory myeloma. This is accompanied by recommendations of how to manage and prevent adverse events associated with lenalidomide-based therapy. PMID:22956884

  2. Systemic treatment in severe cases of recurrent aphthous stomatitis: an open trial

    Directory of Open Access Journals (Sweden)

    Maria Angela Martins Mimura

    2009-03-01

    Full Text Available PURPOSE: This study aimed to evaluate the efficacy of the systemic drugs thalidomide, dapsone, colchicine, and pentoxifylline in the treatment of severe manifestations of RAS. METHODS: An open, 4-year clinical trial was carried out for 21 consecutive patients with severe RAS. Initially, patients were given a 2-week course of prednisone to bring them to a baseline status. Simultaneously, one of the four test drugs was assigned to each patient to be taken for a period of 6 months. During the course of the trial, patients were switched to one of the other three drugs whenever side effects or a lack of satisfactory results occurred, and the 6-month limit of the treatment was then reset. RESULTS: The most efficient and best-tolerated drug was thalidomide, which was administered to a total of eight patients and resulted in complete remission in seven (87.5%. Dapsone was prescribed for a total of nine patients, of whom eight (89% showed improvement in their symptoms, while five showed complete remission. Colchicine was administered to a total of ten patients, with benefits observed in nine (90%, of whom four showed complete remission. Pentoxyfilline was administered to a total of five patients, with benefits observed in three (60%, of whom one patient showed complete remission. CONCLUSION: The therapeutic methods used in this trial provided significant symptom relief. Patients experienced relapses of the lesions; however, this occurred after withdrawal of their medication during the follow-up period.

  3. Maintenance therapy in multiple myeloma

    Directory of Open Access Journals (Sweden)

    Jean-Luc Harousseau

    2009-08-01

    Full Text Available The treatment of multiple myeloma (MM has changed dramatically in the past twenty years with the introduction of high-dose therapy plus autologous stem-cell transplantation (ASCT in younger patients and, more recently, of three novel agents (thalidomide, bortezomib, and lenalidomide. When conventional chemotherapy was the only available possibility, complete responses (CR were very rare and the objective of maintenance was to prolong remission duration by continuing the same type of treatment that induced the initial response. With recent therapeutic improvements, CR achievement becomes a realistic goal that, in most cases, is significantly correlated with the outcome (1. Therefore, both the nature and the impact of maintenance therapy have changed. Maintenance therapy is based currently on novel agents, and its objective is not only to control the clone but also to further decrease the tumor burden and improve the quality of response. A number of randomized studies show a benefit from maintenance therapy with novel agents (until now, mostly thalidomide, at least in terms of response rate and progression-free survival (PFS. However, there is still a debate as concerns the impact on overall survival (OS and the optimal administration of maintenance therapy.

  4. Imatinib mesylate induces responses in patients with liver metastases from gastrointestinal stromal tumor failing intra-arterial hepatic chemotherapy

    Directory of Open Access Journals (Sweden)

    Fiorentini Giammaria

    2006-01-01

    Full Text Available Background: Imatinib mesylate represents a real major paradigm shift in cancer therapy, targeting the specific molecular abnormalities, crucial in the etiology of tumor. Intra-arterial hepatic chemotherapy (IAHC followed by embolization, has been considered an interesting palliative option for patients with liver metastases from gastrointestinal stromal tumor (GIST, due to the typically hypervascular pattern of the tumor. Aims: We report our experience with IAHC followed by Imatinib mesylate, in order to show the superiority of the specific molecular approach in liver metastases from GIST. Materials and Methods: Three patients (pts with pretreated massive liver metastases from GIST, received IAHC with Epirubicin 50 mg/mq, every 3 weeks for 6 cycles. At the evidence of progression, they received Imatinib mesylate. Results: We observed progressive diseases in all cases. In 1998, one patient underwent Thalidomide at 150 mg orally, every day for 4 months, with evidence of stable disease and clinical improvement. In 2001, two patients received Imatinib mesylate at 400 mg orally, every day, with evidence of partial response lasting 18+ months and 16 months. One of them had grade 3 neutropenia, with suspension of therapy for 3 weeks. Conclusion: No patient treated with IAHC, reported objective responses, but two of them obtained partial response after the assumption of Imatinib mesylate and one showed temporary stabilization with thalidomide. Imatinib mesylate represents a new opportunity in GIST therapy, targeting the specific molecular alteration. It seems to be superior to conventional intra arterial hepatic chemotherapy.

  5. Clinical characterization of the HOXA1 syndrome BSAS variant

    Science.gov (United States)

    Bosley, T.M.; Salih, M.A.; Alorainy, I.A.; Oystreck, D.T.; Nester, M.; Abu-Amero, K.K.; Tischfield, M.A.; Engle, E.C.

    2010-01-01

    Background: The Bosley-Salih-Alorainy syndrome (BSAS) variant of the congenital human HOXA1 syndrome results from autosomal recessive truncating HOXA1 mutations. We describe the currently recognized spectrum of ocular motility, inner ear malformations, cerebrovascular anomalies, and cognitive function. Methods: We examined nine affected individuals from five consanguineous Saudi Arabian families, all of whom harbored the same I75-I76insG homozygous mutation in the HOXA1 gene. Patients underwent complete neurologic, neuro-ophthalmologic, orthoptic, and neuropsychological examinations. Six individuals had CT, and six had MRI of the head. Results: All nine individuals had bilateral Duane retraction syndrome (DRS) type 3, but extent of abduction and adduction varied between eyes and individuals. Eight patients were deaf with the common cavity deformity of the inner ear, while one patient had normal hearing and skull base development. Six had delayed motor milestones, and two had cognitive and behavioral abnormalities meeting Diagnostic and Statistical Manual of Mental Disorders-IV criteria for autism spectrum disorder. MRI of the orbits, extraocular muscles, brainstem, and supratentorial brain appeared normal. All six appropriately studied patients had cerebrovascular malformations ranging from unilateral internal carotid artery hypoplasia to bilateral agenesis. Conclusions: This report extends the Bosley-Salih-Alorainy syndrome phenotype and documents the clinical variability resulting from identical HOXA1 mutations within an isolated ethnic population. Similarities between this syndrome and thalidomide embryopathy suggest that the teratogenic effects of early thalidomide exposure in humans may be due to interaction with the HOX cascade. PMID:17875913

  6. Weight loss update.

    Science.gov (United States)

    1996-11-01

    Unwanted weight loss in people with HIV can be caused by one or more factors simultaneously. A two-pronged approach that addresses the factors causing weight loss and malnutrition, and maintaining or gaining weight is critical. Many opportunistic infections (OIs) can cause diarrhea, but both the drugs used to treat diarrhea and the infections themselves can contribute to weight loss. Lactose intolerance is a common cause of diarrhea in people living with HIV. Because some of the drugs used to treat HIV and OIs are packaged with lactose, it may be necessary to replace the enzymes needed to break down lactose. Appetite loss may also contribute to wasting, and the lack of nutrients from a lost appetite can tax the body and further aggravate the problem. Appetite stimulants, vitamin supplements, or weight gain products that promote the building of protein are possible treatment options. Lean body mass production may require the use of anabolic (protein building) steroids or testosterone replacement therapy. Another wasting intervention option involves recombinant human growth hormone (rHGH), however, unsubstantiated safety concerns have arisen on the use of rHGH, and may require increased monitoring. Finally, counteracting weight loss may require adjusting the elevated levels of an immune system chemical called tumor necrosis factor (TNF) with thalidomide. Because of thalidomide's association with birth defects, sexually active heterosexual women should be advised to use multiple contraceptive mechanisms.

  7. An interesting case of Lucio phenomenon triggered by activation of hepatitis C infection

    Directory of Open Access Journals (Sweden)

    Jacob Mareen

    2016-01-01

    Full Text Available Lucio phenomenon (LP or erythema necroticans is a rare type of reaction pattern found in untreated patients with diffuse non-nodular leprosy. It is important to distinguish this from vasculonecrotic erythema nodosum because thalidomide with high-dose steroids is the mainstay of treatment for the latter, whereas LP shows no response to thalidomide. We report a case of a 60-year-old man who presented with purpuric patches, hemorrhagic blisters, and ulcers over extremities of 15 days duration. On cutaneous examination, there were multiple stellate purpuric patches, hemorrhagic bullae, and deep necrotic ulcers, mainly over extremities. Slit-skin smear examination from six sites revealed bacteriological index 6+ with globi, and morphological index 5%. Histopathology revealed diffuse infiltration of bacilli in epidermis, dermis, and endothelial cells along with neutrophilic and lymphocytic infiltrate. Fibrinoid necrosis and thrombosis of blood vessels was also noted. The above clinicohistopathological features helped in making the diagnosis of LP. Concomitantly he was found to be infected with hepatitis C virus. Many triggering factors have been described in literature; however, activation of hepatitis C as a trigger for Lucio phenomenon has not been reported. In addition, IgM and IgG anticardiolipin antibodies were found to be positive. The patient was started on high-dose steroids along with multibacillary antileprosy therapy and improved within 2 weeks.

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

    Directory of Open Access Journals (Sweden)

    Giampaolo Talamo

    2012-06-01

    Full Text Available 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 second- ary 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.

  9. Risk factors for MDS and acute leukemia following total therapy 2 and 3 for multiple myeloma.

    Science.gov (United States)

    Usmani, Saad Z; Sawyer, Jeffrey; Rosenthal, Adam; Cottler-Fox, Michele; Epstein, Joshua; Yaccoby, Shmuel; Sexton, Rachael; Hoering, Antje; Singh, Zeba; Heuck, Christoph J; Waheed, Sarah; Chauhan, Nabeel; Johann, Donald; Abdallah, Al-Ola; Muzaffar, Jameel; Petty, Nathan; Bailey, Clyde; Crowley, John; van Rhee, Frits; Barlogie, Bart

    2013-06-06

    Lenalidomide has been linked to myelodysplastic syndrome (MDS) after autotransplants for myeloma. Total therapy trials (TT; TT2(-/+) thalidomide) and TT3 (TT3a with bortezomib, thalidomide; TT3b with additional lenalidomide) offered the opportunity to examine the contribution of these immune-modulatory agents to MDS-associated cytogenetic abnormalities (MDS-CA) and clinical MDS or acute leukemia ("clinical MDS/AL"). Of 1080 patients with serial cytogenetic studies, MDS-CA occurred in 11% and clinical MDS/AL in 3%. Risk features of MDS-CA included TT3b, age ≥65 years, male gender, levels of β-2-microglobulin >5.5 mg/L, and multiple myeloma relapse. Clinical MDS/AL occurred less frequently in the control arm of TT2 and more often with TT3a and TT3b. Since MDS-CA often antedated clinical disease, periodic cytogenetic monitoring is recommended. Larger CD34 quantities should be collected upfront as the risk of MDS could be reduced by applying higher CD34 doses with transplant. Thus, treatment, host, and myeloma features could be linked to MDS development after therapy for this malignancy. This trial was registered at www.clinicaltrials.gov: TT3A: NCT00081939, TT3B: NCT00572169.

  10. Lenalidomide: a brief review of its therapeutic potential in myelodysplastic syndromes

    Science.gov (United States)

    Giagounidis, Aristoteles A N; Germing, Ulrich; Haase, Sabine; Aul, Carlo

    2007-01-01

    Lenalidomide is a novel thalidomide analogue with enhanced immunomodulatory and antiangiogenic action lacking most of the typical thalidomide-associated adverse events. In myelodysplastic syndromes (MDS), it has been used primarily in the IPSS low- and intermediate-1 risk setting. Several trials have demonstrated its potential to lead to both erythroid and cytogenetic responses in these disease groups. In a clinical trial of patients with a del(5q) chromosomal abnormality, lenalidomide treatment resulted in red blood cell (RBC) transfusion independence in 67% of patients. Moreover, 45% of patients achieved a complete cytogenetic remission, and 28% achieved a minor cytogenetic remission. This result was independent of karyotype complexity. Lenalidomide might also induce long-term remissions in del(5q) patients with an elevated medullary blast count. In non-del(5q) patients, 43% of patients with confirmed low- and intermediate-1 risk achieved transfusion independence or a reduction of at least 50% of pre-treatment RBC transfusion levels. Adverse events are common but manageable and include neutropenia and thrombocytopenia, pruritus, rash, diarrhea, and others. Lenalidomide will prove an essential part in the armamentarium of MDS therapeutics. Combination therapies with cytokines, demethylating agents, tyrosine kinase inhibitors, or chemotherapy are being investigated and may show additional benefit in both low- and high risk MDS. PMID:18472976

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

    Science.gov (United States)

    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.

  12. Lenalidomide, Melphalan, and Prednisone Association Is an Effective Salvage Therapy in Relapsed Plasma Cell Leukaemia

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    Tommasina Guglielmelli

    2009-01-01

    Full Text Available Plasma cell leukemia (PCL is a rare and aggressive plasma cell disorder, characterized by the presence of a peripheral blood absolute plasma cell count of at least 2×109/l and more than 20% circulating plasma cells. The prognosis of PCL patients remains poor. Even by using autologous or allogenic transplant procedures, median survival does not exceed 3 years (Saccaro et al., 2005. Thalidomide, bortezomib and lenalidomide (Revlimid have emerged as high active agents in the treatment of PCL (Johnston and abdalla, 2002; Musto et al., 2007; Finnegan et al., 2006. In particular, Lenalidomide is a structural analogue of thalidomide with similar but more potent biological activity; it is used as first line therapy in MM (Palumbo et al., 2007; Niesvizky et al., 2007, although information regarding its associated use with dexamethasone use as salvage therapy in PCL derives from anecdotal single case reports (Musto et al., 2008. We would like to describe a case of primary PCL with adverse cytogenetic in which excellent response was achieved with the combination of lenalidomide, melphalan, and prednisone as salvage therapy.

  13. TNF-α/TNFR1 Signaling is Required for the Full Expression of Acute and Chronic Itch in Mice via Peripheral and Central Mechanisms.

    Science.gov (United States)

    Miao, Xiuhua; Huang, Ya; Liu, Teng-Teng; Guo, Ran; Wang, Bing; Wang, Xue-Long; Chen, Li-Hua; Zhou, Yan; Ji, Ru-Rong; Liu, Tong

    2018-02-01

    Increasing evidence suggests that cytokines and chemokines play crucial roles in chronic itch. In the present study, we evaluated the roles of tumor necrosis factor-alpha (TNF-α) and its receptors TNF receptor subtype-1 (TNFR1) and TNFR2 in acute and chronic itch in mice. Compared to wild-type (WT) mice, TNFR1-knockout (TNFR1-KO) and TNFR1/R2 double-KO (DKO), but not TNFR2-KO mice, exhibited reduced acute itch induced by compound 48/80 and chloroquine (CQ). Application of the TNF-synthesis inhibitor thalidomide and the TNF-α antagonist etanercept dose-dependently suppressed acute itch. Intradermal injection of TNF-α was not sufficient to evoke scratching, but potentiated itch induced by compound 48/80, but not CQ. In addition, compound 48/80 induced TNF-α mRNA expression in the skin, while CQ induced its expression in the dorsal root ganglia (DRG) and spinal cord. Furthermore, chronic itch induced by dry skin was reduced by administration of thalidomide and etanercept and in TNFR1/R2 DKO mice. Dry skin induced TNF-α expression in the skin, DRG, and spinal cord and TNFR1 expression only in the spinal cord. Thus, our findings suggest that TNF-α/TNFR1 signaling is required for the full expression of acute and chronic itch via peripheral and central mechanisms, and targeting TNFR1 may be beneficial for chronic itch treatment.

  14. New drugs in the therapy of multiple myeloma Novas drogas na terapia do mieloma múltiplo

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    Antonio Palumbo

    2008-06-01

    Full Text Available The advances in the understanding of the pathogenesis of multiple myeloma and the mechanism of drug resistance have led to the development of novel targeted therapies that are able to overcome resistance and show additive or synergistic effects with old chemotherapeutic agents. Thalidomide, its immunomodulatory derivative lenalidomide, and the proteasome inhibitor bortezomib, in combination with oral melphalan in the elderly and with intravenous melphalan in younger patients, are changing the traditional treatment paradigm of multiple myeloma. High-dose melphalan followed by autologous stem cell transplantation in the younger patients and oral melphalan-prednisone-thalidomide in the elderly are the standard of care for newly diagnosed multiple myeloma. In younger patients, combinations incorporating thalidomide or lenalidomide or bortezomib significantly increase the pre-transplant response rate before high-dose melphalan and autologous transplantation, and may further improve the response rate and survival achieved after transplant. Prospective randomized studies incorporating new agents and stratifying patients based on cytogenetic abnormalities, are needed to define the therapeutic algorithm in high-risk disease.O avanço do conhecimento da patogênese do mieloma múltiplo e do mecanismo de resistência a drogas propiciou o desenvolvimento de novas terapias alvo que vençam a resistência e apresentem efeitos sinérgicos e aditivos aos velhos agentes quimioterápicos. A talidomida, e o seu derivado imonumodulador, lenalidomida, e o inibidor da proteasoma bortezomib, em combinação com o melfalano no idoso e intravenoso no jovem, estão mudando os paradigmas tradicionais de tratamento do mieloma múltiplo. Altas doses de melfalano seguidas do transplante de células-tronco autólogo no paciente jovem e o tratamento oral de melfalano-predimisona- talidomida no idoso são agora tratamentos padrões para os portadores de mieloma múltiplo rec

  15. Dynamic MRI of the lumbar spine for the evaluation of microcirculation during anti-angiogenetic therapy in patients with myelodysplastics syndromes; Dynamische MRT der Lendenwirbelsaeule zur Beurteilung der Mikrozirkulation unter anti-angiogenetischer Therapie bei Patienten mit myelodysplastischen Syndromen

    Energy Technology Data Exchange (ETDEWEB)

    Scherer, A.; Wittsack [Institut fuer Diagnostische Radiologie, Duesseldorf (Germany); Strupp, C. [Klinik fuer Haematologie, Onkologie und klinische Immunologie, Duesseldorf (Germany); Engelbrecht, V. [Institut fuer Diagnostische Radiologie, Duesseldorf (DE)] (and others)

    2002-02-01

    Material and Methods: In 20 healthy normal persons and 28 MDS patients a dynamic contrast-enhanced MRI (d-MRI) of the lumbar spine was performed. After the initial d-MRI-investigation 24 of the 28 MDS patients received an antiangiogenetic therapy with thalidomide. With an average of 4.2 months after the beginning of therapy a d-MRI-follow-up examination in 9 of these patients was performed. The amplitude and exchange-rate constant were calculated and a statistical comparison of these values between healthy persons and MDS patients as well as a correlation with the clinical course was executed. Results: Compared with the normal controls the MDS patients showed a higher amplitude (normal persons: 14.4{+-}5.2, MDS: 24.8{+-}8.1) and exchange-rate constant (normal persons: 0.124{+-}0.042, MDS: 0.136{+-}0.036). In 7 of 9 MDS patients undergoing thalidomide therapy a reduction of the amplitude and exchange rate constant values was evident in the d-MRI follow-up examinations. Clinically these patients showed a therapy response with complete or partial disease remission. (orig.) [German] Material und Methode: Bei 20 gesunden Normalpersonen und 28 MDS-Patienten wurde eine kontrastmittelunterstuetzte dynamische MRT (d-MRT) der LWS durchgefuehrt. Bei 24 der 28 MDS-Patienten wurde nach der initialen d-MRT-Untersuchung eine anti-angiogenetische Therapie mit Thalidomid begonnen. Durchschnittlich 4,2 Monate nach Therapiebeginn erfolgte bei 9 dieser Patienten eine d-MRT-Verlaufsuntersuchung. Anhand der Signalintensitaets-Zeit-Kurven der d-MRT wurden die Amplitude und Austauschratenkonstante berechnet und ein statistischer Vergleich der Werte zwischen Probanden und Patienten sowie eine Korrelation der klinischen Verlaufsparameter der MDS-Patienten mit den d-MRT-Ergebnissen durchgefuehrt. Ergebnisse: Bei den 28 MDS-Patienten wurden im Vergleich zu den Normalpersonen durchschnittlich hoehere Amplituden (Normalpersonen: 14,4{+-}5,2, MDS: 24,8{+-}8,1) und Austauschratenkonstanten

  16. Multiple myeloma presenting with high-output heart failure and improving with anti-angiogenesis therapy: two case reports and a review of the literature

    Directory of Open Access Journals (Sweden)

    Robin Jason

    2008-07-01

    Full Text Available Abstract Introduction Common manifestations of multiple myeloma include osteolytic lesions, cytopenias, hypercalcemia, and renal insufficiency. Patients may also exhibit heart failure which is often associated with either past therapy or cardiac amyloidosis. A less recognized mechanism is high-output heart failure. Diuretic therapy in this setting has little efficacy in treating the congested state. Furthermore, effective pharmacotherapy has not been established. We report two patients with multiple myeloma and high-output heart failure who failed diuretic therapy. The patients were given dexamethasone in conjunction with lenalidomide and thalidomide, respectively. Shortly thereafter, each patient demonstrated a significant improvement in symptoms. This is the first report of successful treatment of multiple myeloma-induced high-output failure via the utilization of these agents. Case presentation Two patients with multiple myeloma were evaluated for volume overload. The first was a 50-year-old man with refractory disease. Magnetic resonance imaging demonstrated diffuse marrow replacement throughout the pelvis. Cardiac catheterization conveyed elevated filling pressures and a cardiac output of 15 liters/minute. He quickly decompensated and required mechanical ventilation. The second patient was a 61-year-old man recently diagnosed with multiple myeloma and volume overload. Skeletal survey demonstrated numerous lytic lesions throughout the pelvis. His cardiac catheterization also conveyed elevated filling pressures and a cardiac output of 10 liters/minute. Neither patient responded to diuretic therapy and they were subsequently started on dexamethasone plus lenalidomide and thalidomide, respectively. The first patient's brisk diuresis allowed for extubation within 48 hours after the first dose. He had a net negative fluid balance of 15 liters over 10 days. The second patient also quickly diuresed and on repeat cardiac catheterization, his cardiac

  17. Cost-effectiveness of bortezomib for multiple myeloma: a systematic review

    Directory of Open Access Journals (Sweden)

    Chen W

    2016-05-01

    Full Text Available Wendong Chen,1 Yicheng Yang,2 Yi Chen,3 Fen Du,3 Huan Zhan3 1Normin Health, Toronto, ON, Canada; 2Xian Janssen, Beijing, People's Republic of China; 3Normin Health Changsha Representative Office, Changsha, People's Republic of China Objectives: To review published cost-effectiveness analyses (CEA assessing bortezomib (BTZ for multiple myeloma (MM and explore possible bias affecting the cost-effectiveness of BTZ. Methods: Literature was searched for published CEAs assessing BTZ or BTZ-containing regimens for MM from 2003 to 2015. The reported incremental cost-effectiveness ratios (ICER were adjusted by 2014 country-specific gross domestic product per capita (GDPPC to compare the cost-effectiveness threshold of the World Health Organization (3 GDPPC per gained quality-adjusted life year [QALY]. Results: A total of 17 published CEAs were included in this review. When compared to non-BTZ treatments, BTZ-containing regimens were cost-effective for induction treatment prior to stem cell transplantation (SCT in Canada, Poland, and Germany (ICER per QALY: 0.9299–2.254 GDPPC. BTZ/melphalan/prednisolone (VMP was cost-effective for previously untreated and SCT-ineligible MM patients when compared to melphalan plus prednisolone (MP, melphalan/prednisone/lenalidomide with lenalidomide maintenance, and cyclophosphamide/thalidomide/dexamethasone (CTD (ICER per QALY: dominant to 2.374 GDPPC in Canada, UK, and USA. BTZ was cost-effective for relapsed/refractory MM when compared to best supportive care (ICER per life year: 0.9317–1.8210 GDPPC in the UK and the USA, thalidomide in USA (0.5178 GDPPC/LY, and dexamethasone (DEX in four Nordic countries (€54,451–€81,560/QALY. However, the cost-effectiveness for VMP versus MP plus thalidomide (MPT and continuous lenalidomide (LEN plus low-dose DEX (RD for previously untreated and SCT-ineligible MM patients and BTZ versus LEN/DEX for relapsed/refractory MM patients could be unreliable because of the bias

  18. Cost-effectiveness of bortezomib for multiple myeloma: a systematic review.

    Science.gov (United States)

    Chen, Wendong; Yang, Yicheng; Chen, Yi; Du, Fen; Zhan, Huan

    2016-01-01

    To review published cost-effectiveness analyses (CEA) assessing bortezomib (BTZ) for multiple myeloma (MM) and explore possible bias affecting the cost-effectiveness of BTZ. Literature was searched for published CEAs assessing BTZ or BTZ-containing regimens for MM from 2003 to 2015. The reported incremental cost-effectiveness ratios (ICER) were adjusted by 2014 country-specific gross domestic product per capita (GDPPC) to compare the cost-effectiveness threshold of the World Health Organization (3 GDPPC per gained quality-adjusted life year [QALY]). A total of 17 published CEAs were included in this review. When compared to non-BTZ treatments, BTZ-containing regimens were cost-effective for induction treatment prior to stem cell transplantation (SCT) in Canada, Poland, and Germany (ICER per QALY: 0.9299-2.254 GDPPC). BTZ/melphalan/prednisolone (VMP) was cost-effective for previously untreated and SCT-ineligible MM patients when compared to melphalan plus prednisolone (MP), melphalan/prednisone/lenalidomide with lenalidomide maintenance, and cyclophosphamide/thalidomide/dexamethasone (CTD) (ICER per QALY: dominant to 2.374 GDPPC) in Canada, UK, and USA. BTZ was cost-effective for relapsed/refractory MM when compared to best supportive care (ICER per life year: 0.9317-1.8210 GDPPC) in the UK and the USA, thalidomide in USA (0.5178 GDPPC/LY), and dexamethasone (DEX) in four Nordic countries (€54,451-€81,560/QALY). However, the cost-effectiveness for VMP versus MP plus thalidomide (MPT) and continuous lenalidomide (LEN) plus low-dose DEX (RD) for previously untreated and SCT-ineligible MM patients and BTZ versus LEN/DEX for relapsed/refractory MM patients could be unreliable because of the bias associated with model design and the indirect comparisons of treatment effects. Published CEAs suggested that BTZ or BTZ-containing regimens were cost-effective when compared to most non-BTZ treatments for MM. However, the conflicting cost-effectiveness for VMP versus MPT

  19. Synthesis and biological evaluation of the natural product komaroviquinone and related compounds aiming at a potential therapeutic lead compound for high-risk multiple myeloma.

    Science.gov (United States)

    Suto, Yutaka; Sato, Mariko; Fujimori, Kota; Kitabatake, Shotaro; Okayama, Mikio; Ichikawa, Daiju; Matsushita, Maiko; Yamagiwa, Noriyuki; Iwasaki, Genji; Kiuchi, Fumiyuki; Hattori, Yutaka

    2017-10-01

    Alternatives of treatments for multiple myeloma (MM) have become increasingly available with the advent of new drugs such as proteasome inhibitors, thalidomide derivatives, histone deacetylase inhibitors, and antibody drugs. However, high-risk MM cases that are refractory to novel drugs remain, and further optimization of chemotherapeutics is urgently needed. We had achieved asymmetric total synthesis of komaroviquinone, which is a natural product from the plant Dracocephalum komarovi. Similar to several leading antitumor agents that have been developed from natural compounds, we describe the antitumor activity and cytotoxicity of komaroviquinone and related compounds in bone marrow cells. Our data suggested that komaroviquinone-related agents have potential as starting compounds for anticancer drug development. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Mechanism of auditory hypersensitivity in human autism using autism model rats.

    Science.gov (United States)

    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.

  1. Synthesis and Pharmacological Evaluation of Novel Phenyl Sulfonamide Derivatives Designed as Modulators of Pulmonary Inflammatory Response

    Directory of Open Access Journals (Sweden)

    Lídia Moreira Lima

    2012-12-01

    Full Text Available In this paper we report the design, synthesis and pharmacological evaluation of a new series of phenyl sulfonamide derivatives 2a–h and 3–8 planned by structural modification on the anti-inflammatory prototype LASSBio-468 (1. Among the synthesized analogues, the tetrafluorophthalimide LASSBio-1439 (2e stands out showing an in vitro anti-TNF-α effect similar to the standard thalidomide. The relevance of tetrafluorination of the phthalimide nucleus was also confirmed by the anti-inflammatory profile of 2e, through oral administration, in a murine model of pulmonary inflammation. The corresponding tetrafluorocarboxyamide metabolite LASSBio-1454 (15, generated from partial hydrolysis of the derivative 2e, presented a significant in vitro effect and a pronounced anti-inflammatory activity in vivo.

  2. POLYMORPHOUS LIGHT ERUPTION – A REVIEW

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    Yogeesh Hosahalli Rajaiah

    2013-07-01

    Full Text Available Polymprhouos light eruption is the most common idiopathic photodermatosis. It is a sun induced cutaneous reaction characterized by onset itchy erathematous papules, plaques, vesicles or erythema multiforme type of lesions after brief exposure to sunlight. Sun-exposed areas of the body or rarely the partially covered areas are commonly involved. PLE is more common in temperate climates than in tropics. It begins usually at the onset of summer and moderates as the summer progresses. In most patients it usually runs a benign course. Diagnosis is mainly on clinical grounds. Therapy involves avoidance of sun-exposure and use of sunscreens. Cases not responding to simple measures require PUVA (Psoralen and Ultraviolet A or UVB (ultraviolet B therapy. Other alternative suggested therapies with variable success include oral hydroxychloroquine, beta-carotene, thalidomide and nicotinamide.

  3. Risk, statistical inference, and the law of evidence: The use of epidemiological data in toxic tort cases

    Energy Technology Data Exchange (ETDEWEB)

    Brannigan, V.M. [Univ. of Maryland, College Park, MD (United States); Bier, V.M. [Univ. of Wisconsin, Madison, WI (United States); Berg, C. [Georgetown Univ. School of Medicine, Washington, DC (United States)

    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 that other product liability cases on indirect or statistical proof of injury in toxic 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. 23 refs.

  4. [Primary myelofibrosis complicated by acquired hemophilia A and subsequent development of acute myeloid leukemia].

    Science.gov (United States)

    Kuroda, Hiroyuki; Ishikawa, Kazuma; Jomen, Wataru; Yoshida, Masahiro; Yamada, Michiko; Abe, Tomoyuki; Sakurai, Tamaki; Fujii, Shigeyuki; Maeda, Masahiro; Matsuno, Teppei; Sato, Masanori; Fujita, Miri; Nagashima, Kazuo; Ieko, Masahiro; Kato, Junji

    2013-12-01

    A 77-year-old man diagnosed with primary myelofibrosis (PMF), successfully controlled by thalidomide and prednisolone, was referred to us for massive subcutaneous bleeding involving the face, body, and all four limbs. Hemostatic studies showed prolonged activated partial thromboplastin time, decreased factor VIII coagulation, and a high factor VIII inhibitor titer, resulting in a diagnosis of acquired hemophilia A (AHA) for which he was treated with prednisolone and cyclophosphamide on admission. He developed right femoral intramuscular hemorrhage soon after immunosuppressive therapy and was treated with rituximab combined with activated prothrombin complex concentrates. Furthermore, he suffered complications of respiratory failure with increasing throat hemorrhaging. Recombinant activated factor VII (rFVIIa) was administered combined with methylprednisolone pulse therapy. Bleeding, including respiratory failure, was ameliorated with rFVIIa. Immunosuppressive rituximab therapy resolved AHA with marked efficacy. He died of Pneumocystis jiroveci pneumonitis. Autopsy showed transformation from PMF to acute myeloid leukemia.

  5. Type 2 lepra reaction in an immunocompromised patient precipitated by filariasis.

    Science.gov (United States)

    Singh, Satyendra Kumar; Sharma, Taniya; Rai, Tulika; Prabhu, Anand

    2014-01-01

    Though patients affected with both acquired immuno deficiency syndrome (AIDS) and leprosy commonly present with type 1 lepra reaction, there are few isolated reports of type 2 lepra reaction in retropositive patients affected with leprosy. We are presenting a case report of 35-year-old male affected with AIDS, tubercular lymphadenitis, and lepromatous leprosy with recurrent episodes of type 2 lepra reaction manifesting as erythema nodosum leprosum (ENL). Dipstick enzyme-linked immunosorbent assay (ELISA) for filarial antigen was also positive. The patient was treated with 100 mg thalidomide daily, 300 mg diethylcarbamazine, and modified multidrug therapy (MDT) for leprosy. He responded well and has not had any further reaction in the last 6 months.

  6. A Rare Case of Nonsecretory Multiple Myeloma in Lagos, Nigeria: A Case Report and Literature Review

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    Ebele Uche

    2015-01-01

    Full Text Available Multiple myeloma (MM is a plasma cell disorder associated with clonal proliferation of plasma cells. Nonsecretory multiple myeloma (NSMM is a rare variant of MM and accounts for approximately 1% to 5% of all cases. It is defined as symptomatic myeloma without detectable monoclonal immunoglobulin on serum or urine electrophoresis. This variant usually poses a diagnostic challenge to the clinician. We present a 60-year-old Nigerian man who was investigated extensively for bone pain, weight loss, and anaemia. He was eventually diagnosed as having nonsecretory multiple myeloma based on histology and immunohistochemistry results of bone marrow trephine biopsy. He is currently being managed with bortezomib, doxorubicin, and thalidomide, as well as zoledronic acid. He is also on anticoagulation. He continues to show remarkable clinical improvement. We describe this case report and literature review for better awareness amongst medical practitioners and pathologists.

  7. Bias against the null hypothesis: scaring pregnant women about drugs in pregnancy.

    Science.gov (United States)

    Koren, Gideon; Madjunkova, Svetlana; Maltepe, Caroline

    2014-05-01

    Since the thalidomide disaster, medicine is practised as if every drug is teratogenic, when in fact very few medications are. Pregnant women are often ready to refuse treatment even for life-threatening conditions owing to misinformation and misperceptions about fetal risks. How can I reassure my patients and prevent misinformation from affecting their treatment? Physicians must provide evidence-based counseling to their patients. For example, antihistamines for morning sickness have been proven safe in numerous studies, but are commonly the subject of media reports overstating the risks to the fetus. Family physicians and obstetricians must take an active role in preventing pregnant patients from being misinformed. Copyright© the College of Family Physicians of Canada.

  8. Optimizing quality of life in multiple myeloma patients: current options, challenges and recommendations.

    Science.gov (United States)

    Maes, Helena; Delforge, Michel

    2015-06-01

    Multiple myeloma (MM) is a plasma cell neoplasm with a chronic disease course that primarily affects elderly individuals. The introduction of novel agents such as thalidomide, lenalidomide and bortezomib has significantly improved the outcome for MM patients, including the elderly. Quality of life in MM is influenced by disease-related symptoms, treatment-related toxicity and treatment response. In addition to conventional endpoints as response, quality of life should be carefully evaluated during each therapeutic phase. Caring for older adults with MM is particularly challenging because of the heterogeneity of aging and the presence of comorbidities and frailty, with a potential risk of over- or under-treatment. Moreover, elderly patients may sometimes prioritize maintaining quality of life above prolonging survival. A careful evaluation of comorbidities and a geriatric assessment can facilitate risk-stratification of elderly patients to identify the older population fit enough to tolerate standard drug dosing, and to detect the frail patients who need age-adapted treatment.

  9. Recurrent Obscure Gastrointestinal Bleeding: Dilemmas and Success with Pharmacological Therapies. Case Series and Review

    Directory of Open Access Journals (Sweden)

    Majid Almadi

    2009-01-01

    Full Text Available The present article describes three difficult cases of recurrent bleeding from obscure causes, followed by a review of the pitfalls and pharmacological management of obscure gastrointestinal bleeding. All three patients underwent multiple investigations. An intervening complicating diagnosis or antiplatelet drugs may have compounded long-term bleeding in two of the cases. A bleeding angiodysplasia was confirmed in one case but was aggravated by the need for anticoagulation. After multiple transfusions and several attempts at endoscopic management in some cases, long-acting octreotide was associated with decreased transfusion requirements and increased hemoglobin levels in all three cases, although other factors may have contributed in some. In the third case, however, the addition of low-dose thalidomide stopped bleeding for a period of at least 23 months.

  10. Kidney involvement in Crow-Fukase syndrome

    Directory of Open Access Journals (Sweden)

    Karim Zouaghi

    2015-01-01

    Full Text Available Crow-Fukase syndrome, also known as POEMS syndrome, is a rare plasma dyscrasia characterized by monoclonal gammopathy and various combinations of polyneuropathy, organomegaly, endocrinopathy and dermatological changes, and their initials stand for the acronym POEMS. Substantial kidney involvement is rarely related to this disease. Our report is about five patients suffering from the POEMS syndrome with kidney involvement that rapidly progressed to end-stage renal disease. Our report is about three females and two males with a mean age of 60.6 years. Neuropathy was noted in all the cases. Endocrinopathy included hypothyroidism and/or diabetes. Skin changes were noted in one case, and included peri-orbital hyperpigmentation. Monoclonal gammopathy was present in all the cases and was related to multiple myeloma in three cases. Kidney involvement presented in all the five cases. Treatment included Melphalan, Thalidomid, steroids and hemodialysis. Survival was short for three patients, from five to 34 months.

  11. Management of Multiple Myeloma and Usage of Bortezomib: Perspective from India and Ukraine.

    Science.gov (United States)

    Garg, Amit; Morgunskyy, Mykhaylo; Belagali, Yogesh; Gupta, Namita; Akku, Shyam Prasad

    2016-01-01

    Novel treatment strategies have remarkably improved the multiple myeloma (MM) patients' survival, with associated increased costs. A joint panel meet of international experts from India and Ukraine was held in New Delhi on May 19, 2016 focusing on MM management, bortezomib role, unmet medical needs, and current challenges. The health-care system for oncology in India is majorly private vs. government-based in Ukraine. In India, electrophoresis, serum-free light chain assays, bone marrow tests, and X-rays are available modes of diagnosis. Despite of the numerous cancer centers and stem cell transplant centers, most patients do not prefer transplant owing to its high-cost and social stigma. Majority of the patients are treated with bortezomib or lenalidomide-based regimens. Most patients buy drug themselves. The expanding generic drugs market is a ray of hope for the affordable drugs. In Ukraine, immuno-fixation, bone marrow analysis, and magnetic resonance imaging are common diagnostic modalities. Due to high cost, only few patients undergo transplant. Bortezomib-based regimens are preferred in most of the patients; however, usage is limited due to high costs and lack of funds. Thalidomide-based regimens are used for maintenance therapy due to affordability. In case of relapsed MM, bortezomib is preferred in triple therapy; however, more affordable option is cyclophosphamide, thalidomide, and dexamethasone (CTD). Issues, such as cost containment, common treatment strategies, enhanced collaboration, and improved health-care access, need immediate attention. High-quality generics access will improve outcomes and support health-care cost containment. Pharmacoeconomic studies and head-to-head trials are warranted to determine the cost-effectiveness and benefit of novel therapies in MM.

  12. Community-Based Phase IIIB Trial of Three UPFRONT Bortezomib-Based Myeloma Regimens.

    Science.gov (United States)

    Niesvizky, Ruben; Flinn, Ian W; Rifkin, Robert; Gabrail, Nashat; Charu, Veena; Clowney, Billy; Essell, James; Gaffar, Yousuf; Warr, Thomas; Neuwirth, Rachel; Zhu, Yanyan; Elliott, Jennifer; Esseltine, Dixie-Lee; Niculescu, Liviu; Reeves, James

    2015-11-20

    The US community-based, phase IIIB UPFRONT trial was designed to compare three frontline bortezomib-based regimens in transplantation-ineligible patients with myeloma. Patients (N = 502) were randomly assigned 1:1:1 to 24 weeks (eight 21-day cycles) of induction with bortezomib-dexamethasone (VD; n = 168; intravenous bortezomib 1.3 mg/m(2), days 1, 4, 8, and 11 plus oral dexamethasone 20 mg, days 1, 2, 4, 5, 8, 9, 11, and 12 [cycles 1 to 4], or 1, 2, 4, and 5 [cycles 5 to 8]), bortezomib-thalidomide-dexamethasone (VTD; n = 167; bortezomib and dexamethasone as before plus oral thalidomide 100 mg, days 1 to 21), or bortezomib-melphalan-prednisone (VMP; n = 167; bortezomib as before plus oral melphalan 9 mg/m(2) and oral prednisone 60 mg/m(2), days 1 to 4, every other cycle), followed by 25 weeks (five 35-day cycles) of bortezomib maintenance (1.6 mg/m(2), days 1, 8, 15, and 22). The primary end point was progression-free survival. After 42.7 months' median follow-up, median progression-free survival with VD, VTD, and VMP was 14.7, 15.4, and 17.3 months, respectively; median overall survival was 49.8, 51.5, and 53.1 months, with no significant differences among treatments for either end point (global P = .46 and P = .79, respectively, Wald test). Overall response rates were 73% (VD), 80% (VTD), and 70% (VMP). Adverse events were more common with VTD than VD or VMP. Bortezomib maintenance was feasible without producing cumulative toxicity. Although all bortezomib-containing regimens produced good outcomes, VTD and VMP did not appear to offer an advantage over VD in transplantation-ineligible patients with myeloma treated in US community practice. © 2015 by American Society of Clinical Oncology.

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

    Directory of Open Access Journals (Sweden)

    Damase-Michel C

    2008-03-01

    Full Text Available 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.Methods: 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.Results: 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.Conclusion: 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.

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

    Science.gov (United States)

    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 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.

  15. Evaluation of antiangiogenic and antiproliferative potential of the organic extract of green algae chlorella pyrenoidosa

    Science.gov (United States)

    Kyadari, Mahender; Fatma, Tasneem; Azad, Rajvardhan; Velpandian, Thirumurthy

    2013-01-01

    Objective: algae isolates obtained from fresh and marine resources could be one of the richest sources of novel bioactive secondary metabolites expected to have pharmaceutical significance for new drug development. This study was conducted to evaluate the antiangiogenic and antiproliferative activity of Chlorella pyrenoidosa in experimental models of angiogenesis and by MTT assay. Materials and Methods: lyophilized extract of C. pyrenoidosa was extracted using dichloromethane/methanol (2:1), concentrated and vacuum evaporated to obtain the dried extract. The crude extract was evaluated in the vascular endothelial growth factor (VEGF)-induced angiogenesis in in ovo chick chorioallantoic membrane assay (CAM) at various concentrations (n = 8) using thalidomide and normal saline as positive and untreated control groups, respectively. The crude extract was also subjected to the antiangiogenic activity in the silver nitrate/potassium nitrate cautery model of corneal neovascularization (CN) in rats where topical bevacizumab was used as a positive control. The vasculature was photographed and blood vessel density was quantified using Aphelion imaging software. The extract was also evaluated for its anti proliferative activity by microculture tetrazolium test (MTT) assay using HeLa cancer cell line (ATCC). Results: VEGF increased the blood vessel density by 220% as compared to normal and thalidomide treatment decreased it to 67.2% in in ovo assay. In the in-vivo CN model, the mean neovascular density in the control group, the C. pyrenoidosa extract and bevacizumab group were found to be 100%, 59.02%, and 32.20%, respectively. The Chlorella pyrenoidosa extract negatively affected the viability of HeLa cells. An IC50 value of the extract was 570 μg/ml, respectively. Conclusion: a significant antiangiogenic activity was observed against VEGF-induced neovascularization and antiproliferative activity by MTT assay. In this study, it could be attributed that the activity may be

  16. Synthesis and evaluation of 4-[{sup 18}F]fluorothalidomide for the in vivo studies of angiogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Dong Hyun [Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710 (Korea, Republic of); Choe, Yearn Seong [Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710 (Korea, Republic of)]. E-mail: ysnm.choe@samsung.com; Jung, Kyoung-Ho [Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710 (Korea, Republic of); Lee, Kyung-Han [Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710 (Korea, Republic of); Choi, Yong [Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710 (Korea, Republic of); Kim, Byung-Tae [Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710 (Korea, Republic of)

    2006-02-15

    In this study, we prepared 2-(2,6-dioxopiperidin-3-yl)-4-[{sup 18}F]fluoroisoindole-1,3-dione (4-[{sup 18}F]fluorothalidomide; [{sup 18}F]1) for the in vivo studies of angiogenesis. Radiochemical synthesis of [{sup 18}F]1 was carried out by labeling 4-trimethylammoniumthalidomide trifluoromethanesulfonate with nBu{sub 4}N[{sup 18}F]F in dimethyl sulfoxide (DMSO), followed by reverse-phase HPLC purification. Decay-corrected radiochemical yield of [{sup 18}F]1 was 50-60%, with an effective specific activity of 42-120 GBq/{mu}mol (end of synthesis). Incubation of the radioligand with human umbilical vein endothelial cells (HUVEC-C; American Type Culture Collection) showed a time-dependent increase in the uptake of the radioligand, and the uptake was inhibited by 8-11% in the presence of 10 {mu}M thalidomide, indicating nonspecific binding of the radioligand. Positron emission tomography (PET) images of mice implanted with tumors in their right flanks revealed a marked accumulation of radioactivity in the livers, kidneys and bladders of the mice, and brain uptake appeared at approximately 40 min after injection. However, no radioactivity uptake was detected in the implanted tumor. Thin-layer chromatography (TLC), HPLC and LC-MS analyses of mouse liver microsomal metabolites of [{sup 18}F]1 and 1 with or without nicotinamide adenine dinucleotide phosphate (NADPH) clearly revealed that the radioligand did not go through metabolic activation but underwent nonenzymatic hydrolysis at physiological pH. Therefore, these results would appear to indicate that [{sup 18}F]1 may not be suitable for the in vivo studies of angiogenesis at least in mice, although it was reported that thalidomide and/or its hydrolysis products may be responsible for its activity in humans.

  17. Glutarimides: Biological activity, general synthetic methods and physicochemical properties

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    Popović-Đorđević Jelena B.

    2015-01-01

    Full Text Available Glutarimides, 2,6-dioxopiperidines are compounds that rarely occur in natural sources, but so far isolated ones exert widespread pharmacological activities, which makes them valuable as potential pharmacotherapeutics. Glutarimides act as androgen receptor antagonists, anti-inflammatory, anxiolytics, antibacterials, and tumor suppressing agents. Some synthetic glutarimide derivatives are already in use as immunosuppressive and sedative (e.g., thalidomide or anxiolytics (buspirone drugs. The wide applicability of this class of compounds, justify the interest of scientists to explore new pathways for its syntheses. General methods for synthesis of six-membered imide ring, are presented in this paper. These methods include: a reaction of dicarboxylic acids with ammonia or primary amine, b reactions of cyclization: amido-acids, diamides, dinitriles, nitrilo-acids, amido-nitriles, amido-esters, amidoacyl-chlorides or diacyl-chlorides, c adition of carbon-monoxide on a,b-unsaturated amides, d oxidation reactions, e Michael adition of active methylen compounds on methacrylamide or conjugated amides. Some of the described methods are used for closing glutarimide ring in syntheses of farmacological active compounds sesbanimide and aldose reductase inhibitors (ARI. Analyses of the geometry, as well as, the spectroscopic analyses (NMR and FT-IR of some glutarimides are presented because of their broad spectrum of pharmacological activity. To elucidate structures of glutarimides, geometrical parameters of newly synthesized tert-pentyl-1-benzyl-4-methyl-glutarimide-3-carboxylate (PBMG are analyzed and compared with the experimental data from X-ray analysis for glutarimide. Moreover, molecular electrostatic potential (MEP surface which is plotted over the optimized geometry to elucidate the reactivity of PBMG molecule is analyzed. The electronic properties of glutarimide derivatives are explained on the example of thalidomide. The Frontier Molecular Orbital

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

    Science.gov (United States)

    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

  19. Clinical utility and patient consideration in the use of lenalidomide for multiple myeloma in Chinese patients

    Directory of Open Access Journals (Sweden)

    Wang J

    2015-06-01

    Full Text Available Jing Wang, Hongfeng Guo, Xin Zhou Department of Hematology, Wuxi People’s Hospital, Nanjing Medical University, Wuxi, People’s Republic of China Abstract: Multiple myeloma (MM is an incurable hematologic malignancy caused by the autonomous growth of malignant plasma cells. In the last decade, the introduction of novel targeted agents such as thalidomide, bortezomib, and lenalidomide has dramatically improved the clinical outcome of MM patients in both the frontline and recurrent settings. Lenalidomide is a synthetic derivative of thalidomide, which has been shown to significantly improve overall survival, time to progression, and overall response rates in patients with MM. The China Food and Drug Administration approved the use of lenalidomide in patients with MM in 2013. In a Phase II trial, lenalidomide plus low-dose dexamethasone was associated with a high response rate and acceptable safety profile in heavily pretreated Chinese patients with relapsed/refractory MM, including those with renal impairment and IgD subtype. However, lenalidomide will remain as a second-line antimyeloma drug in the near future because of its high price and the policy of health insurance reimbursement in People’s Republic of China. In this review, we summarize the clinical utility and patient considerations in the use of lenalidomide for MM in Chinese patients. Further studies with larger sample sizes are required to investigate the better quality, longer duration, and more clinically meaningful outcomes of lenalidomide in the treatment of MM in Chinese patients. Keywords: lenalidomide, multiple myeloma, clinical efficacy, Chinese patients

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

    Directory of Open Access Journals (Sweden)

    Zeng ZH

    2017-07-01

    Full Text Available Zi-Hang Zeng,1,2 Jia-Feng Chen,1,2 Yi-Xuan Li,1,2 Ran Zhang,1,2 Ling-Fei Xiao,1,2 Xiang-Yu Meng1,2 1Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, 2Department of Evidence-Based Medicine and Clinical Epidemiology, Second Clinical College of Wuhan University, Wuhan, People’s Republic of China 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. Keywords: multiple myeloma, newly diagnosed, transplant-eligible, induction therapies, network meta-analysis

  1. Evaluation of antiangiogenic and antiproliferative potential of the organic extract of green algae Chlorella pyrenoidosa.

    Science.gov (United States)

    Kyadari, Mahender; Fatma, Tasneem; Azad, Rajvardhan; Velpandian, Thirumurthy

    2013-01-01

    algae isolates obtained from fresh and marine resources could be one of the richest sources of novel bioactive secondary metabolites expected to have pharmaceutical significance for new drug development. This study was conducted to evaluate the antiangiogenic and antiproliferative activity of Chlorella pyrenoidosa in experimental models of angiogenesis and by MTT assay. lyophilized extract of C. pyrenoidosa was extracted using dichloromethane/methanol (2:1), concentrated and vacuum evaporated to obtain the dried extract. The crude extract was evaluated in the vascular endothelial growth factor (VEGF)-induced angiogenesis in in ovo chick chorioallantoic membrane assay (CAM) at various concentrations (n = 8) using thalidomide and normal saline as positive and untreated control groups, respectively. The crude extract was also subjected to the antiangiogenic activity in the silver nitrate/potassium nitrate cautery model of corneal neovascularization (CN) in rats where topical bevacizumab was used as a positive control. The vasculature was photographed and blood vessel density was quantified using Aphelion imaging software. The extract was also evaluated for its anti proliferative activity by microculture tetrazolium test (MTT) assay using HeLa cancer cell line (ATCC). VEGF increased the blood vessel density by 220% as compared to normal and thalidomide treatment decreased it to 67.2% in in ovo assay. In the in-vivo CN model, the mean neovascular density in the control group, the C. pyrenoidosa extract and bevacizumab group were found to be 100%, 59.02%, and 32.20%, respectively. The Chlorella pyrenoidosa extract negatively affected the viability of HeLa cells. An IC50 value of the extract was 570 μg/ml, respectively. a significant antiangiogenic activity was observed against VEGF-induced neovascularization and antiproliferative activity by MTT assay. In this study, it could be attributed that the activity may be due to the presence of secondary metabolites in the C

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

    Energy Technology Data Exchange (ETDEWEB)

    Wada, Takeyoshi [Faculty of Science and Engineering, Waseda University, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo, 162-8480 (Japan); Asahi, Toru [Faculty of Science and Engineering, Waseda University, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo, 162-8480 (Japan); Research Organization for Nano & Life Innovation, Waseda University #03C309, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo, 162-8480 (Japan); Sawamura, Naoya, E-mail: naoya.sawamura@gmail.com [Faculty of Science and Engineering, Waseda University, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo, 162-8480 (Japan); Research Organization for Nano & Life Innovation, Waseda University #03C309, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo, 162-8480 (Japan)

    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 a 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.

  3. AUTISM WITH OPHTHALMOLOGIC MALFORMATIONS: THE PLOT THICKENS

    Science.gov (United States)

    Miller, Marilyn T; Strömland, Kerstin; Ventura, Liana; Johansson, Maria; Bandim, Jose M; Gillberg, Christopher

    2004-01-01

    ABSTRACT Purpose To review the association of autism spectrum disorder (ASD) in individuals manifesting thalidomide embryopathy and Möbius sequence and compare them with three new studies in which ASD was also associated with ocular and systemic malformations: (1) a Swedish study of individuals with CHARGE association (Coloboma, Heart, choanal Atresia, developmental or growth Retardation, Genital anomaly, and Ear involvement); (2) a Swedish study of Goldenhar syndrome; and (3) Brazilian Möbius syndrome (sequence) study. Methods In the Swedish CHARGE study, 31 patients met the inclusion criteria (3+ or 4 of the common characteristics of the CHARGE syndrome). The same team of investigators also evaluated 20 Swedish patients with Goldenhar syndrome. In the Brazilian Möbius study, 28 children with a diagnosis of Möbius sequence were studied; some children had a history of exposure during their mother’s pregnancy to the abortifacient drug misoprostol in an unsuccessful abortion attempt Results In the CHARGE study, five patients had the more severe autism disorder and five had autistic-like condition. In the Goldenhar study, two had autism disorder and one had autistic-like condition. In the Brazilian Möbius study, the systemic findings of the misoprostol-exposed and misoprostol-unexposed patients were almost undistinguishable, and ASD was present in both groups (autism disorder in five and autistic-like condition in three). Conclusion Autism spectrum disorder has been reported in two conditions with known early pregnancy exposure to the teratogenic agents thalidomide and misoprostol. In the Brazilian Möbius study, autism also occurred in both the misoprostol-exposed and misoprostol-unexposed groups. Autism also was present in patients with both CHARGE association and Goldenhar syndrome. PMID:15747750

  4. Management of Multiple Myeloma and Usage of Bortezomib: Perspective from India and Ukraine

    Directory of Open Access Journals (Sweden)

    India and Ukraine Haemato-oncology Group

    2016-11-01

    Full Text Available Novel treatment strategies have remarkably improved the multiple myeloma (MM patients’ survival, with associated increased costs.A joint panel meet of international experts from India and Ukraine was held in New Delhi on 19th May 2016 focusing on: MM management, bortezomib role, unmet medical needs, and current challenges.The healthcare system for oncology in India is majorly private versus government-based in Ukraine. In India, electrophoresis, serum-free light chain assays, bone marrow tests, and X-rays are available modes of diagnosis. Despite of the numerous cancer centers and stem cell transplant centers, most patients do not prefer transplant owing to its high-cost and social stigma. Majority of the patients are treated with bortezomib or lenalidomide-based regimens. Most patients buy drug themselves. The expanding generic drugs market is a ray of hope for the affordable drugs.In Ukraine, immuno-fixation, bone-marrow analysis, and magnetic-resonance-imaging are common diagnostic modalities. Due to high-cost, only few patients undergo transplant. Bortezomib-based regimens are preferred in most of the patients, however usage is limited due to high costs and lack of funds. Thalidomide-based regimens are used for maintenance therapy due to affordability. In case of relapsed MM, bortezomib is preferred in triple therapy, however more affordable option is cyclophosphamide, thalidomide, and dexamethasone (CTD. Issues such as cost containment, common treatment strategies, enhanced collaboration, and improved healthcare access need immediate attention. High-quality generics access will improve outcomes and support healthcare cost containment. Pharmacoeconomic studies and head-to-head trials are warranted to determine the cost-effectiveness and benefit of novel therapies in MM.

  5. Infection risk with immunomodulatory and proteasome inhibitor-based therapies across treatment phases for multiple myeloma: A systematic review and meta-analysis.

    Science.gov (United States)

    Teh, Benjamin W; Harrison, Simon J; Worth, Leon J; Thursky, Karin A; Slavin, Monica A

    2016-11-01

    The objective of this review was to determine the impact of immunomodulatory drugs (IMiDs) and proteasome inhibitor (PI)-based therapy on infection risk in patients with myeloma across three treatment periods: induction, maintenance therapy and relapse/refractory disease (RRMM). A systematic review and meta-analysis of randomised controlled trials (RCT) of IMiD and PI-based therapy versus conventional therapy from 1990 to 2015 using MEDLINE, EMBASE and CENTRAL was conducted. Study methods, characteristics, interventions, outcomes and rate of infection were extracted using a standardised tool. Thirty RCTs of 13,105 patients fulfilled inclusion criteria. The rate of severe infection with the use of IMiD-based therapy was 13.4%, 22.4%, 10.5% and 16.6% for induction therapy for non-transplant- and transplant-eligible patients, maintenance therapy and therapy for RRMM, respectively. Rate of severe infection with PI-based induction in transplant-eligible patients was 19.7%. Compared to conventional therapy, use of IMiD-based induction therapy was associated with reduced risk for transplant patients (RR 0.76, p risk of severe infection, respectively. Compared to thalidomide, bortezomib-based induction therapy and lenalidomide maintenance therapy were associated with increased risk of severe infection (RR 2.03, p risk for infection and the effect of treatment phases upon risk have now been established. Thalidomide is associated with the lowest risk of severe infection when used for induction and maintenance therapy. Fight Cancer Foundation. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Tratamento de primeira linha no Mieloma Múltiplo First line treatment in Multiple Myeloma

    Directory of Open Access Journals (Sweden)

    Gisele W. B. Colleoni

    2007-03-01

    stem-cell mobilization (such as alkylating agents. Thus, their treatment options are: dexamethasone, VAD and thalidomide (with or without dexamethasone. Thalidomide should be preferentially used in the context of clinical trials due to increased risks of neuropathy and thrombosis. Patients older than 65-70 years old and those with bad performance status, concurrent diseases or deterioration of renal function can receive alkylating agents (such as melphalan/prednisone because they are not candidates for stem cell transplantation. The aim of their treatment is to reach a disease plateau with low toxicity rates. Other alkylating agents, thalidomide and corticosteroid combinations have higher response rates than melphalan/prednisone however, these combinations present more side effects and do not increase overall survival.

  7. A review of current and future treatment strategies for malignant astrocytomas in adults

    Energy Technology Data Exchange (ETDEWEB)

    Nieder, C. [Texas Univ., Houston, TX (United States). Dept. of Experimental Radiation Oncology; Nestle, U. [Universitaet des Saarlandes, Homburg/Saar (Germany). Radiologische Klinik

    2000-06-01

    This review discusses available laboratory and clinical data as well as recent advances in our knowledge about prognostic factors and their implications for the design of future clinical trials. Results: Elucidation of the biology of malignant astrocytomas allowed for development of rational new approaches, such as gene therapy and immunotherapy, which could interfere with established treatment regimens or being used independently. Possible strategies include the restoration of defective cancer-inhibitory genes, cell transduction or transfection with antisense DNA corresponding to genes coding for growth factors and their receptors, or with the so-called suicide genes. Several antiangiogenic approaches such as administration of thalidomide, protamine, or monoclonal antibodies against vascular endothelial growth factor have been developed, too. Further treatment possibilities include modulation of drug resistance, e.g. by P-glycoprotein antagonists or O6-alkyl-guanine-DNA-transferase inhibitors, inhibition of matrix metalloproteinases, inhibition of protein kinase C, and administration of agents such as phenylbutyrate or valproic acid that showed promising antiproliferative effects in vitro. Conclusions: Several rational new approaches are now entering clinical trials. In the light of limited survival after standard treatment it is recommended that patients should be offered participation in such trials. (orig.) [German] In dieser Arbeit werden sowohl die verfuegbaren Labor- und klinischen Daten als auch die aktuellen Fortschritte auf dem Gebiet prognostischer Faktoren und deren Bedeutung fuer das Design kuenftiger klinischer Studien diskutiert. Ergebnisse: Die Aufklaerung der Biologie dieser Tumoren ermoeglichte die Entwicklung rationaler neuer Strategien, zum Beispiel basierend auf der Gen- und Immuntherapie, die entweder zusammen mit etablierten Methoden oder allein anwendbar sind. Moegliche Strategien bestehen in der Wiederherstellung defekter

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

    Science.gov (United States)

    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

  9. Diffuse Cavernous Hemangioma of the Colon.

    Science.gov (United States)

    Mirioglu, S; Cavus, B; Iliaz, R; Besisik, F

    2016-01-01

    A 70-year-old man was admitted to our clinic with a history of rectal bleeding and constipation, his colonoscopy revealed varicosities and bluish nodular lesions of the rectum (Figure 1). Abdominal CT showed multiple nodular lesions beginning from the distal descending colon and extending to the rectum, calcifications suggesting phleboliths were also seen in these lesions. A contrast enhanced pelvic MRI demonstrated multiple tubular lesions showing hyperintensity on T2-weighted images and hypointensity on T1-weighted images, consistent with the affected areas on the CT scan (Figure 2). It was a diffuse cavernous hemangioma, which mostly affects the rectosigmoid colon in the gastrointestinal tract, and can clinically mimic internal hemorrhoids, ulcerative colitis or cancer (1). Gastrointestinal hemangioma is a rare benign vascular neoplasm, and might be associated with a congenital disorder like Osler-Weber-Rendu disease, Maffucci's syndrome, Klippel-Trénaunay syndrome, or the congenital blue rubber bleb nevus syndrome (2). Even though there are different medical treatment options targeting VEGF and FGF-mediated pathways such as bevacizumab and thalidomide, and endoscopic approaches like sclerotherapy and electrocautery; complete resection of the hemangioma is the only curative treatment method (1, 3). Therefore, the patient was referred to department of surgery for a definitive treatment, and lost to follow-up.

  10. Chemical approaches to targeted protein degradation through modulation of the ubiquitin-proteasome pathway.

    Science.gov (United States)

    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).

  11. Leflunomide in the Treatment of a Pseudotumoral Genital Herpes Simplex Virus Infection in an HIV Patient

    Directory of Open Access Journals (Sweden)

    Marie R. Roger

    2017-01-01

    Full Text Available The patient is a 52-year-old African American man with a past medical history of HIV infection (on antiretroviral therapy, CD4 count 399 cells/µL, and undetectable HIV viral load and recurrent genital herpes. While on valacyclovir, the patient presented with four tumorous lesions on the perineum and scrotum. A biopsy specimen stained positively with HSV-1 and HSV-2 immunostains and displayed a lymphoplasmacytic infiltrate. The patient received foscarnet and imiquimod for two weeks with minimal improvement. Based on the previous activity of leflunomide, which has both antiviral and immunomodulatory properties, in cytomegalovirus and herpes simplex infections, leflunomide 20 mg orally twice daily was started. The patient received 23 days of foscarnet, 14 days of topical imiquimod, and 11 days of leflunomide with approximately 80% reduction in the size of the perineal lesion. After nine months on leflunomide there was complete regression of the large perineal lesion and only two small ulcerations remained on the scrotum. Pseudotumoral herpes lesions in HIV patients represent an immune reconstitution event and are poorly responsive to the usual anti-herpes agents. This report demonstrates the successful use of leflunomide in the treatment of an HIV patient with pseudotumoral herpes. Thalidomide has also been used with some success.

  12. Adverse events and intravenous versus oral bisphosphonate use in patients with osteoporosis and cancer in the U.S.

    Science.gov (United States)

    Skrepnek, Grant H; Seal, Brian; Tangirala, Muralikrishna; Jeffcoat, Marjorie K; Watts, Nelson B; Hay, Joel W

    2010-01-01

    This observational study utilized a patient-level database of more than 55 million patients and 70 U.S.-based health plans compiled from 2000-2006. Patients diagnosed with osteoporosis or various cancers were categorized according to bisphosphonate use (via IV, oral, or none). Continuous enrollment for at least six months pre- and post-index diagnosis was required. Outcomes of adverse events were defined as inflammatory conditions of the jaw, including osteonecrosis; major jaw surgery for necrotic or inflammatory conditions; or jaw surgeries for malignancies. Propensity scores and multivariate regression analyses were used to determine adjusted odds ratios for adverse events based on IV or oral bisphosphonate use relative to no bisphosphonate use, controlling for patient demographics, co-morbidities, prior dental or oral surgery, physician likelihood of prescribing oral versus IV bisphosphonates, and antibiotic, hormonal treatment, or thalidomide use. Subgroup analyses-excluding patients using oral corticosteroids-were conducted. After controlling for numerous demographic, clinical, and instrumental variables, this study found significant relationships between IV bisphosphonate use and both inflammatory conditions of the jaw and major jaw surgery for necrotic or inflammatory conditions in patients with osteoporosis or various cancers. While no significant relationship was observed for oral bisphosphonates, continued research is warranted to assess the long-term use of the medications and adverse events in patients with osteoporosis.

  13. [Classification and etiology of hyperthyroidism].

    Science.gov (United States)

    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.

  14. Management strategies for HIV-associated aphthous stomatitis.

    Science.gov (United States)

    Kerr, A Ross; Ship, Jonathan A

    2003-01-01

    Recurrent aphthous stomatitis (RAS) is the most common oral mucosal disorder found in men and women of all ages, races, and geographic regions. There are three forms of the lesions (minor, major, and herpetiform), with major aphthous ulcers causing significant pain and potential for scarring. In HIV-infected individuals, these ulcers occur more frequently, last longer, and produce more painful symptoms than in immunocompetent persons. In addition, they may be associated with similar ulcerations involving the esophagus, rectum, anus, and genitals. The diagnosis of HIV-induced RAS requires a careful history of the condition, and a thorough extra- and intra-oral examination. Oral mucosal biopsies are required for non-healing ulcers in order to exclude the possibility of deep fungal infections, viral infections, and neoplasms. The cause of the ulcers in HIV-positive persons has not been elucidated--local diseases, genetic, immunologic, and infectious factors all probably play a role. The goals of current treatments are to promote ulcer healing, to reduce ulcer duration and pain while maintaining nutritional intake, and to prevent or diminish the frequency of recurrence. Initial therapy for infrequent RAS recurrences includes over-the-counter topical protective and analgesic products. Initial therapy for frequent RAS outbreaks requires topical anesthetics, binding agents, and corticosteroids. Major RAS and non-healing minor or herpetiform RAS may require intralesional corticosteroids and systemic prednisone. Second-line immunomodulators for frequent and non-healing ulcers includes thalidomide and other immunomodulators.

  15. Caso para diagnóstico Case for diagnosis

    Directory of Open Access Journals (Sweden)

    Patricia Erica Christofoletti Daldon

    2010-10-01

    Full Text Available Paciente do sexo masculino, negro, 13 anos, apresenta há dois anos lesões pruriginosas, pápulonodulares nos antebraços, associadas a edema do lábio inferior, fotofobia, conjuntivite e pterígio. O exame histopatológico do lábio inferior revelou acantose, espongiose e infiltrado inflamatório perivascular superficial, composto por linfócitos, plasmócitos e eosinófilos, compatível com o diagnóstico de prurigo actínico. As lesões regrediram com o uso de talidomida 100 mg/dia.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.

  16. Haematopoietic stem cell transplantation as first-line treatment in myeloma: a global perspective of current concepts and future possibilities

    Directory of Open Access Journals (Sweden)

    Catriona Elizabeth Mactier

    2012-10-01

    Full Text Available 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.

  17. Pharmacovigilance Discussion Forum--The European Generic Medicines Association's 8th Annual Meeting (January 21, 2015--London, UK).

    Science.gov (United States)

    Lam, S

    2015-01-01

    The practice and science of pharmacovigilance first emerged following the disaster caused by thalidomide in 1961, which led to the initiation of systemic international efforts to address drug safety issues spearheaded by the WHO. Systems were developed in member states of the WHO to analyze cases of adverse drug reactions (ADRs) and collate these data into a central database to aid national drug regulatory authorities in improving safety profiles of medicines. Pharmacovigilance is a key public health function for monitoring all medicinal products to assess their quality, efficacy and safety before and following authorization. These medicines are continually assessed to detect any aspect that could compromise their safety, and ensure that the necessary measures are taken. In July 2012, new legislation for pharmacovigilance in the E.U. came into effect as a result of the changes set out in the Directive 2010/84/EU and the European Commission (EC) implementing Regulation (EU) No 520/2012 to reduce the increasing number of ADRs. The latest developments in pharmacovigilance in Europe, including news on E.U. pharmacovigilance legislation, were discussed at the 8th European Generic Medicines Association (EGA) Pharmacovigilance Discussion Forum. The meeting facilitated constructive dialogue between regulators and industry on a range of topics including how to simplify pharmacovigilance activities and improve the processes of risk management plans, periodic safety update reports, signal detection, joint studies and inspections. Copyright 2015 Prous Science, S.A.U. or its licensors. All rights reserved.

  18. Drug safety in pregnancy--monitoring congenital anomalies.

    Science.gov (United States)

    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.

  19. A study on habit of preservation of prescriptions by pregnant women in India.

    Science.gov (United States)

    Adhikari, A; Biswas, S; Gupta, R K

    2011-03-01

    Irrational use of medicine is very common in developing countries like India. Drug or medicine use during pregnancy is an important event for both mother and child. Thalidomide disaster showed the adverse effects of drugs on the unborn child. Knowledge about use of medicines can play a crucial role in rational drug use. Prescription is an important tool to assess the past clinical condition of patients and the use of medicines for them. The present study explored the habit of preservation of previous prescriptions in the pregnant women of villages of Wardha District of Maharashtra state of India. This is an observational cross sectional survey using predesigned, precoded and pretested questionnaire. This study showed an interesting habit of these women. 81% of pregnant women have a habit of preservation of prescription as an important document. It was clear that with increasing level of formal education there is a definite increase in habit of preservation of prescription among the pregnant women in rural areas of India.

  20. CYP2C19 Phenoconversion by Routinely Prescribed Proton Pump Inhibitors Omeprazole and Esomeprazole: Clinical Implications for Personalized Medicine.

    Science.gov (United States)

    Klieber, Martin; Oberacher, Herbert; Hofstaetter, Silvia; Beer, Beate; Neururer, Martin; Amann, Anton; Alber, Hannes; Modak, Anil

    2015-09-01

    The phenotype pantoprazole-(13)C breath test (Ptz-BT) was used to evaluate the extent of phenoconversion of CYP2C19 enzyme activity caused by commonly prescribed proton pump inhibitors (PPI) omeprazole and esomprazole. The Ptz-BT was administered to 26 healthy volunteers and 8 stable cardiovascular patients twice at baseline and after 28 days of PPI therapy to evaluate reproducibility of the Ptz-BT and changes in CYP2C19 enzyme activity (phenoconversion) after PPI therapy. The average intrapatient interday variability in CYP2C19 phenotype (n = 31) determined by Ptz-BT was considerably low (coefficient of variation, 17%). Phenotype conversion resulted in 25 of 26 (96%) nonpoor metabolizer (non-PM) volunteers/patients as measured by the Ptz-BT at baseline and after PPI therapy. The incidence of PM status by phenotype following administration of omeprazole/esomeprazole (known inhibitors of CYP2C19) was 10-fold higher than those who are genetically PMs in the general population, which could have critical clinical implications for personalizing medications primarily metabolized by CYP2C19, such as clopidogrel, PPI, cyclophosphamide, thalidomide, citalopram, clonazepam, diazepam, phenytoin, etc. The Ptz-BT can rapidly (30 minutes) evaluate CYP2C19 phenotype and, more importantly, can identify patients with phenoconversion in CYP2C19 enzyme activity caused by nongenetic factors such as concomitant drugs. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  1. Overview: developmental toxicology: new directions.

    Science.gov (United States)

    Shuey, Dana; Kim, James H

    2011-10-01

    Since regulatory agencies began implementing the use of standardized developmental toxicology protocols in the mid-1960s, our knowledge base of embryo-fetal development and technologies for experimentation has grown exponentially. These developmental toxicology protocols were a direct result of the thalidomide tragedy from earlier that decade, when large numbers of women were exposed to the drug and over 10,000 cases of phocomelia resulted. In preventing a recurrence of such tragedies, the testing protocols are immensely successful and the field of toxicology has been dedicated to using them to advance safety and risk assessment of chemicals and pharmaceuticals. Recently, our perspectives on toxicity testing have been challenged by a growing awareness that while we have excelled in hazard identification, we are in dire need of improved methodologies for human health risk assessment, particularly with respect to the large numbers of environmental chemicals for which we have little toxicology data and to the growing sentiment that better alternatives to whole animals tests are needed. To provide a forum for scientists, researchers, and regulators, the Developmental and Reproductive Toxicology Technical Committee of the Health and Environmental Sciences Institute organized a 2-day workshop titled "Developmental Toxicology-New Directions" to evaluate lessons learned over the past 30 years and discuss the future of toxicology testing. The following four articles describe different presentations and discussions that were held over the course of those 2 days. © 2011 Wiley Periodicals, Inc.

  2. Vulvovaginal gingival lichen planus: report of two cases and review of literature.

    Science.gov (United States)

    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.

  3. Teratogens: a public health issue – a Brazilian overview

    Directory of Open Access Journals (Sweden)

    Thiago Mazzu-Nascimento

    2017-05-01

    Full Text Available 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.

  4. A Review of the Teratogenic Factors Effect on Embryo

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    Manzarbanoo Shojaei fard

    2017-02-01

    Full Text Available Background & Objectives: Teratology is a branch of embryology science that studies causes, mechanisms and abnormal pattern development. Embryo growth traumatic factors during pregnancy are called teratogens that some teratogens pass the placental barrier and cause adverse effect during development stages and malformation, however a drug may improve general health of the mother, but it might be poisonous for embryo and cause diverse malformation. Since study of embryo health and risk factor in this stage is important, the aim of this review article was the investigation of some types of teratosgens (such as radiation, infectious agents, heat disorders, maternal conditions and particularly the effect of teratogenic drugs on embryo including some legal drugs (such as acetaminophen, thalidomide, acyclovir, sedatives and anticonvulsants and illegal drugs (such as nicotine, alcohol, cocaine and marijuana. Conclusion: In general, teratogens depending on the type and duration of exposure in pregnancyperiod, adversely affect embryo and cause various disorders. A better understanding of these teratogens can contribute to prevent these defects, since many other drugs with similar effects and lower teratogenicity can be used to improve mothers’ health.

  5. Plasmablastic Lymphoma: A Review of Current Knowledge and Future Directions

    Directory of Open Access Journals (Sweden)

    Ghaleb Elyamany

    2015-01-01

    Full Text Available Plasmablastic lymphoma (PBL is an aggressive subtype of non-Hodgkin’s lymphoma (NHL, which frequently arises in the oral cavity of human immunodeficiency virus (HIV infected patients. PBL shows diffuse proliferation of large neoplastic cells resembling B-immunoblasts/plasmablasts, or with plasmacytic features and an immunophenotype of plasma cells. PBL remains a diagnostic challenge due to its peculiar morphology and an immunohistochemical profile similar to plasma cell myeloma (PCM. PBL is also a therapeutic challenge with a clinical course characterized by a high rate of relapse and death. There is no standard chemotherapy protocol for treatment of PBL. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP or CHOP-like regimens have been the backbone while more intensive regimens such as cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, high-dose cytarabine (CODOX-M/IVAC, or dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH are possible options. Recently, a few studies have reported the potential value of the proteasome inhibitor bortezomib and thalidomide in PBL patients. The introduction of genes encoding artificial receptors called chimeric antigen receptors (CARs and CAR-modified T cells targeted to the B cell-specific CD19 antigen have demonstrated promising results in multiple early clinical trials. The aim of this paper is to review the recent advances in epidemiology; pathophysiology; clinical, pathologic, and molecular characteristics; therapy; and outcome in patients with PBL.

  6. Traditional Tongan cures for morning sickness and their mutagenic/toxicological evaluations.

    Science.gov (United States)

    Ostraff, M; Anitoni, K; Nicholson, A; Booth, G M

    2000-07-01

    Every year millions of women become pregnant, and more than 60% of them will develop some form of morning sickness. Yet drugs like Thalidomide, Bendectin and other possibly potent teratogens administered for pre-partum nausea have severely limited any medicinal intervention. In Tonga, women have been treated for morning sickness for hundreds of years. Two types of traditional treatments exist, the first one consists of an infusion of fresh leaves, commonly called vai momoko. The second type of treatment is called vai haka, which is made from the boiled bark of several trees. In this paper we describe the results of 6 months of intensive interviews in Tonga regarding the second type of treatment called vai haka. In addition, we tested vai haka for mutagenic and teratogenic effects. Data from the Ames TA-98 mutagenic bioassay clearly indicate that vai haka is not mutagenic with or without S-9 activation. Twenty-six experimental CD-1 white mice were gavaged with 0.1 ml of vai haka (at 540xthe human dose) while the control group of 17 mice were gavaged with 0.1 ml of water to determine teratogenic and developmental effects of the vai haka. No significant teratogenic or developmental anomalies occurred in the mice dosed with vai haka compared to the controls.

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

    Science.gov (United States)

    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

  8. Brain abscess caused by Nocardia cyriacigeorgica in two patients with multiple myeloma: novel agents, new spectrum of infections.

    Science.gov (United States)

    Pamukçuoğlu, Merve; Emmez, Hakan; Tunçcan, Ozlem Güzel; Oner, Ali Yusuf; Cırak, Meltem Yalınay; Senol, Esin; Sucak, Gülsan Türköz

    2014-04-01

    Introduction of high-dose chemotherapy and the novel agents including bortezomib, Lenalidomide, and Thalidomide has provided a significant progress in the treatment of multiple myeloma (MM) with an increase in median overall survival up to 6-8 years. However, the advances in myeloma treatment comes at a price with new spectrum of treatment-related infectious complications which should be taken into consideration while treating these patients. We report here two patients with Ig G λ MM presenting with intracerebral mass lesions in the abscence of constitutional symptoms that would suggest an infectious etiology. Both patients had severe hypogammaglobulinemia and lymphopenia, which was attributed to treatment regimens including bortezomib. Intervention The surgical intervention-revealed abscess in both cases caused by Nocardia cyriacigeorgica, a relatively new pathogen which rarely causes infections in humans and also an unexpected pathogen in myeloma patients. Although every aspect of immune system is known to be affected in MM, humoral immune deficiency is the hallmark of the inherent immune defect in this disease. Introduction of the novel agents, bortezomib in particular seems to have changed the characteristics of the immune dysfunction and the spectrum of the opportunistic infections by causing qualitative and quantitative changes in cellular immunity. The new spectrum of infectious agents might not be limited to hepatitis B and herpes zoster. Monitoring lymphopenia and administration of prophylactic antimicrobial agents accordingly could be considered in patients treated with bortezomib.

  9. Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics.

    Science.gov (United States)

    Jenkins, Kathy J; Correa, Adolfo; Feinstein, Jeffrey A; Botto, Lorenzo; Britt, Amy E; Daniels, Stephen R; Elixson, Marsha; Warnes, Carole A; Webb, Catherine L

    2007-06-12

    Prevention of congenital cardiovascular defects has been hampered by a lack of information about modifiable risk factors for abnormalities in cardiac development. Over the past decade, there have been major breakthroughs in the understanding of inherited causes of congenital heart disease, including the identification of specific genetic abnormalities for some types of malformations. Although relatively less information has been available on noninherited modifiable factors that may have an adverse effect on the fetal heart, there is a growing body of epidemiological literature on this topic. This statement summarizes the currently available literature on potential fetal exposures that might alter risk for cardiovascular defects. Information is summarized for periconceptional multivitamin or folic acid intake, which may reduce the risk of cardiac disease in the fetus, and for additional types of potential exposures that may increase the risk, including maternal illnesses, maternal therapeutic and nontherapeutic drug exposures, environmental exposures, and paternal exposures. Information is highlighted regarding definitive risk factors such as maternal rubella; phenylketonuria; pregestational diabetes; exposure to thalidomide, vitamin A cogeners, or retinoids; and indomethacin tocolysis. Caveats regarding interpretation of possible exposure-outcome relationships from case-control studies are given because this type of study has provided most of the available information. Guidelines for prospective parents that could reduce the likelihood that their child will have a major cardiac malformation are given. Issues related to pregnancy monitoring are discussed. Knowledge gaps and future sources of new information on risk factors are described.

  10. Common increase of GATA-3 level in PC-12 cells by three teratogens causing autism spectrum disorders.

    Science.gov (United States)

    Rout, Ujjwal K; Clausen, Pete

    2009-06-01

    Autism spectrum disorder (ASD) is a disease of neuro-developmental origin of uncertain etiology. The current understanding is that both genetic and environmental factors contribute to the development of ASD. Exposure to valproate, thalidomide and alcohol during gestation are amongst the environmental triggers that are associated with the development of ASD. These teratogens may disturb the ontogeny of the brain by altering the expression pattern of genes that regulate the normal development of the brain. In this study, a neuron-like PC-12 cell model was used to examine the effects of these compounds on the binding potential of 50 different transcription factors to understand the molecular mechanism/s that may be involved in the teratogenesis caused by these agents. Cells in culture were treated with low or high concentrations of teratogens within a range that are reported in the blood of individuals. A pronounced increase in GATA transcription factor binding was observed for all three teratogens. Furthermore, Western blot analysis showed that GATA-3 level in the nuclear fractions was enhanced by each of the three teratogens. Results suggest that altered gene expression pattern due to heightened GATA-3 activities in the fetral brains following exposure to these teratogens may contribute to the development of ASD.

  11. Annular bullous lesions with atypical erythema multiforme in leprosy.

    Science.gov (United States)

    Shah, Aishani; Mahajan, Rashmi; Ninama, Kishan; Bilimoria, Freny

    2014-09-01

    Erythema nodosum leprosum (ENL) is an immune complex-mediated reaction that may complicate the course of multibacillary leprosy. Bullous lesions in Type II reaction, though reported, are exceedingly rare. We report the case of a 32 year old female patient who presented initially at our OPD with erythema nodosum. Cutaneous examination revealed impaired sensation over dorsum of right foot and thickened right lateral popliteal nerve. Slit skin smear (SSS) from ear lobes revealed AFB with a bacteriological index of 2+. She was started on MDT, tablet ofloxacin 200 mg twice a day, and 30 mg oral prednisolone. Two months later, she presented with generalised pruritus, large target lesions over the back, and hemorrhagic bullae over lower extremities and annular pattern of bullae, over both arms. A SSS was repeated which was positive for AFB. Histopathology from bullous lesions was consistent with ENL. Direct Immunofluorescence (DIF) study was negative. Our patient improved rapidly after she was started on thalidomide 100 mg twice daily, with withdrawal of ofloxacin. Erythema Multiforme (EMF) and annular bullous lesions have been reported in patients on treatment with ofloxacin. This case is being presented due to the unusual and varied manifestation of Type II lepra reaction in a 34 year old female patient.

  12. Novel generation of agents with proven clinical activity in multiple myeloma.

    Science.gov (United States)

    Mateos, María-Victoria; Ocio, Enrique M; San Miguel, Jesús F

    2013-10-01

    The activity observed with proteasome inhibitors and immunomodulatory drugs (IMIDs) in multiple myeloma (MM) has prompted the development of second- and third-generation agents with similar, but not exactly the same, mechanisms of action as their predecessors. This review summarizes the mechanism of action and the available data on the clinical activity of novel proteasome inhibitors (carfilzomib, oprozomib, ixazomib, and marizomib) and novel IMIDs (pomalidomide), stressing the similarities and differences with bortezomib, and with thalidomide and lenalidomide, respectively. In summary, these novel agents have shown clinical activity as single agents and in combination with dexamethasone, with similar or even higher efficacy than their parental drugs; moreover, they may even overcome resistance, indicating that there are some differences in their mechanisms of action and resistance. These data indicate that both the inhibition of the proteasome and the modulation of the immune system are good strategies to target MM tumor cells and this, along with the absence of complete cross-resistance observed among these drugs, open new avenues to optimize their use through the most appropriate sequencing and combinations. © 2013 Elsevier Inc. All rights reserved.

  13. Current treatment options and investigational drugs for Waldenstrom's Macroglobulinemia.

    Science.gov (United States)

    Gavriatopoulou, Maria; Terpos, Evangelos; Kastritis, Efstathios; Dimopoulos, Meletios A

    2017-02-01

    Waldenström's Macroglobulinemia (WM) is a rare, indolent, incurable, low-grade B-cell lymphoplasmacytic neoplasm. This review article provides a modern clinical perspective of the individualized management of patients with symptomatic WM, in the context of the updated treatment guidelines and the currently available trial data. Areas covered: Rituximab-based regimens (such as the dexamethasone, rituximab and cyclophosphamide combination, DRC) are the most widely used in the management of both newly diagnosed and relapsed/refractory patients with WM. Recently, the Bruton's tyrosine kinase inhibitor ibrutinib has been licensed for use in WM with exciting results. Several investigational single agent and combination regimens are being evaluated for response, efficacy and tolerability in phase II clinical trials, including new generation monoclonal antibodies (ofatumumab), immunomodulatory agents (thalidomide and lenalidomide), proteasome inhibitors (bortezomib and carfilzomib), Bruton's tyrosine kinase inhibitors (ibrutinib and acalabrutinib), phosphoinositide 3-kinase/protein kinase B (Akt)/mammalian target of rapamycin pathway inhibitors (everolimus and perifosene), and histone deacetylase inhibitors (panobinostat) both in the setting of newly diagnosed and relapsed/refractory disease. Expert opinion: WM therapeutic approach should be individualized for each patient in accordance to the intensity of the disease characteristics, age, comorbidities, efficacy, tolerability and safety profile of each drug.

  14. [Influence of inflammatory bowel disease on pregnancy and fertility - optimal treatment and management].

    Science.gov (United States)

    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.

  15. Management of inflammatory bowel disease in pregnancy.

    Science.gov (United States)

    Vermeire, Séverine; Carbonnel, Franck; Coulie, Pierre G; Geenen, Vincent; Hazes, Johanna M W; Masson, Pierre L; De Keyser, Filip; Louis, Edouard

    2012-09-01

    Inflammatory bowel disease (IBD) is a chronic disease affecting mainly young people in their reproductive years. IBD therefore has a major impact on patients' family planning decisions. Management of IBD in pregnancy requires a challenging balance between optimal disease control and drug safety considerations. This article aims to provide a framework for clinical decision making in IBD based on review of the literature on pregnancy-related topics. Medline searches with search terms 'IBD', 'Crohn's disease' or 'ulcerative colitis' in combination with keywords for the topics fertility, pregnancy, congenital abnormalities and drugs names of drugs used for treatment of IBD. IBD patients have normal fertility, except for women after ileal pouch-anal anastomosis (IPAA) and men under sulfasalazine treatment. Achieving and maintaining disease remission is a key factor for successful pregnancy outcomes in this population, as active disease at conception carries an increased risk of preterm delivery and low birth weight. Clinicians should discuss the need for drug therapy to maintain remission with their patients in order to ensure therapy compliance. Most IBD drugs are compatible with pregnancy, except for methotrexate and thalidomide. If possible, anti-TNF therapy should be stopped by the end of the second trimester and the choice of delivery route should be discussed with the patient. Disease control prior to conception and throughout pregnancy is the cornerstone of successful pregnancy management in IBD patients. Copyright © 2012 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

  16. [Pregnancy and inflammatory bowel disease: experience in 17 patients].

    Science.gov (United States)

    Vergara A, María Teresa; Rey G, Paula

    2011-11-01

    Inflammatory bowel disease (IBD) has a peak incidence between 15 and 25 years of age, thereby affecting women of reproductive age. Fertility rates with inactive IBD are similar to the general population, and drugs currently used, with the exception of methotrexate and thalidomide, have a good safety and efficacy profile during pregnancy. Starting a pregnancy with inactive IBD significantly reduces the potential maternal and fetal complications. To assess the evolution of pregnancy and the underlying disease in women with IBD. Retrospective and prospective study of female patients with IBD controlled in our hospital who became pregnant from January 1994 to February, 2011. We followed 17 patients with a total of 19 pregnancies. In two patients the onset of IBD occurred during pregnancy and from the remaining, 11 patients became pregnant during remission of IBD. Most of the patients continued the same treatment during pregnancy and the few flares that occurred were treated satisfactorily. Major complications occurred in three patients, all associated with IBD activity. Fifteen patients had full-term deliveries and the majority of the newborns had normal weight and Apgar score. None had malformations. Pregnancies among patients with an inactive IBD, have a good evolution. A multidisciplinary approach and patient education are invaluable to achieve these good results.

  17. Review article: a decision-making algorithm for the management of pregnancy in the inflammatory bowel disease patient.

    Science.gov (United States)

    Habal, F M; Huang, V W

    2012-03-01

    Inflammatory bowel disease affects patients who are in their reproductive years. There are many questions regarding the management of IBD patients who are considering or who are already pregnant. These include the effect of the disease and the medications on fertility and on the pregnancy outcome. To create an evidence-based decision-making algorithm to help guide physicians through the management of pregnancy in the IBD patient. A literature review using phrases that include: 'inflammatory bowel disease', 'Crohn's disease', 'ulcerative colitis', 'pregnancy', 'fertility', 'breast feeding', 'delivery', 'surgery', 'immunomodulators', 'azathioprine', 'mercaptopurine', 'biologics', 'infliximab', 'adalimumab', 'certolizumab'. The four decision-making nodes in the algorithm for the management of pregnancy in the IBD patient, and the key points for each one are as follows: (i) preconception counselling - pregnancy outcome is better if patients remain in remission during pregnancy, (ii) contemplating pregnancy or is already pregnant - drugs used to treat IBD appear to be safe during pregnancy, with the exception of methotrexate and thalidomide, (iii) delivery and (iv) breast feeding - drugs used to treat IBD appear to be safe during lactation, except for ciclosporin. Another key point is that biological agents may be continued up to 30 weeks gestation. The management of pregnancy in the IBD patient should be multi-disciplinary involving the patient and her partner, the family physician, the gastroenterologist and the obstetrician. © 2012 Blackwell Publishing Ltd.

  18. Treatment of pregnant women with a diagnosis of inflammatory bowel disease

    Science.gov (United States)

    Poturoglu, Sule; Ormeci, Asli Ciftcibasi; Duman, Ali Erkan

    2016-01-01

    The frequency of diagnosis of inflammatory bowel disease (IBD) has increased in younger populations. For this reason, pregnancy in patients with IBD is a topic of interest, warranting additional focus on disease management during this period. The main objective of this article is to summarize the latest findings and guidelines on the management of potential problems from pregnancy to the breastfeeding stage. Fertility is decreased in patients with active IBD. Disease remission prior to conception will likely decrease the rate of pregnancy-related complications. Most of the drugs used for IBD treatment are safe during both pregnancy and breastfeeding. Two exceptions are methotrexate and thalidomide, which are contraindicated in pregnancy. Anti-tumor necrosis factor agents are not advised during the third trimester as they exhibit increased transplacental transmission and potentially cause immunosuppression in the fetus. Radiological and endoscopic examinations and surgical interventions should be performed only when absolutely necessary. Surgery increases the fetal mortality rate. The delivery method should be determined with consideration of the disease site and presence of progression or flare up. Treatment planning should be a collaborative effort among the gastroenterologist, obstetrician, colorectal surgeon and patient. PMID:27867682

  19. Alternative temozolomide dosing regimens and novel combinations for the treatment of advanced metastatic melanoma

    Directory of Open Access Journals (Sweden)

    Wen-Jen Hwu

    2011-12-01

    Full Text Available Over the past 30 years, there has been no significant improvement in treatment outcomes for patients with advanced stage IV metastatic melanoma, and prognosis remains poor. Melanoma is known to be responsive to immunomodulatory agents, to be a highly vascular tumor, and to be fairly resistant to standard cytotoxic chemotherapy. Ongoing research is attempting to find novel combinations that may have therapeutic synergy. Alternative dosedense schedules of temozolomide appear promising and are being actively investigated, based on their potential to overcome chemoresistance to alkylating agents and the proven activity of temozolomide in the brain. Outcomes of studies investigating single-agent temozolomide suggest that it has activity similar to single-agent dacarbazine. Other studies combining temozolomide with either interferon- alfa or thalidomide suggest that the addition of these immunomodulatory agents to temozolomide improves response rates and may improve overall survival. The best results have been achieved with the extended, daily, dosedense temozolomide regimen. Further research is needed to determine the optimal temozolomide regimen and best combination approach

  20. LENALIDOMIDE IN COMBINATION WITH DEXAMETHASONE IN ELDERLY PATIENTS WITH ADVANCED, RELAPSED OR REFRACTORY MULTIPLE MYELOMA AND RENAL FAILURE

    Directory of Open Access Journals (Sweden)

    Patrizia Tosi

    2013-06-01

    Full Text Available Salvage therapy of elderly patients with advanced, relapsed and refractory multiple myeloma (MM is often limited by poor marrow reserve and multi-organ impairment. In particular, renal failure occurs in up to 50% of such patients, an this can potentially limit the therapeutic options. Both thalidomide and bortezomib have proven effective in these patients, with an acceptable toxicity, while, in clinical practice, lenalidomide is generally not considered a first-choice drug for MM patients with renal failure as early reports showed an increased hematological toxicity unless appropriate dose reduction is applied. Aim of this study was a retrospective evaluation of the efficacy of the combination Lenalidomide +Dexamethasone in a population of elderly MM patients treated in 5 Italian Centers. The study included 20 consecutive MM patients (9 M, 11 F, median age 76.5 years with relapsed (N= 6 or refractory (N=13 MM and moderate to severe renal failure, defined as creatinine clearance (Cr Cl partial response was observed in 8 patients (40%, 1 of whom obtained a VGPR; 4 additional patients achieved a minor response. Median response duration was 16 months (range 2-19+ months. A complete and partial renal response was obtained in 4 and 3 patients, respectively, all of them were responsive to Lenalidomide-dexamethasone According to our data, LEN+DEX has shown efficacy and acceptable toxicity in this population of elderly patients with advanced MM and renal failure

  1. Brazilian blood donation eligibility criteria for dermatologic patients.

    Science.gov (United States)

    Wambier, Carlos Gustavo; Pereira, Caroline Silva; Prado Júnior, Benedito de Pina Almeida; Foss, Norma Tiraboschi

    2012-01-01

    A focused and commented review on the impact of dermatologic diseases and interventions in the solidary act of donating blood is presented to dermatologists to better advise their patients. This is a review of current Brazilian technical regulations on hemotherapeutic procedures as determined by Ministerial Directive #1353/2011 by the Ministry of Health and current internal regulations of the Hemotherapy Center of Ribeirão Preto, a regional reference center in hemotherapeutic procedures. Criteria for permanent inaptitude: autoimmune diseases (>1 organ involved), personal history of cancer other than basal cell carcinoma, severe atopic dermatitis or psoriasis, pemphigus foliaceus, porphyrias, filariasis, leprosy, extra pulmonary tuberculosis or paracoccidioidomycosis, and previous use of etretinate. Drugs that impose temporary ineligibility: other systemic retinoids, systemic corticosteroids, 5-alpha-reductase inhibitors, vaccines, methotrexate, beta-blockers, minoxidil, anti-epileptic, and anti-psychotic drugs. Other conditions that impose temporary ineligibility: occupational accident with biologic material, piercing, tattoo, sexually transmitted diseases, herpes, and bacterial infections, among others. Thalidomide is currently missing in the teratogenic drugs list. Although finasteride was previously considered a drug that imposed permanent inaptitude, according to its short halflife current restriction of 1 month is still too long. Dermatologists should be able to advise their patients about proper timing to donate blood, and discuss the impact of drug withdrawal on treatment outcomes and to respect the designated washout periods.

  2. LNO3 AND L3 Are Associated With Antiproliferative And Pro-Apoptotic Action In Hepatoma Cells

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    Leonardo Campos Zanelatto

    2016-06-01

    Full Text Available Abstract The identification of antitumoral substances is the focus of intense biomedical research. Two structural analogues of thalidomide, LNO3 and L3, are two synthetic compounds that might possess such antitumor properties. We evaluated the toxicological effects of these substances, including cytotoxicity, genotoxicity and induction of apoptosis in HTC cells. Additionally, the production of free radicals (nitric oxide and superoxide was investigated, and the expression of caspases genes 3, 8, and 9 were determined by RT-qPCR. The compounds exhibited cytotoxic effects that resulted in inhibited cell proliferation. LNO3 showed to be more effective and toxic than L3 in all assays. LNO3 stimulated the release of NO and superoxide, which was accompanied by the formation of peroxynitrite. Apoptosis was induced in a dose-dependent manner by both compounds; however, the expression of caspases 3, 8 and 9 was unchanged. These results suggested that L3 and LNO3 possess antiproliferative and pro-apoptotic effects in HTC cells. Additionally, although they exhibited cytotoxicity, L3 and LNO3 might be useful coadjuvants in tumor treatment studies.

  3. Intra-laboratory validation of a human cell based in vitro angiogenesis assay for testing angiogenesis modulators

    Directory of Open Access Journals (Sweden)

    Jertta-Riina Sarkanen

    2011-01-01

    Full Text Available The developed standardized human cell based in vitro angiogenesis assay was intra-laboratory validated to verify that the method is reliable and relevant for routine testing of modulators of angiogenesis e.g. pharmaceuticals and industrial chemicals. This assay is based on the earlier published method but it was improved and shown to be more sensitive and rapid than the previous assay. The performance of the assay was assessed by using 6 reference chemicals, which are widely used pharmaceuticals that inhibit angiogenesis: acetyl salicylic acid, erlotinib, 2-methoxyestradiol, levamisole, thalidomide, and anti-vascular endothelial growth factor. In the intra-laboratory validation, the sensitivity of the assay (upper and lower limits of detection and linearity of response in tubule formation, batch to batch variation in tubule formation between different Master cell bank batches, and precision as well as the reliability of the assay (reproducibility and repeatability were tested. The pre-set acceptance criteria for the intra-laboratory validation study were met. The relevance of the assay in man was investigated by comparing the effects of reference chemicals and their concentrations to the published human data. The comparison showed a good concordance, which indicates that this human cell based angiogenesis model predicts well the effects in man and has the potential to be used to supplement and/or replace of animal tests.

  4. Pathobiology of cancer chemotherapy-induced peripheral neuropathy (CIPN

    Directory of Open Access Journals (Sweden)

    Yaqin eHan

    2013-12-01

    Full Text Available Chemotherapy induced peripheral neuropathy (CIPN is a type of neuropathic pain that is a major dose-limiting side-effect of potentially curative cancer chemotherapy treatment regimens that develops in a ‘stocking and glove’ distribution. When pain is severe, a change to less effective chemotherapy agents may be required, or patients may choose to discontinue treatment. Medications used to alleviate CIPN often lack efficacy and/or have unacceptable side-effects. Hence the unmet medical need for novel analgesics for relief of this painful condition has driven establishment of rodent models of CIPN. New insights on the pathobiology of CIPN gained using these models are discussed in this review. These include mitochondrial dysfunction and oxidative stress that are implicated as key mechanisms in the development of CIPN. Associated structural changes in peripheral nerves include neuronopathy, axonopathy and/or myelinopathy, especially intra-epidermal nerve fiber (IENF degeneration. In patients with CIPN, loss of heat sensitivity is a hallmark symptom due to preferential damage to myelinated primary afferent sensory nerve fibers in the presence or absence of demyelination. The pathobiology of CIPN is complex as cancer chemotherapy treatment regimens frequently involve drug combinations. Adding to this complexity, there are also subtle differences in the pathobiological consequences of commonly used cancer chemotherapy drugs, viz platinum compounds, taxanes, vincristine, bortezomib, thalidomide and ixabepilone, on peripheral nerves.

  5. What causes autism? Exploring the environmental contribution.

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    Liping Fan

    2017-01-01

    Full Text Available 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.

  7. The role of teratology information services in screening for teratogenic exposures: challenges and opportunities.

    Science.gov (United States)

    Chambers, Christina

    2011-08-15

    Teratology Information Services (TIS) located throughout the world have long played a key role in screening for potential new human teratogens. Using a basic prospective cohort study design, TIS recruit pregnant women from among callers to the Services who have had an exposure of interest and at the same time identify an unexposed comparison group from the same pool of callers. Women in both groups are followed to pregnancy outcome and a range of adverse outcomes including major congenital anomalies, birth size, pregnancy loss, and preterm delivery are evaluated, while controlling for potential confounding. Particularly for rare exposures or newly marketed medications, TIS may be uniquely suited to gathering this information in a timely and efficient fashion. The primary limitation of these studies is the unknown representativeness of the volunteer sample, and the typical small to moderate sample sizes. Methods to increase the proportion of exposed pregnancies that are recruited should be developed. However, small sample size TIS studies, especially when considering new or rare exposures, often fulfill the important function of providing some reassurance to women who have already had the exposure of interest by ruling out major risks for teratogenicity, that is, on the order of thalidomide. Collaborations across TIS nationally and internationally help to address the sample size challenges. A formal collaboration between the TIS cohort study model with a case-control study design is also underway and will provide complementary strengths. Copyright © 2011 Wiley-Liss, Inc.

  8. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS.

    Science.gov (United States)

    Krönke, Jan; Fink, Emma C; Hollenbach, Paul W; MacBeth, Kyle J; Hurst, Slater N; Udeshi, Namrata D; Chamberlain, Philip P; Mani, D R; Man, Hon Wah; Gandhi, Anita K; Svinkina, Tanya; Schneider, Rebekka K; McConkey, Marie; Järås, Marcus; Griffiths, Elizabeth; Wetzler, Meir; Bullinger, Lars; Cathers, Brian E; Carr, Steven A; Chopra, Rajesh; Ebert, Benjamin L

    2015-07-09

    Lenalidomide is a highly effective treatment for myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)). Here, we demonstrate that lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1α) by the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4(CRBN)), resulting in CK1α degradation. CK1α is encoded by a gene within the common deleted region for del(5q) MDS and haploinsufficient expression sensitizes cells to lenalidomide therapy, providing a mechanistic basis for the therapeutic window of lenalidomide in del(5q) MDS. We found that mouse cells are resistant to lenalidomide but that changing a single amino acid in mouse Crbn to the corresponding human residue enables lenalidomide-dependent degradation of CK1α. We further demonstrate that minor side chain modifications in thalidomide and a novel analogue, CC-122, can modulate the spectrum of substrates targeted by CRL4(CRBN). These findings have implications for the clinical activity of lenalidomide and related compounds, and demonstrate the therapeutic potential of novel modulators of E3 ubiquitin ligases.

  9. Imbalance between TNFα and progranulin contributes to memory impairment and anxiety in sleep-deprived mice.

    Science.gov (United States)

    Zhang, Kun; Li, Yu-Jiao; Feng, Dan; Zhang, Peng; Wang, Ya-Tao; Li, Xiang; Liu, Shui-Bing; Wu, Yu-Mei; Zhao, Ming-Gao

    2017-03-16

    Sleep disorder is becoming a widespread problem in current society, and is associated with impaired cognition and emotional disorders. Progranulin (PGRN), also known as granulin epithelin precursor, promotes neurite outgrowth and cell survival, and is encoded by the GRN gene. It is a tumor necrosis factor α receptor (TNFR) ligand which is implicated in many central nervous system diseases. However, the role PGRN in sleep disorder remains unclear. In the present study, we found that sleep deprivation (S-DEP) impaired the memory and produced thigmotaxis/anxiety-like behaviors in mice. S-DEP increased the levels of TNFα but decreased PGRN levels in the hippocampus. The intracerebroventricular (ICV) injection of PGRN or intraperitoneal injection of TNFα synthesis blocker thalidomide (25 mg/kg), prevented the memory impairment and anxiety behaviors induced by S-DEP. PGRN treatment also restored dendritic spine density in the hippocampus CA1 region and neurogenesis in hippocampus dentate gyrus (DG). These results indicate that an imbalance between TNFα and PGRN contributes to memory impairment and thigmotaxis/anxiety caused by sleep deprivation.

  10. Primary oral tuberculosis in a patient with lepromatous leprosy: Diagnostic dilemma.

    Science.gov (United States)

    Ganesan, Vithiya; Mandal, Jharna

    2016-03-01

    Pulmonary tuberculosis (TB) is the most common form of TB. Primary infection can also affect the pharynx, cervical lymph node, intestine, or oral mucosa. Historically, the observed incidence of concomitant infection with leprosy and TB is high. However, reports of concomitant infection in modern literature remain scarce. Most cases reported in the literature had borderline/lepromatous leprosy and pulmonary tuberculosis. Extrapulmonary tuberculosis is reported in only 3.2% of leprosy cases. To the best of our knowledge, this is the first case report of primary oral tuberculosis of the tongue in a patient with lepromatous leprosy with Type 2 lepra reaction. The patient was referred to Directly Observed Treatment, Short-Course clinic and started on Category I treatment. She received oral prednisolone for lepra reaction, which was subsequently tapered and stopped, however, she continued to receive other antileprotic drugs (thalidomide and clofazimine). The patient's general condition improved and she is on regular follow up. Copyright © 2015 Asian African Society for Mycobacteriology. Published by Elsevier Ltd. All rights reserved.

  11. New drugs in multiple myeloma - role of carfilzomib and pomalidomide.

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    Jurczyszyn, Artur; Legieć, Wojciech; Helbig, Grzegorz; Hus, Marek; Kyrcz-Krzemień, Sławomira; Skotnicki, Aleksander B

    2014-01-01

    Carfilzomib (CFZ), an epoxyketone with specific chymotrypsin-like activity, is a second-generation proteasome inhibitor with significant activity in patients with relapsed and refractory multiple myeloma. On July 20, 2012, the US Food and Drug Administration approved CFZ to treat patients with multiple myeloma who have received at least two prior therapies including bortezomib (BORT) and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Cytogenetic abnormalities did not appear to have a significant impact on the CFZ activity. Carfilzomib was well tolerated and demonstrated promising efficacy in patients with renal insufficiency. Pomalidomide (POM) (CC-4047) is a novel immunomodulatory derivative (IMID) with a stronger in vitro anti-myeloma effect compared with "older" IMIDs - thalidomide and lenalidomide (LEN). On February 8, 2013, the US Food and Drug Administration approved POM (Pomalyst, Celgene) for the treatment of MM patients who have received at least two prior therapies including LEN and BORT and have demonstrated progression on or within 60 days of completion of the last therapy. Pomalidomide is a novel IMID with significant anti-myeloma activity and manageable toxicity. This compound has shown high efficacy in MM patients who were resistant to prior use of LEN/BORT as well as in patients with a high-risk cytogenetic profile. Carfilzomib and POM have very high efficacy and will be used also in first line therapy in future.

  12. New drugs in multiple myeloma – role of carfilzomib and pomalidomide

    Science.gov (United States)

    Legieć, Wojciech; Helbig, Grzegorz; Hus, Marek; Kyrcz-Krzemień, Sławomira; Skotnicki, Aleksander B.

    2014-01-01

    Carfilzomib (CFZ), an epoxyketone with specific chymotrypsin-like activity, is a second-generation proteasome inhibitor with significant activity in patients with relapsed and refractory multiple myeloma. On July 20, 2012, the US Food and Drug Administration approved CFZ to treat patients with multiple myeloma who have received at least two prior therapies including bortezomib (BORT) and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Cytogenetic abnormalities did not appear to have a significant impact on the CFZ activity. Carfilzomib was well tolerated and demonstrated promising efficacy in patients with renal insufficiency. Pomalidomide (POM) (CC-4047) is a novel immunomodulatory derivative (IMID) with a stronger in vitro anti-myeloma effect compared with “older” IMIDs – thalidomide and lenalidomide (LEN). On February 8, 2013, the US Food and Drug Administration approved POM (Pomalyst, Celgene) for the treatment of MM patients who have received at least two prior therapies including LEN and BORT and have demonstrated progression on or within 60 days of completion of the last therapy. Pomalidomide is a novel IMID with significant anti-myeloma activity and manageable toxicity. This compound has shown high efficacy in MM patients who were resistant to prior use of LEN/BORT as well as in patients with a high-risk cytogenetic profile. Carfilzomib and POM have very high efficacy and will be used also in first line therapy in future. PMID:24876816

  13. Study on the Association Between miRNA-202 Expression and Drug Sensitivity in Multiple Myeloma Cells.

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    Shen, Xianjuan; Guo, Yuehua; Qi, Jing; Shi, Wei; Wu, Xinhua; Ni, Hongbing; Ju, Shaoqing

    2016-07-01

    An increasing amount of experimental evidence has shown that miRNAs play a causal role in hematologic tumorigenesis. In this study, we characterized the role of miR-202 in multiple myeloma (MM) drug sensitivity. The potential binding site of miR-202 and B cell-activating factor (BAFF) was confirmed by luciferase reporter assay. MM cells were transfected with miR-202 mimics and inhibitor. Cells growth was measured by WST-1 cell proliferation assay and Annexin V-FLUOS apoptosis assay. BAFF and miR-202 mRNA levels were measured by real-time PCR. Meanwhile, BAFF, Bcl-2 family survival proteins and MAPK pathway proteins were measured by Western blot. It was found that miR-202 was functioned as a modulator of BAFF expression. miR-202 over-expression sensitized MM cells to bortezomib (Bort) but less to Thalidomide (Thal) and dexamethasone (Dex). miR-202 mimics in combination with Bort inhibited MM cell survival more effectively as compared with Bort treatment alone. Our study also provided experimental evidence that JNK/SAPK signaling pathway was involved in the regulatory effect of miR-202 on drug resistance of MM cells. These results suggest that the regulatory mechanism of miR-202 expression may be a promising target for fine-tuning anti-myeloma therapy.

  14. From rumors to genetic isolates

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    Eduardo E. Castilla

    2014-01-01

    Full Text Available Here we propose a registration process for population genetic isolates, usually geographic clusters of genetic disorders, based on the systematic search of rumors, defined as any type of account regardless of its reliability. Systematically ascertained rumors are recorded, and validated through a progressive process of pre-established steps. This paper outlines the conceptual basis for this approach and presents the preliminary results from a rumor-based nationwide registry of genetically isolated populations, named CENISO (Censo Nacional de Isolados, operating in Brazil since 2009. During the first four years of its existence (2009-2013, a total of 191 Rumors were registered and validated, resulting in a prevalence rate of one per million inhabitants of Brazil. When the five statutory geographic regions of Brazil were considered, more Rumors were registered for the Northeast (2.11; 1.74-2.54 per 10(6 than for the remaining four regions, North, Center-West, Southeast, and South, which did not differ among themselves. About half (86/191 of the recorded rumors were proven to be geographic clusters; of these disorders, 58 were autosomal recessive, 17 autosomal dominant, 5 X-linked, 3 multifactorial, and one environmental (thalidomide embryopathy.

  15. Treatment of multiple myeloma in Celje general hospital in the five-year period from 2007–2011

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    Mateja Grat

    2012-12-01

    Full Text Available We found 55 newly diagnosed patients with multiple myeloma in the five-year observation period. There were 8 to 13 new patients per year; patient’s average age was 67.8.years. 20/55 (36.4 % of patients were under 65 years old and 19/55 (34.6 % were 75 years or older. We assessed the international prognostic score (ISS in most patients (50/55; 90.9 % and cytogenetic analysis of bone marrow before initial treatment. These findings influenced our choice of regimens for initial therapy based on bortezomib and thalidomide. Treatment regimens based on melphalan and farmorubicin were used less frequently. In 19/55 (34.6 % of patients the treatment regimen included avtologous stem-cell transplantation (ASCT. Patients treated with ASCT have longer time to progression (median 12.4 months versus 8.7 months and better survival (44.3 months versus 33.3 months. New active agents have changed responses to treatment (partial response in 46/55 and very good partial response in 19/55 patients. In five-year period 18 patients died, most of them due to progression of the disease. Despite the era of new active agents, multiple myeloma is still incurable disease.

  16. Imbalance between TNFα and progranulin contributes to memory impairment and anxiety in sleep-deprived mice

    Science.gov (United States)

    Zhang, Kun; Li, Yu-jiao; Feng, Dan; Zhang, Peng; Wang, Ya-tao; Li, Xiang; Liu, Shui-bing; Wu, Yu-mei; Zhao, Ming-gao

    2017-01-01

    Sleep disorder is becoming a widespread problem in current society, and is associated with impaired cognition and emotional disorders. Progranulin (PGRN), also known as granulin epithelin precursor, promotes neurite outgrowth and cell survival, and is encoded by the GRN gene. It is a tumor necrosis factor α receptor (TNFR) ligand which is implicated in many central nervous system diseases. However, the role PGRN in sleep disorder remains unclear. In the present study, we found that sleep deprivation (S-DEP) impaired the memory and produced thigmotaxis/anxiety-like behaviors in mice. S-DEP increased the levels of TNFα but decreased PGRN levels in the hippocampus. The intracerebroventricular (ICV) injection of PGRN or intraperitoneal injection of TNFα synthesis blocker thalidomide (25 mg/kg), prevented the memory impairment and anxiety behaviors induced by S-DEP. PGRN treatment also restored dendritic spine density in the hippocampus CA1 region and neurogenesis in hippocampus dentate gyrus (DG). These results indicate that an imbalance between TNFα and PGRN contributes to memory impairment and thigmotaxis/anxiety caused by sleep deprivation. PMID:28300056

  17. A novel phenylphthalimide derivative, pegylated TC11, improves pharmacokinetic properties and induces apoptosis of high-risk myeloma cells via G2/M cell-cycle arrest.

    Science.gov (United States)

    Aida, Shuji; Hozumi, Masashi; Ichikawa, Daiju; Iida, Kazuki; Yonemura, Yuko; Tabata, Noriko; Yamada, Taketo; Matsushita, Maiko; Sugai, Takeshi; Yanagawa, Hiroshi; Hattori, Yutaka

    2017-11-04

    Despite the development of new drugs for multiple myeloma (MM), the prognosis of MM patients with high-risk cytogenetic abnormalities such as t (4; 14) and del17p remains poor. We reported that a novel phenylphthalimide derivative, TC11, induced apoptosis of MM cells in vitro and in vivo, and TC11 directly bound to α-tubulin and nucleophosmin-1 (NPM1). However, TC11 showed low water solubility and poor pharmacokinetic properties. Here we synthesized a water-soluble TC11-derivative, PEG(E)-TC11, in which HOEtO-TC11 is pegylated with PEG through an ester bond, and we examined its anti-myeloma activity. We observed that PEG(E)-TC11 and its hydrolyzed product, HOEtO-TC11, induced G2/M arrest and the apoptosis of MM cells. Intraperitoneal administration of PEG(E)-TC11 to xenografted mice revealed improved pharmacokinetic properties and significantly delayed tumor growth. TC11 and its derivatives did not bind to cereblon (CRBN), which is a responsible molecule for thalidomide-induced teratogenicity. These results suggest that PEG(E)-TC11 is a good candidate drug for treating high-risk MM. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. April 2015 critical care case of the month: half-sided light house

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    Loftsgard T

    2015-04-01

    Full Text Available No abstract available. Article truncated after 150 words. History of Present Illness: A 55 year old woman was transferred to the ICU from the general medicine ward for tachycardia and acute hypoxic respiratory distress. She has multiple myeloma and had received cycle one of bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide (VDT-PACE and radiotherapy to T7 for a pathologic compression. She was admitted for pain control from mucositis.Past Medical History: In addition to the multiple myeloma she has a past medical history of asthma, ovarian cysts, diverticulitis, eczema, pneumonia, laparoscopic cholecystectomy, total abdominal hysterectomy with bilateral salpingo-oophorectomy, appendectomy, ectopic pregnancy in the past, and left Bell's palsy. Current Medications: Acyclovir 400 mg BID, Albuterol 90 HFA prn, Allopurinol 300 mg daily, Fluconazole 200 mg BID, Gabapentin 300 mg BID, Hydromorphone , Levofloxacin 500 daily, Morphine, Omeprazole, Bactrim 400-80 mg daily for PCP prophylaxis, Thalomid 200 mg capsule daily, Ativan 0.5 mg just prior to transfer. Physical Examination ...

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

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    Isabelle Jalenques

    2017-05-01

    Full Text Available 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.

  20. [Pomalidomide for multiple myeloma].

    Science.gov (United States)

    Fouquet, G; Macro, M; Decaux, O; Fohrer, C; Guidez, S; Demarquette, H; Le Grand, C; Prodhomme, C; Renaud, L; Bories, C; Herbaux, C; Karlin, L; Roussel, M; Benboubker, L; Hulin, C; Arnulf, B; Leleu, X

    2015-09-01

    Once characterized by a very poor outcome, multiple myeloma (MM) now has a significantly prolonged survival, with major improvements allowed by the use of "novel agents": proteasome inhibitors (first-in-class bortezomib) and immunomodulatory compounds (IMiDs; first-in-class thalidomide and lenalidomide). However, the vast majority - if not all - of patients with MM ultimately end up being refractory to all existing drugs, including these efficient novel agents. There is a clear unmet medical need in this situation, which warrants the development of the next generation of proteasome inhibitors and IMiDs, as well as new drug classes. This review focuses on pomalidomide, the next generation IMiD, recently approved by the US FDA and the EMA for patients with relapsed or refractory MM who have received at least two prior therapies, including lenalidomide and bortezomib, and have demonstrated disease progression on their last therapy. Copyright © 2015 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  1. Leukaemic Transformation of Multiple Myeloma in Post Chemotherapy Remission Phase.

    Science.gov (United States)

    Agarwal, Palak; Nayak, Prachi; Singh, Premala Anthony; Mishra, Bal Krishna

    2016-04-01

    Plasma cell leukaemia is diagnosed when plasma cells are >20% in the peripheral blood. Plasma cell leukaemia may be present at the time of diagnosis (primary plasma cell leukaemia) or may evolve from multiple myeloma (secondary plasma cell leukaemia). We report case of a 62-year-old male who was diagnosed with multiple myeloma. He was treated with combination of prednisolone, melphalan and thalidomide. After 6 years he had Worsening of symptoms and also developed a scalp swelling. The swelling was diagnosed as plasmacytoma on fine needle aspiration cytology and confirmed on histopathology. Complete haemogram showed-Haemoglobin - 8g/dl, Total Leucocyte Count - 4300/μl, Differential leucocyte count - Neutrophil-40%, Lymphocyte-28%, Eosinophil-01%, Monocyte-10%, Atypical cells-21%, Platelet count- 1.5 lacs/μl. Peripheral blood showed rouleaux formation and plasma cells. Serum protein electrophoresis revealed an M spike (3.26 g/dl). So, patient was diagnosed as secondary plasma cell leukaemia. Weekly bortezomib and dexamethasone combination chemotherapy was given to the patient. Patient is on monthly follow up. Here we present a detailed case history of this patient.

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

    Science.gov (United States)

    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.

  3. Light chain (AL amyloidosis: update on diagnosis and management

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    Rosenzweig Michael

    2011-11-01

    Full Text Available Abstract Light chain (AL amyloidosis is a plasma cell dyscrasia characterized by the pathologic production of fibrillar proteins comprised of monoclonal light chains which deposit in tissues and cause organ dysfunction. The diagnosis can be challenging, requiring a biopsy and often specialized testing to confirm the subtype of systemic disease. The goal of treatment is eradication of the monoclonal plasma cell population and suppression of the pathologic light chains which can result in organ improvement and extend patient survival. Standard treatment approaches include high dose melphalan (HDM followed by autologous hematopoietic stem cell transplantation (SCT or oral melphalan with dexamethasone (MDex. 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. A risk adapted approach to SCT followed by novel agents as consolidation reduces treatment related mortality with promising outcomes. Immunotherapeutic approaches targeting pathologic plasma cells and amyloid precursor proteins or fibrils are being developed. Referral of patients to specialized centers focusing on AL amyloidosis and conducting clinical trials is essential to improving patient outcomes.

  4. Tratamento do Mieloma Múltiplo recidivado Relapsed Multiple Myeloma treatment

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    Vania T. M. Hungria

    2007-03-01

    therapy, prior therapy and specially prior autologous stem cell transplantation, performance status, hematopoietic reserve. If relapse occurs more than 6 months after therapy ended, the initial chemotherapy regimen should be reinstituted. Autologous stem cell transplantation can be proposed as consolidation therapy in chemosensitive relapses or as salvage therapy if stem cells have been collected earlier. Thalidomide has been tested in relapsed multiple myeloma and is now considered as standard treatment for patients relapsing after conventional chemotherapy or after autologous stem cell transplantation. Thalidomide alone can induce objective responses in at least one-third of heavily pretreated patients and, combined with chemotherapy, objective responses can be achieved by two-thirds of the patients. Bortezomib is indicated, alone or in combination with other agents, for relapsed patients and can produce an overall response rate of 43% to 76%. The most appropriate management must be individualized depending on the age, bone marrow function, prior therapy and the timing of the relapse.

  5. Subsidies for Oral Chemotherapy and Use of Immunomodulatory Drugs Among Medicare Beneficiaries With Myeloma.

    Science.gov (United States)

    Olszewski, Adam J; Dusetzina, Stacie B; Eaton, Charles B; Davidoff, Amy J; Trivedi, Amal N

    2017-10-10

    Purpose The low-income subsidy (LIS) substantially lowers out-of-pocket costs for qualifying Medicare Part D beneficiaries who receive orally administered chemotherapy. We examined the association of LIS with the use of novel oral immunomodulatory drugs (IMiDs; lenalidomide and thalidomide) among beneficiaries with myeloma, who can receive either orally administered or parenteral (bortezomib-based) therapy. Methods Using SEER-Medicare data, we identified Part D beneficiaries diagnosed with myeloma in 2007 to 2011. In multivariable models adjusted for sociodemographic and clinical characteristics, we analyzed associations between the LIS and use of IMiD-based therapy, delays between IMiD refills, and select health outcomes during the first year of therapy. Results Among 3,038 beneficiaries, 41% received first-line IMiDs. Median out-of-pocket cost for the first IMiD prescription was $3,178 for LIS nonrecipients and $3 for LIS recipients, whereas the respective median costs for the first year of therapy were $5,623 and $6, respectively. Receipt of the LIS was associated with a 32% higher (95% CI, 16% to 47%) probability of receiving IMiDs among beneficiaries age 75 to 84 years and a significantly lower risk of delays between refills in all age groups (adjusted relative risk, 0.54; 95% CI, 0.32 to 0.92). Duration of therapy did not significantly differ between LIS recipients and nonrecipients (median, 7.6 months). Patients treated with IMiDs had significantly fewer emergency department visits and hospitalizations compared with patients receiving bortezomib (without IMiDs), but 1-year overall survival and cumulative Medicare costs were similar. Conclusion Medicare beneficiaries with myeloma who do not receive LISs face a substantial financial barrier to accessing orally administered anticancer therapy, warranting urgent attention from policymakers. Limiting out-of-pocket costs for expensive anticancer drugs like the IMiDs may improve access to oral therapy for patients