Sample records for chlorambucil

  1. Chlorambucil-Induced Acute Interstitial Pneumonitis

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    Hammad Shafqat


    Full Text Available Chlorambucil is an alkylating agent commonly used in treatment of chronic lymphocytic leukemia (CLL. We report a case of interstitial pneumonitis developing in an 83-year-old man 1.5 months after completing a six-month course of chlorambucil for CLL. The interstitial pneumonitis responded to therapy with prednisone. We performed a systematic review of literature and identified 13 other case reports of chlorambucil-induced pulmonary toxicity, particularly interstitial pneumonitis. No unifying risk factor could be discerned and the mechanism of injury remains unknown. In contrast, major randomized trials of chlorambucil therapy in CLL have not reported interstitial pneumonitis as an adverse effect, which may be due to the rarity of the phenomenon or due to underreporting of events occurring after completion of treatment. Clinicians should consider drug-induced interstitial pneumonitis in the differential diagnosis of a suggestive syndrome developing even after discontinuation of chlorambucil.

  2. Studies on the pharmacokinetics of chlorambucil and prednimustine in man.


    Newell, D. R.; Calvert, A. H.; Harrap, K. R.; McElwain, T. J.


    1 Chlorambucil (10 mg) and prednimustine (20 mg), the prednisolone ester of chlorambucil, were administered orally on separate occasions to six patients. 2 Chlorambucil was rapidly absorbed such that the parent compound was observed in the plasma 30 min after administration. 3 A preliminary comparison of chlorambucil levels following oral and intravenous administration, and after repeat oral dosage indicated that chlorambucil was well (greater than 70%) and consistently absorbed. 4 Following ...

  3. Chlorambucil (United States)

    ... is also used to treat non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (types of cancer that begin ... in, tightly closed, and out of reach of children. Store it in the refrigerator. Throw away any ...

  4. Obinutuzumab Plus Chlorambucil for Patients with Chronic Lymphocytic Leukemia and Comorbidities (United States)

    A summary of results from an international phase III trial that compared the combination of obinutuzumab (Gazyva™) and chlorambucil (Leukeran®) versus chlorambucil alone, as well as obinutuzumab plus chlorambucil versus rituximab (Rituxan®) plus chloramb

  5. Synthesis and Biophysical Characterization of Chlorambucil Anticancer Ether Lipid Prodrugs

    DEFF Research Database (Denmark)

    Pedersen, Palle Jacob; Christensen, Mikkel Stochkendahl; Ruysschaert, Tristan;


    The synthesis and biophysical characterization of four prodrug ether phospholipid conjugates are described. The lipids are prepared from the anticancer drug chlorambucil and have C16 and C18 ether chains with phosphatidylcholine or phosphatidylglycerol headgroups. All four prodrugs have the ability...

  6. Steroid-dependent nephrotic syndrome in lupus nephritis. Response to chlorambucil. (United States)

    Abuelo, J G; Esparza, A R; Garella, S


    Nephrotic syndrome associated with mesangial lupus nephritis developed in a young woman. The heavy proteinuria exhibited a striking steroid-dependent course during a three-year period of time, with ten relapses occurring whenever attempts were made to withdraw prednisone therapy. A prolonged remission was induced by the administration of chlorambucil.

  7. Preparation and bioevaluation of a 99mTc-labeled chlorambucil analog as a tumor targeting agent

    International Nuclear Information System (INIS)

    Chlorambucil belongs to a group of nitrogen mustards which are used for the treatment of variety of cancers. Hence, a chlorambucil derivative has been radiolabeled with [99mTc(CO)3(H2O)3]+ core and its efficacy as a tumor targeting agent has been evaluated. Radiochemical yield of the complex was >98% as observed by HPLC. The in vitro studies in MCF-7 breast cancer cells showed about 30% inhibition of the radiolabeled complex in presence of the cold chlorambucil derivative. Biodistribution studies in Swiss mice bearing fibrosarcoma tumor showed an uptake of 3.2±0.3% ID/g at 3 h.p.i.

  8. Nitrogen mustard (Chlorambucil) has a negative influence on early vascular development

    International Nuclear Information System (INIS)

    The sulphur and nitrogen mustards are strong alkylating agents, which induces inflammations of the skin including blistering right up to ulcerations. Depending on the severity, the wounds may need weeks to heal. In the past it was shown that sulphur mustard has a destructive effect on endothelial precursor cells, which have been shown to play a pivotal role in the wound healing reaction by inducing neovascularisation. However, for these alkylating agents as well as for sulphur mustard nothing is known about their effects on endothelial precursors. Therefore, we investigated and compared the influence of Chlorambucil on proliferation, apoptosis and differentiation of endothelial cells in intact mouse embryoid bodies (EB). EBs were treated at different developmental stages and with different periods of Chlorambucil treatment. It was found that in each developmental stage and under each treatment period's Chlorambucil has an extremely negative effect on the vascularisation with a vessel reduction of around 99%. Of particular importance was the negative effect of treatment around day 3 of the development. On this day we found 377 vessels under control conditions but only 1.6 vessels under 24 h treatment of Chlorambucil. At this point in time many endothelial precursors can be found in the EB. Moreover, a negative effect on all stem cells was evident at this point in time, shown by an extreme reduction in EB size with 17.9 mm2 for the control and only 1.55 mm2 under Chlorambucil treatment. This negative effect on the vascularisation, on endothelial precursors but also on stem cells in general is of possible importance for impaired wound healing.

  9. Vibrational spectra and normal coordinate analysis on structure of chlorambucil and thioguanine

    Indian Academy of Sciences (India)

    S Gunasekaran; S Kumaresan; R Arun Balaji; G Anand; S Seshadri


    A normal coordinate analysis on chlorambucil and thioguanine has been carried out with a set of symmetry coordinates following Wilson's – matrix method. The potential constants evaluated for these molecules are found to be in good agreement with literature values thereby confirming the vibrational assignments. To check whether the chosen set of vibrational frequencies contribute maximum to the potential energy associated with the normal coordinates of the molecule, the potential energy distribution has been evaluated.

  10. OPEC chemotherapy (vincristine, prednisolone, etoposide and chlorambucil) for refractory and recurrent Hodgkin's disease. (United States)

    Barnett, M J; Man, A M; Richards, M A; Waxman, J H; Wrigley, P F; Lister, T A


    Fifteen adults with refractory or recurrent Hodgkin's disease were treated with a combination of: vincristine, prednisolone, etoposide and chlorambucil (OPEC). All had previously received mustine, vinblastine, procarbazine and prednisolone (MVPP) and seven had subsequently been treated with alternative regimens. Responses were achieved in four, but complete remission in only one. Toxicity was considerable and five died of treatment related complications. Only two are alive (one in complete remission) more than three years after therapy. The toxicity of the OPEC regimen outweighed its benefit in this group of poor prognosis patients. PMID:3596472

  11. Cutaneous necrobiotic xanthogranuloma (NXG)--successfully treated with low dose chlorambucil.


    Machado, S; Alves, R.; M. Lima; I. Leal; Massa, A


    Eur J Dermatol. 2001 Sep-Oct;11(5):458-62. Cutaneous necrobiotic xanthogranuloma (NXG)--successfully treated with low dose chlorambucil. Machado S, Alves R, Lima M, Leal I, Massa A. SourceService of Dermatology, Hospital Geral Santo António, Rua D. Manuel II, Edifício ex: Cicap, 4099-001 Porto, Portugal. Abstract We report a case of necrobiotic xanthogranuloma in a 51 year-old white male patient presenting with a 6-year history of multiple indurated viola...

  12. Activity and safety of combined rituximab with chlorambucil in patients with mantle cell lymphoma. (United States)

    Bauwens, Deborah; Maerevoet, Marie; Michaux, Lucienne; Théate, Ivan; Hagemeijer, Anne; Stul, Michel; Danse, Etienne; Costantini, Sabrina; Vannuffel, Pascal; Straetmans, Nicole; Vekemans, Marie-Christiane; Deneys, Véronique; Ferrant, Augustin; Van Den Neste, Eric


    We evaluated the combination of rituximab with chlorambucil in patients with mantle cell lymphoma (MCL) not eligible for aggressive therapy. Fourteen patients (male/female: 9/5) were included (two newly diagnosed, 12 relapsed/refractory). The toxicities were neutropenia, thrombopenia and infection. Nine (64%) patients responded; five (36%) achieved complete remission and four (29%) achieved partial remission. The median progression-free survival for responders was 26 months (95% CI, 4-48). Marrow polymerase chain reaction negativity was attained in seven responders. These results suggest that this schedule may have notable antitumour activity in patients with MCL, including patients in relapse after autologous stem cell transplantation. PMID:16225653

  13. Targeted gene correction using psoralen, chlorambucil and camptothecin conjugates of triplex forming peptide nucleic acid (PNA)

    DEFF Research Database (Denmark)

    Birkedal, Henrik; Nielsen, Peter E


    Gene correction activation effects of a small series of triplex forming peptide nucleic acid (PNA) covalently conjugated to the DNA interacting ligands psoralen, chlorambucil and camptothecin targeted proximal to a stop codon mutation in an EGFP reporter gene were studied. A 15-mer homopyrimidine...... interstrand crosslinked adducts with dsDNA dramatically decreased the frequency of targeted repair/correction. The PNA conjugates were also studied in mammalian cell lines upon transfection of PNA bound EGFP reporter vector and scoring repair of the EGFP gene by FACS analysis of functional EGFP expression...... suggest that simple triplex forming PNAs have little effect on proximal gene correctional events whereas PNA conjugates capable of forming DNA adducts and interstrand crosslinks are strong inhibitors. Most interestingly the PNA conjugated to the topoisomerase inhibitor, camptothecin enhanced repair...

  14. Reprogramming the mechanism of action of chlorambucil by coupling to a G-quadruplex ligand. (United States)

    Di Antonio, Marco; McLuckie, Keith I E; Balasubramanian, Shankar


    The nitrogen mustard Chlorambucil (Chl) generates covalent adducts with double-helical DNA and inhibits cell proliferation. Among these adducts, interstrand cross-links (ICLs) are the most toxic, as they stall replication by generating DNA double strand breaks (DSBs). Conversely, intrastrand cross-links generated by Chl are efficiently repaired by a dedicated Nucleotide Excision Repair (NER) enzyme. We synthesized a novel cross-linking agent that combines Chl with the G-quadruplex (G4) ligand PDS (PDS-Chl). We demonstrated that PDS-Chl alkylates G4 structures at low μM concentrations, without reactivity toward double- or single-stranded DNA. Since intramolecular G4s arise from a single DNA strand, we reasoned that preferential alkylation of such structures might prevent the generation of ICLs, while favoring intrastrand cross-links. We observed that PDS-Chl selectively impairs growth in cells genetically deficient in NER, but did not show any sensitivity to the repair gene BRCA2, involved in double-stranded break repair. Our findings suggest that G4 targeting of this clinically important alkylating agent alters the overall mechanism of action. These insights may inspire new opportunities for intervention in diseases specifically characterized by genetic impairment of NER, such as skin and testicular cancers. PMID:24697838

  15. Enthalpy-driven nuclease-like activity and mechanism of peptide-chlorambucil conjugates. (United States)

    Yang, Robin C K; Huang, Jonathan T B; Chen, Yu-Ling; Hung, Chia-Chun; Liao, Mokai; Yao, Wen-Chen; Chen, Chiu-Heng; Liou, Chien-Chung; Waring, Michael J; Sheh, Leung


    We report the results of attaching the anticancer drug chlorambucil (CLB) to two high-affinity DNA binding peptides: Met-Hyp-Arg-Lys-(Py)4-Lys-Arg-NH2 (HyM-10) and Gln-Hyp-Arg-Lys-(Py)4-Lys-Arg-NH2 (HyQ-10). These CLB-peptide conjugates cleave DNA very effectively and sequence-selectively without the use of chemicals, heat, or UV irradiation. Polyacrylamide gel electrophoresis identifies the sites where CLB-HyM-10 and CLB-HyQ-10 attack a complementary pair of 5'-(32)P-labeled duplexes derived from pBR322 in the absence of piperidine or other chemical additives. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) has confirmed the preferential cleavage sites as well as a novel stepwise cleavage mechanism of sequence-selective DNA cleavage. Resembling restriction endonucleases, the CLB-peptide conjugates appear to be capable of producing double strand DNA breaks. Circular dichroism studies show that CLB-HyM-10 and CLB-HyQ-10 induce significant local conformational changes in DNA via the minor groove, possibly with dimeric binding stoichiometry. The energetic basis of DNA binding by these conjugates has been investigated by isothermal titration calorimetry, revealing that the binding of both the peptides and their CLB conjugates is overwhelmingly enthalpy-driven. The maintenance of a conserved negative binding free energy in DNA-conjugate interactions is a crucial feature of the universal enthalpy-entropy compensation phenomenon. The strongly enthalpy-driven binding of CLB-peptide conjugates to preferred loci in DNA furnishes the required proximity effect to generate the observed nuclease-like sequence-selective cleavage.

  16. Complex karyotypes and KRAS and POT1 mutations impact outcome in CLL after chlorambucil-based chemotherapy or chemoimmunotherapy. (United States)

    Herling, Carmen Diana; Klaumünzer, Marion; Rocha, Cristiano Krings; Altmüller, Janine; Thiele, Holger; Bahlo, Jasmin; Kluth, Sandra; Crispatzu, Giuliano; Herling, Marco; Schiller, Joanna; Engelke, Anja; Tausch, Eugen; Döhner, Hartmut; Fischer, Kirsten; Goede, Valentin; Nürnberg, Peter; Reinhardt, Hans Christian; Stilgenbauer, Stephan; Hallek, Michael; Kreuzer, Karl-Anton


    Genetic instability is a feature of chronic lymphocytic leukemia (CLL) with adverse prognosis. We hypothesized that chromosomal translocations or complex karyotypes and distinct somatic mutations may impact outcome after first-line chemoimmunotherapy of CLL patients. We performed metaphase karyotyping and next-generation sequencing (NGS) of 85 genes in pretreatment blood samples obtained from 161 patients registered for CLL11, a 3-arm phase 3 trial comparing frontline chlorambucil (Clb) vs Clb plus rituximab (Clb-R) or Clb plus obinutuzumab in CLL patients with significant comorbidity. Chromosomal aberrations as assessed by karyotyping were observed in 68.8% of 154 patients, 31.2% carried translocations, and 19.5% showed complex karyotypes. NGS revealed 198 missense/nonsense mutations and 76 small indels in 76.4% of patients. The most frequently mutated genes were NOTCH1, SF3B1, ATM, TP53, BIRC3, POT1, XPO1, and KRAS Sole chemotherapy, treatment with Clb-R, or genetic lesions in TP53 (9.9% of patients) and KRAS (6.2% of patients) were significantly associated with nonresponse to study therapy. In multivariate models, complex karyotypes and POT1 mutations (8.1% of patients) represented significant prognostic factors for an unfavorable survival, independently of IGHV mutation status, Binet stage, and serum β-2-microglobuline. Patients with the copresence of complex karyotypes and deletions/mutations involving TP53 demonstrated a particularly short survival. In summary, this is the first prospective, controlled study in CLL patients that shows a role of complex karyotype aberrations as an independent prognostic factor for survival after front-line therapy. Moreover, the study identifies mutations in KRAS and POT1 as novel determinants of outcome after chemoimmunotherapy using chlorambucil and anti-CD20 treatment. PMID:27226433

  17. The interaction of the chemotherapeutic drug chlorambucil with human glutathione transferase A1-1: kinetic and structural analysis. (United States)

    Karpusas, Michael; Axarli, Irine; Chiniadis, Lykourgos; Papakyriakou, Athanasios; Bethanis, Kostas; Scopelitou, Katholiki; Clonis, Yannis D; Labrou, Nikolaos E


    Glutathione transferases (GSTs) are enzymes that contribute to cellular detoxification by catalysing the nucleophilic attack of glutathione (GSH) on the electrophilic centre of a number of xenobiotic compounds, including several chemotherapeutic drugs. In the present work we investigated the interaction of the chemotherapeutic drug chlorambucil (CBL) with human GSTA1-1 (hGSTA1-1) using kinetic analysis, protein crystallography and molecular dynamics. In the presence of GSH, CBL behaves as an efficient substrate for hGSTA1-1. The rate-limiting step of the catalytic reaction between CBL and GSH is viscosity-dependent and kinetic data suggest that product release is rate-limiting. The crystal structure of the hGSTA1-1/CBL-GSH complex was solved at 2.1 Å resolution by molecular replacement. CBL is bound at the H-site attached to the thiol group of GSH, is partially ordered and exposed to the solvent, making specific interactions with the enzyme. Molecular dynamics simulations based on the crystal structure indicated high mobility of the CBL moiety and stabilization of the C-terminal helix due to the presence of the adduct. In the absence of GSH, CBL is shown to be an alkylating irreversible inhibitor for hGSTA1-1. Inactivation of the enzyme by CBL followed a biphasic pseudo-first-order saturation kinetics with approximately 1 mol of CBL per mol of dimeric enzyme being incorporated. Structural analysis suggested that the modifying residue is Cys112 which is located at the entrance of the H-site. The results are indicative of a structural communication between the subunits on the basis of mutually exclusive modification of Cys112, indicating that the two enzyme active sites are presumably coordinated.

  18. Apoptosis induced by Magnolia Grandiflora extract in chlorambucil-resistant B-chronic lymphocytic leukemia cells

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    Marin Gustavo


    Full Text Available Background: B-cell chronic lymphocitic leukemia (B-CLL still remains as an uncurable disease. Even the newest antineoplastic agents have demonstrated limitations in their efficacy. For this reason, further research of new compounds must be done. New pharmacological properties can be obtained from a great diversity botanical species. Among these products, Magnolia Grandiflora receives our attention since it mainly contains Honokiol which had demonstrated effect against B-CLL cells activating different cell death pathways. Aim: To test the ability of Magnolia Grandiflora extracts to induce apoptosis of B-CLL cells in vitro. Materials and Methods: Herb′s extraction: Twenty grams of powdered material were submitted to three consecutives decoctions with 500 ml of distilled water (96 °C, filtered and followed by ultrafiltration with cellulose membrane, lyophilized and reconstituted in AIM-V medium at a final concentration of 10 mg/ml solution. B-CLL chlorambucil- resistant cells were separated and cultivated in the presence of Magnolia′s extract. Samples of cells were taken from the cultures at 24, 48 and 72 h for apoptosis analysis by flow cytometry measuring positive annexin V (0.1 μg/ml cells. Statistics: Apoptosis values were represented by the mean plus or minus SD (± SD for five independent experiments. Statistical significance was determined by Student′s t -test. A P value of 0.05 or less was considered as significant. Results and Conclusion: This article discusses the apoptosis properties of Magnolia on B-CLL cells. The evidence suggests a potentially effective repertoire for B-CLL treatment. This herb extract might have promising therapy strategies in treating B-CLL or other hematological disease resistant to alkylating agents in clinical practice.

  19. Economic evaluation of obinutuzumab in combination with chlorambucil in first-line treatment of patients with chronic lymphocytic leukemia in Spain

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    Casado LF


    Full Text Available Luis Felipe Casado,1 Amparo Burgos,2 Eva González-Haba,3 Javier Loscertales,4 Tania Krivasi,5 Javier Orofino,6 Carlos Rubio-Terres,7 Darío Rubio-Rodríguez7 1Hematology Department, Hospital Virgen de la Salud, Toledo, Spain; 2Pharmacy Department, Hospital General Universitario de Alicante, Alicante, Spain; 3Pharmacy Department, Hospital Universitario Gregorio Marañón, Madrid, Spain; 4Hematology Deparment, Hospital Universitario De La Princesa, Madrid, Spain; 5Hoffmann-La Roche Ltd., Basel, Switzerland; 6Roche Farma SA, Madrid, Spain; 7Health Value, Madrid, Spain Objective: To evaluate the cost-effectiveness of obinutuzumab in combination with chlorambucil (GClb versus rituximab plus chlorambucil (RClb in the treatment of adults with previously untreated chronic lymphocytic leukemia (CLL and with comorbidities that make them unsuitable for full-dose fludarabine-based therapy, from the perspective of the Spanish National Health System.Methods: A Markov model was developed with three mutually exclusive health states: progression-free survival (with or without treatment, progression, and death. Survival time for the two treatments was modeled based on the results of CLL11 clinical trial and external sources. Each health state was associated with a utility value and direct medical costs. The utilities were obtained from a utility elicitation study conducted in the UK. Costs and general background mortality data were obtained from published Spanish sources. Deterministic and probabilistic analyses were conducted, with a time frame of 20 years. The health outcomes were measured as life years (LYs gained and quality-adjusted life years (QALYs gained. Efficiency was measured as the cost per LY or per QALY gained of the most effective regimen.Results: In the deterministic base case analysis, each patient treated with GClb resulted in 0.717 LYs gained and 0.673 QALYs gained versus RClb. The cost per LY and per QALY gained with GClb versus RClb was

  20. A p-Hydroxyphenacyl-Benzothiazole-Chlorambucil Conjugate as a Real-Time-Monitoring Drug-Delivery System Assisted by Excited-State Intramolecular Proton Transfer. (United States)

    Barman, Shrabani; Mukhopadhyay, Sourav K; Biswas, Sandipan; Nandi, Surajit; Gangopadhyay, Moumita; Dey, Satyahari; Anoop, Anakuthil; Pradeep Singh, N D


    Among the well-known phototriggers, the p-hydroxyphenacyl (pHP) group has consistently enabled the very fast, efficient, and high-conversion release of active molecules. Despite this unique behavior, the pHP group has been ignored as a delivery agent, particularly in the area of theranostics, because of two major limitations: Its excitation wavelength is below 400 nm, and it is nonfluorescent. We have overcome these limitations by incorporating a 2-(2'-hydroxyphenyl)benzothiazole (HBT) appendage capable of rapid excited-state intramolecular proton transfer (ESIPT). The ESIPT effect also provided two unique advantages: It assisted the deprotonation of the pHP group for faster release, and it was accompanied by a distinct fluorescence color change upon photorelease. In vitro studies showed that the p-hydroxyphenacyl-benzothiazole-chlorambucil conjugate presents excellent properties, such as real-time monitoring, photoregulated drug delivery, and biocompatibility. PMID:26919455

  1. Economic evaluation of obinutuzumab in combination with chlorambucil in first-line treatment of patients with chronic lymphocytic leukemia in Spain (United States)

    Casado, Luis Felipe; Burgos, Amparo; González-Haba, Eva; Loscertales, Javier; Krivasi, Tania; Orofino, Javier; Rubio-Terres, Carlos; Rubio-Rodríguez, Darío


    Objective To evaluate the cost-effectiveness of obinutuzumab in combination with chlorambucil (GClb) versus rituximab plus chlorambucil (RClb) in the treatment of adults with previously untreated chronic lymphocytic leukemia (CLL) and with comorbidities that make them unsuitable for full-dose fludarabine-based therapy, from the perspective of the Spanish National Health System. Methods A Markov model was developed with three mutually exclusive health states: progression-free survival (with or without treatment), progression, and death. Survival time for the two treatments was modeled based on the results of CLL11 clinical trial and external sources. Each health state was associated with a utility value and direct medical costs. The utilities were obtained from a utility elicitation study conducted in the UK. Costs and general background mortality data were obtained from published Spanish sources. Deterministic and probabilistic analyses were conducted, with a time frame of 20 years. The health outcomes were measured as life years (LYs) gained and quality-adjusted life years (QALYs) gained. Efficiency was measured as the cost per LY or per QALY gained of the most effective regimen. Results In the deterministic base case analysis, each patient treated with GClb resulted in 0.717 LYs gained and 0.673 QALYs gained versus RClb. The cost per LY and per QALY gained with GClb versus RClb was €23,314 and €24,838, respectively. The results proved stable in most of the univariate and probabilistic sensitivity analyses, with a probabilistic cost per QALY gained of €24,734 (95% confidence interval: €21,860–28,367). Conclusion Using GClb to treat patients with previously untreated CLL for whom full-dose fludarabine-based therapy is unsuitable allows significant gains in terms of LYs and QALYs versus treatment with RClb. Treatment with GClb versus RClb can be regarded as efficient when considered the willingness to pay thresholds commonly used in Spain. PMID:27703384

  2. Effects of intra-arterial chemotherapy with a new lipophilic anticancer agent, estradiol-chlorambucil (KM2210), dissolved in lipiodol on experimental liver tumor in rats

    International Nuclear Information System (INIS)

    Anticancer effects and biodistribution of a new lipophilic anticancer agent, estradiol-chlorambucil (KM2210), dissolved in lipiodol (LPD) were investigated as an intra-arterial chemotherapy (IAC) on Walker 256 carcinosarcoma grown in the liver of 136 Wistar rats. All rats treated with KM2210 (10 mg)-LPD survived for 90 days after administration, whereas none of the rats with LPD alone were alive for more than 19 days. Histological examination revealed that there was no viable tumor cell in the encapsulated necrotic tumor at 21 days after administration. There was no significant liver dysfunction or leukopenia due to KM2210. The biodistribution study using [14C, 3H]KM2210-LPD solution showed that KM2210 accumulated selectively in tumor and that the tumor-to-normal-liver and tumor-to-blood ratios were 10 and 1,000, respectively, at 21 days after administration. These results suggest that KM2210 has potential clinical application in the treatment of human liver cancer

  3. Comparative study of genetic activity of chlorambucil's active metabolite steroidal esters: The role of steroidal skeleton on aneugenic potential

    Energy Technology Data Exchange (ETDEWEB)

    Efthimiou, M.; Ouranou, D.; Stephanou, G. [Division of Genetics, Cell and Developmental Biology, Department of Biology, University of Patras, Rion, 26 500 Patras (Greece); Demopoulos, N.A., E-mail: [Division of Genetics, Cell and Developmental Biology, Department of Biology, University of Patras, Rion, 26 500 Patras (Greece); Nikolaropoulos, S.S. [Laboratory of Medicinal Chemistry, Department of Pharmacy, University of Patras, 26 500 Patras (Greece); Alevizos, Ph. [Department of Mathematics, University of Patras, 26 500 Patras (Greece)


    p-N,N-bis(2-chloroethyl)aminophenylacetic acid (PHE), a nitrogen mustard analogue and chlorambucil's active metabolite used as chemotherapeutic agent, has been shown that, in addition to its clastogenic activity, induces chromosome delay. In the present study an efford has been made (a) to investigate if the steroidal analogues of PHE (EA-92, EA-97, AK-333, AK-409 and AK-433) exert the same genetic activity as the parent compound, (b) to further analyze the aneugenic activity of nitrogen mustard analogues, (c) to investigate the mechanism by which they exert aneugenic potential and (d) to correlate the genetic activity with chemical structure. For this purpose the Cytokinesis Block Micronucleus (CBMN) assay was conducted in human lymphocytes in vitro and the micronucleus (MN) frequency was determined to investigate their genetic activity. The mechanism of micronucleation was determined in combination with Fluorescence In Situ Hybridization (FISH) using pancentromeric DNA probe. Since one of the mechanisms that chemicals cause aneuploidy is through alterations in the mitotic spindle, we also investigated the effect of the above compounds on the integrity and morphology of the mitotic spindle using double immunofluorescence of {beta}- and {gamma}-tubulin in C{sub 2}C{sub 12} mouse cell line. We found that PHE and its steroidal analogues, EA-92, EA-97, AK-333, AK-409 and AK-433, affect cell proliferation in human lymphocytes and C{sub 2}C{sub 12} mouse cells. All studied compounds are capable of inducing chromosome breakage events, as indicated by the enhanced C{sup -}MN frequencies. The less lipophilic compounds are the most genetically active molecules. PHE and only two of the studied analogues, AK-409 and AK-433, the most hydrophilic ones, showed aneugenic potential, by increasing the frequencies of MN containing a whole chromosome. The aneugenic potential of the above referred analogues is associated with amplification of centrosome number, since they caused

  4. Chlorambucil and cyclosporine A in Brazilian patients with Behçet's disease uveitis: a retrospective study Clorambucil e ciclosporina A em pacientes brasileiros com doença de Behçet e uveíte: estudo retrospectivo


    Juliana Marques Zaghetto; Mirian Mina Yamamoto; Murilo Barreto Souza; Felipe Theodoro Bezerra Gaspar Carvalho da Silva; Carlos Eduardo Hirata; Edilberto Olivalves; Joyce Hisae Yamamoto


    PURPOSE: To assess the efficacy and side effects of immunosuppressive therapy in patients with Behçet's disease uveitis. METHODS: A nonrandomized retrospective case-series study analyzed data from 22 patients with Behçet's disease uveitis, from a single Uveitis Service, São Paulo, Brazil (period 1978-2007), under systemic chlorambucil and/or cyclosporine A, for at least 6 months with a minimum one-year follow-up. Drug efficacy was measured by reduction in relapse rate and reduction of prednis...

  5. Chlorambucil and cyclosporine A in Brazilian patients with Behçet's disease uveitis: a retrospective study Clorambucil e ciclosporina A em pacientes brasileiros com doença de Behçet e uveíte: estudo retrospectivo

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    Juliana Marques Zaghetto


    Full Text Available PURPOSE: To assess the efficacy and side effects of immunosuppressive therapy in patients with Behçet's disease uveitis. METHODS: A nonrandomized retrospective case-series study analyzed data from 22 patients with Behçet's disease uveitis, from a single Uveitis Service, São Paulo, Brazil (period 1978-2007, under systemic chlorambucil and/or cyclosporine A, for at least 6 months with a minimum one-year follow-up. Drug efficacy was measured by reduction in relapse rate and reduction of prednisone dose. RESULTS: Patients (10M/12F mean age was 29 (range 10-43 years-old at the onset of uveitis. The median duration of followup was 11 (range 1-29 years-old. Chlorambucil (2-6 mg/day was used in 13 patients and cyclosporine A (3-5 mg/kg/day in 9 patients at initiation. Drugs were switched because of no effectiveness or side-effects. Chlorambucil was effective in 78.5% (11/14 and induced disease remission in 43% (6/14 of patients, whereas cyclosporine A was effective in 57% (8/14 of patients. Chlorambucil and cyclosporine A were discontinued due to side effects in 21% (leucopenia and in 57% of patients (nephrotoxicity, 36% and gastrointestinal complications, 21%, respectively. No case of late malignancy was observed. 36% (16/44 of eyes had final visual acuity OBJETIVOS: Avaliar a eficácia e efeitos colaterais da terapia imunossupressora em pacientes com uveíte associada à doença de Behçet. MÉTODOS: Estudo retrospectivo não randomizado no qual são analisados dados de 22 pacientes com uveíte associada à doença de Behçet que utilizaram clorambucil e/ou ciclosporina A sistêmica por período mínimo de 6 meses, acompanhados pelo período mínimo de 1 ano, num único Serviço de Uveíte, São Paulo, Brasil (período 1978-2007. A eficácia do tratamento foi avaliada pela redução no número de recidivas da inflamação e pela redução na dose diária de prednisona. RESULTADOS: Vinte e dois pacientes (10 M/12 F, com idade média de 29 (varia

  6. Peptide conjugates containing chlorambucil or tetradentate aminopyridine ligands for anticancer treatment


    Soler Vives, Marta


    Nowadays, the search for new drugs against cancer is one of the major goals to improve the quality of life of patients. The development of more selective treatments against cancer cells may lead to a significant reduction of the side-effects, being one of the most important topics in current research. In this regard, cell-penetrating peptides (CPPs) have been described to efficiently transport therapeutic molecules across the cell membrane. Furthermore, some metal complexes based on platinum ...

  7. Drugs Approved for Hodgkin Lymphoma (United States)

    ... Ask about Your Treatment Research Drugs Approved for Hodgkin Lymphoma This page lists cancer drugs approved by the ... that are not listed here. Drugs Approved for Hodgkin Lymphoma Adcetris (Brentuximab Vedotin) Ambochlorin (Chlorambucil) Amboclorin (Chlorambucil) Becenum ( ...

  8. Drugs Approved for Non-Hodgkin Lymphoma (United States)

    ... about Your Treatment Research Drugs Approved for Non-Hodgkin Lymphoma This page lists cancer drugs approved by the ... are not listed here. Drugs Approved for Non-Hodgkin Lymphoma Abitrexate (Methotrexate) Adcetris (Brentuximab Vedotin) Ambochlorin (Chlorambucil) Amboclorin ( ...

  9. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) (United States)

    ... the relapsed/refractory setting include: • Alemtuzumab (Campath) • Fludarabine (Fludara) • Bendamustine (Treanda) • Ofatumumab (Arzerra) • Chlorambucil (Leukeran) • Rituximab (Rituxan) Some common combination treatment regimens used in ...

  10. 苯丁酸氮芥及环磷酰胺对大鼠肝微粒体谷胱甘肽S-转移酶的激活%Activation of rat liver microsomal glutathione S-transferase by chlorambucil and cyclophosphamide in vitro

    Institute of Scientific and Technical Information of China (English)

    郑英; 李杨; 张捷; 楼宜嘉


    目的 探索苯丁酸氮芥(CHB)和环磷酰胺(CP)在体外是否通过烷化激活大鼠肝微粒体谷胱甘肽S-转移酶(mGST).方法 微粒体粗提物与CHB或CP体外共孵育,测定mGST催化动力学改变,结合N-乙基马来酰亚胺(NEM)再激活实验和结合二硫苏糖醇(DTT)逆转实验,研究酶激活机制.结果 CHB或CP浓度(0~5 mmol·L-1)与时间(0~5 min)依赖性地激活mGTS.增强的mGST活性能被NEM进一步增强,不被二硫键断裂剂DTT逆转,NEM对CHB或CP活化后的mGST活性的增强效应与NEM单独的增强效应无差异.结论 CHB或CP体外可激活大鼠肝mGST,激活机制可能与mGST的Cys49的巯基被CHB或CP修饰激活有关.

  11. [Personal experience with VP-16 in the treatment of malignant lymphomas at the Chemotherapy Clinic of the Oncology Center--M. Skłodowskiej-Curie Institute in Warsaw]. (United States)

    Pałucka, A; Walewski, J; Siedlecki, P; Zborzil, J


    Eighteen patients with advanced malignant lymphomas who had progressed with previous chemotherapy were treated with LEPP (chlorambucil, VP-16, procarbazine, prednisone). One complete response and 5 partial remissions were observed, yielding an overall response rate of 33%, with median response duration of about 2 months. Twenty three patients with advanced Hodgkin's disease all who had progressed with previous chemotherapy (MOPP and ABVD) and 19 of them also after radiation therapy were treated with third line salvage chemotherapy consisting of OPEC (VP- 16, chlorambucil, vincristine and prednisone). Two complete response and 3 partial remissions were obtained for overall response rate of 21% with median duration of about 9 months. PMID:2356146

  12. Protection of chymotrypsin from inactivation by a N-mustard analog. (United States)

    Brecher, A S; Koenig, M J


    Chymotrypsin activity is rapidly inactivated by the N-mustard anti-tumor drug, chlorambucil. Since mustards react with thiols, amines, carboxyls, imidazoles, and sulfide sites on proteins, N-acetylcysteine, 2 proprietary protein hydrolyzates, beta-mercaptoethanol, ethanolamine, and sodium lactate were tested for their capacity to protect chymotrypsin from inactivation by the mustard. In each instance, protection was afforded to chymotrypsin. In as much as N-acetylcysteine protected chymotrypsin from inactivation by chlorambucil, it is suggested that this thiol compound may serve as a detoxication agent and may not require prior transformation into glutathione by cells in order to reduce mustard levels within the cells, as suggested by Smith and Gross (Proceedings of the NATO Panel VIII meeting, Grenoble, France, 1991.) It is further suggested that amino acids present as biosynthetic and degradative components of cells may detoxify mustards. PMID:7701511

  13. Ovarian carcinoma: improved survival following abdominopelvic irradiation in patients with a completed pelvic operation

    International Nuclear Information System (INIS)

    A prospective, stratified, randomized study of 190 postoperative ovarian carcinoma patients with Stages IB, II, and III (asymptomatic) presentations is reported. The median time of follow-up was 52 months. Patients in whom bilateral salpingo-oophorectomy and hysterectomy (BSOH) could not be completed because of extensive pelvic tumor had a poor prognosis which did not differ for any of the therapies tested. When BSOH was completed, pelvic plus abdominopelvic irradiation (P + AB) with no diaphragmatic shielding significantly improved patient survival rate and long-term control of occult upper abdominal disease in approximately 25% more patients than pelvic irradiation alone or followed by adjuvant daily chlorambucil therapy. The effectiveness of P + AB in BSOH-completed patients was independent of stage or tumor grade and was most clearly appreciated in patients with all gross tumor removed. Chlorambucil added to pelvic irradiation delayed the time to treatment failure without reducing the number of treatment failures

  14. Second look laparotomy in the management of epithelial cell carcinoma of the ovary.


    Mead, G. M.; Williams, C. J.; MacBeth, F. R.; Boyd, I. E.; Whitehouse, J M


    Case histories from 20 patients undergoing postchemotherapy "second look" laparotomy for metastatic epithelial cell carcinoma of the ovary were reviewed in an attempt to evaluate the usefulness of this procedure and its likely impact on patient survival. The patient population comprised 18 patients treated with a combination of cisplatin, adriamycin and cyclophosphamide (PACe) and 2 patients treated with chlorambucil. The findings at second look were often predictable, and related to the adeq...

  15. Factors influencing the extent and selectivity of alkylation within triplexes by reactive G/A motif oligonucleotides.


    Lampe, J N; Kutyavin, I V; Rhinehart, R; Reed, M W; Meyer, R. B.; Gamper, H B


    G/A motif triplex-forming oligonucleotides (TFOs) complementary to a 21 base pair homopurine/homopyrimidine run were conjugated at one or both ends to chlorambucil. These TFOs were incubated with several synthetic duplexes containing the targeted homopurine run flanked by different sequences. The extent of mono and interstrand cross-linking was compared with the level of binding at equilibrium. Covalent modification took place within a triple-stranded complex and usually occurred at guanine r...

  16. Repair of triplex-directed DNA alkylation by nucleotide excision repair


    Ziemba, Amy; Derosier, L. Chris; Methvin, Russell; Song, Chun-Yan; Clary, Eric; Kahn, Wendy; Milesi, David; Gorn, Vladimir; Reed, Mike; Ebbinghaus, Scot


    Triplex-forming oligonucleotides (TFOs) are being investigated as highly specific DNA binding agents to inhibit the expression of clinically relevant genes. So far, they have been shown to inhibit transcription from the HER-2/neu gene in vitro, whereas their use in vivo has been studied to a limited extent. This study uses a TFO–chlorambucil (chl) conjugate capable of forming site-specific covalent guanine adducts within the HER-2/neu promoter. We demonstrate that nucleotide excision repair (...

  17. Nitrogen mustard inhibits transcription and translation in a cell free system.


    Masta, A; Gray, P J; D. R. Phillips


    Nitrogen mustard and its derivatives such as cyclophosphamide, chlorambucil and melphalan are widely used anti-cancer agents, despite their non-specific reaction mechanism. In this study, the effect of alkylation by nitrogen mustard of DNA and RNA (coding for a single protein) was investigated using both a translation system and a coupled transcription/translation system. When alkylated DNA was used as the template for coupled transcription and translation, a single translation product corres...

  18. Targeted treatment for chronic lymphocytic leukemia: clinical potential of obinutuzumab

    Directory of Open Access Journals (Sweden)

    Smolej L


    Full Text Available Lukáš Smolej 4th Department of Internal Medicine – Hematology, University Hospital Hradec Králové and Charles University in Prague, Faculty of Medicine in Hradec Králové, Hradec Králové, Czech Republic Abstract: Introduction of targeted agents revolutionized the treatment of chronic lymphocytic leukemia (CLL in the past decade. Addition of chimeric monoclonal anti-CD20 antibody rituximab to chemotherapy significantly improved efficacy including overall survival (OS in untreated fit patients; humanized anti-CD52 antibody alemtuzumab and fully human anti-CD20 antibody ofatumumab lead to improvement in refractory disease. Novel small molecule inhibitors such as ibrutinib and idelalisib demonstrated excellent activity and were very recently licensed in relapsed/refractory CLL. Obinutuzumab (GA101 is the newest monoclonal antibody approved for the treatment of CLL. This novel, glycoengineered, type II humanized anti-CD20 antibody is characterized by enhanced antibody-dependent cellular cytotoxicity and direct induction of cell death compared to type I antibodies. Combination of obinutuzumab and chlorambucil yielded significantly better OS in comparison to chlorambucil monotherapy in untreated comorbid patients. These results led to approval of obinuzutumab for the treatment of CLL. Numerous clinical trials combining obinutuzumab with other cytotoxic drugs and novel small molecules are currently under way. This review focuses on the role of obinutuzumab in the treatment of CLL. Keywords: chronic lymphocytic leukemia, anti-CD20 antibodies, chlorambucil, rituximab, ofatumumab, obinutuzumab, overall survival

  19. Cytotoxicity of weak electrolytes after the adaptation of cells to low pH: role of the transmembrane pH gradient. (United States)

    Kozin, S V; Gerweck, L E


    Theory suggests that the transmembrane pH gradient may be a major determinant of the distribution of lipophilic weak electrolytes across the cell membrane. The present study evaluates the extent to which this factor contributes to pH-dependent changes in the cytotoxicity of two such chemotherapeutic drugs: chlorambucil and mitoxantrone. Experiments were performed with two cell types of the same origin but exhibiting different pH gradients at the same extracellular pH (pHe): CHO cells cultured under normal physiological conditions (pH 7.4) and acid-adapted cells obtained by culturing under low pH conditions (6.8). Over the pHe range examined (6.0-7.6), the difference between intracellular pH (pHi) and pHe increased with decreasing pHe. Acid-adapted cells were more resistant to acute changes in pHi than normal cells, resulting in substantially larger gradients in these cells. Drug cell survival curves were performed at pHe values of 6.4, 6.8 and 7.4. The cytotoxicity of chlorambucil, a weak acid, increased with decreasing pHe, and low pH-adapted cells were more sensitive than normal cells at the same pHe. In contrast, for the weak base, mitoxantrone, cytotoxicity increased with pHe and was more pronounced in normal cells. As predicted by the theory, the cytotoxicity of both drugs changed exponentially as a function of the pH gradient, regardless of cell type. For mitoxantrone, the rate of such change in cytotoxicity with the gradient was approximately two times greater than for chlorambucil. This difference is probably due to the presence of two equally ionizable crucial groups on mitoxantrone vs one group on chlorambucil. It is concluded that the cellular pH gradient plays a major role in the pH-dependent modulation of cytotoxicity in these weak electrolytes. The data obtained also suggest that a pronounced differential cytotoxicity may be expected in vivo in tumour vs normal tissue. In comparison with normal cells at a pHe of 7.4 (a model of cells in normal tissues

  20. Neurologic complications of polycythemia and their impact on therapy

    Energy Technology Data Exchange (ETDEWEB)

    Newton, L.K. (MD Anderson Cancer Center, Houston, TX (USA))


    Polycythemia vera, a clonal stem cell disorder, produces neurologic problems in 50-80% of patients. Some symptoms, such as headache and dizziness, are related to hyperviscosity, and respond immediately to reduction of cell counts. Others seem to result from an associated coagulopathy. Patients with polycythemia tend to develop both arterial and venous thrombosis and are prone to hemorrhages. Treatments for polycythemia include phlebotomy, chlorambucil supplemented with phlebotomy, and {sup 32}P plus phlebotomy. Whatever treatment is chosen, the aim of therapy should be to reduce the hematocrit to approximately 40-45%.37 references.

  1. Bullous leukemia cutis mimicking facial cellulitis* (United States)

    Caldato, Luciana de Sales; Britto, Juliana de Sousa; Niero-Melo, Ligia; Miot, Hélio Amante


    Bullous leukemia cutis is an uncommon clinical manifestation of cutaneous infiltration by leukemic cells, from B-cell chronic lymphocytic leukemia. We present the case of a 67-year-old, female, chronic lymphocytic leukemia patient. She was taking chlorambucil and developed facial edema with erythema and warmth, misjudged as facial cellulitis. Two days later, she developed bullous lesions in the arms, legs, neck and face. The histopathology of facial and bullous lesions confirmed leukemia cutis. All lesions disappeared following the administration of rituximab combined with cycles of fludarabine and cyclophosphamide. Although soft tissue infections are common complications in patients undergoing chemotherapy, leukemia cutis can also resemble cellulitis. PMID:27192532

  2. New developments in the management of chronic lymphocytic leukemia: role of ofatumumab

    Directory of Open Access Journals (Sweden)

    Laurenti L


    Full Text Available Luca Laurenti,1 Idanna Innocenti,1 Francesco Autore,1 Simona Sica,1 Dimitar G Efremov2 1Department of Hematology, Catholic University of the Sacred Heart, Rome, 2Molecular Hematology, International Centre for Genetic Engineering and Biotechnology, Monterotondo, Italy Abstract: Ofatumumab is one of the three anti-CD20 monoclonal antibodies currently available for the treatment of chronic lymphocytic leukemia (CLL. The US Food and Drug Administration (FDA approved the use of ofatumumab in patients with CLL refractory to fludarabine and alemtuzumab in 2009, and the European Medicines Agency (EMA granted approval for the same indication in 2010. Subsequent positive results of ofatumumab in combination with chlorambucil in treatment-naïve patients led the FDA in April 2014 to approve the use of this combination for first-line treatment of patients with CLL for whom fludarabine-based therapy is considered inappropriate. Later that year, the EMA approved the use of ofatumumab in combination with chlorambucil or bendamustine for the same indication. Ofatumumab has also shown potential as maintenance therapy for patients with relapsed CLL; an application to broaden the label for ofatumumab as maintenance therapy was submitted earlier this year to the EMA and FDA. Finally, ofatumumab has shown promising activity in combination with ibrutinib or idelalisib in relapsed/refractory CLL patients; combinations of ofatumumab with B-cell-receptor pathway inhibitors could represent another potential use of this antibody in the near future. Keywords: CLL, ofatumumab, monoclonal antibodies, immunotherapy

  3. Strategies of reducing the carcinogenic risk of cytostatic agents on the basis of bioassay evaluation. (United States)

    Berger, M R


    This article described strategies that can be used to reduce the carcinogenic risk of cytostatic chemotherapy and summarizes our recent experimental results. Reduction of neoplasms caused by the carcinogenic potency inherent in cytostatic agents can be obtained. (A) by chemical modifications such as: (1) exchanging a chlorine atom in N, N'-bis-(2-chloroethyl)-N-nitrosourea (BCNU) in the chloroethyl group at N'-position for a hydroxyl group to form the less carcinogenic analog N-(2-chloroethyl)-N'-(2-hydroxyethyl)-N-nitrosourea (HECNU); (2) linking chlorambucil to the steroid prednisolone to obtain a conjugate (prednimustine) with distinctly lower carcinogenic potential than chlorambucil; (3) progressive ring halogenation of phenyl-triazenes to generate agents with decreased long-term toxic risk; (B) by replacing cyclophosphamide within the carcinogenic drug combination of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) by vincristine to form the combination VMF which has no detectable carcinogenic potential; (C) by coadministration of cyclophosphamide and mesna to achieve a dose-related reduction of cyclophosphamide-induced urinary bladder carcinomas; (D) by administration of dinaline, a compound which reduces the spontaneous incidence of malignant tumors in rats. These examples demonstrate that the carcinogenic risk of single agents and drug combinations used for antineoplastic chemotherapy has successfully been reduced, as assessed in long-term bioassays. Such strategies should be considered in the treatment of patients with long life expectancy following cytotoxic chemotherapy.

  4. Extranodal marginal zone non Hodgkin's lymphoma of the lung: A ten-year experience

    Directory of Open Access Journals (Sweden)

    Milošević Violeta


    Full Text Available Background/Aim. Bronchus-associated lymphoid tissue (BALT lymphoma is a rare subtype of low grade marginal zone B cell lymphoma representing 10% of all MALT lymphomas. The purpose of this study was to analyze the outcome of this group of patients comparing prognostic parameters and therapy modalities. Methods. A total of eight patients with BALT lymphoma had diagnosed between January 1998 - April 2008 at the Institute of Hematology, Clinical Center of Serbia, Belgrade, and they were included in this retrospective analysis. Results. Male/female ratio was 2/6, the median age was 64 years (range 37-67 years. Six patients had nonspecific respiratory symptoms and all of them had B symptoms. The patients were seronegative for HIV, HCV and HBsAg. Three patients had Sjogren's syndrome, rheumatoid arthritis and pulmonary tuberculosis, respectively. Seven patients were diagnosed by transbronchial biopsy and an open lung biopsy was done in one patient. Patohistological findings revealed lymphoma of marginal zone B cell lymphoma: CD20+/CD10-/CD5-/CyclinD1- /CD23-/IgM- with Ki-67+<20% of all cells. According to the Ferraro staging system, five patients had localized disease (CS I-IIE and three had stage IVE; bulky tumor mass had 3 patients. All patients had Eastern Cooperative Oncology Group (ECOG performance status (PS 0 or 1. Five patients received monochemotherapy with chlorambucil and 3 were treated with CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisone. A complete response (CR was achieved in 5 patients and a partial response (PR in 3 of them, treated with chlorambucil monotherapy and CHOP regimen. All patients were alive during a median follow-up period of 49 months (range 6- 110 months. Three patients relapsed after monochemotherapy into the other extranodal localization. They were treated with CHOP regimen and remained in stable PR. Conclusion. BALT lymphoma tends to be localised disease at the time of diagnosis, responds well

  5. Nephrotic syndrome due to immunoglobulin M mesangial glomerulonephritis preceding juvenile idiopathic arthritis. (United States)

    Voyer, Luis E; Alvarado, Caupolican; Cuttica, Rubén J; Balestracci, Alejandro; Zardini, Marta; Lago, Néstor


    The association between nephrotic syndrome and juvenile idiopathic arthritis have rarely been described in pediatric patients. We report a child with steroid-responsive nephrotic syndrome, with frequent relapses, who presented with a new relapse of nephrotic syndrome associated with arthritis and uveitis at 21 months in remission after treatment with chlorambucil. Juvenile idiopathic arthritis was diagnosed and kidney biopsy examination showed mesangial glomerulonephritis with immunoglobulin M deposits. To our knowledge, only 2 cases of nephrotic syndrome preceding juvenile idiopathic arthritis have been reported, one without histopathology assessment and the other with minimal change disease. Although mesangial glomerulonephritis with nephrotic syndrome and juvenile idiopathic arthritis could have been coincidental, the immune pathogenic mechanism accepted for both diseases suggests they could be related.

  6. Care of children with anterior uveitis. (United States)

    Kanski, J J


    The clinical features of 290 children with anterior uveitis are presented. The vast majority suffered from chronic uveitis. Specific uveitis entities in children include the syndrome of 'chronic iridocyclitis' in girls, heterochromic cyclitis, and pars planitis. Systemic associations include sarcoidosis, the Vogt-Harada-Koyanagi syndrome, and the seronegative arthritides (juvenile chronic arthritis, juvenile ankylosing spondylitis, psoriatic arthritis, and rarely Reiter's and Beçet's syndromes). Children with a pauciarticular onset of juvenile chronic arthritis, especially when combined with positive findings for antinuclear antibody, are at particular risk of developing chronic anterior uveitis. Most cases of chronic anterior uveitis can be controlled with topical corticosteroids. Those that are resistant to both topical and systemic corticosteroids may have to be treated with chlorambucil. The operation of lensectomy is a great advance in the management of complicated cataract. Secondary glaucoma is the most devastating complication of chronic anterior uveitis in children and responds poorly to therapy.

  7. Clinical epidemiological aspects of chronic lymphoid leukaemia

    International Nuclear Information System (INIS)

    A descriptive and retrospective study of 71 patients with chronic lymphoid leukemia, attended at the Hematology Service from 'Dr Juan Bruno Zayas Alfonso' Teaching General Hospital in Santiago de Cuba was carried out from January, 2001 to November, 2006, in order to identify some clinical epidemiological variables on them, to show the therapeutical variables more used, as well as to assess survival, mortality, and the main causes of the clinical entity. Elderly, male sex, and high risk category related to advanced stage were predominant in the series. The therapeutical schedule of chlorambucil and prednisone was the most used, achieving good results in the majority of the case material. The survival of patients, in general, ranged among 1-5 years, whereas deaths occurred due to disease progression, infectious respiratory processes, pro-lymphocytic transformation, second neoplasias, and strokes. (author)

  8. Synthesis of a new conjugated polymer for DNA alkylation and gene regulation. (United States)

    Nie, Chenyao; Zhu, Chunlei; Feng, Liheng; Lv, Fengting; Liu, Libing; Wang, Shu


    A new polyfluorene derivative containing pendent alkylating chlorambucil (PFP-Cbl) was synthesized and characterized. Under direct incubation with DNA in vitro, PFP-Cbl could undergo an efficient DNA alkylating reaction and induce DNA cross-linking. In vitro transcription and translation experiment exhibited that the PFP-Cbl significantly down-regulated the gene expression of luciferase reporter plasmid. The down-regulation of gene expression was also verified through the transfection experiment of p-EGFP plasmid, which showed decreased green fluorescent protein (GFP) in cells. Meanwhile, the self-luminous property of PFP-Cbl could make it able to trace the internalized PFP-Cbl and plasmid complexes resulted from cross-linking in cells by fluorescent microscopy. Combining the features of alkylating function, multivalent binding sites, and fluorescent characteristics, PFP-Cbl provides a new insight in the area of gene regulation and extends the new applications of conjugated polymers (CPs). PMID:23548104

  9. Juvenile idiopathic arthritis complicated by amyloidosis with secondary nephrotic syndrome - effective treatment with tocilizumab. (United States)

    Kwiatkowska, Małgorzata; Jednacz, Ewa; Rutkowska-Sak, Lidia


    A case report of a boy with juvenile idiopathic arthritis since the age of 2 years, generalized onset, complicated by nephrotic syndrome due to secondary type A amyloidosis is presented. In the patient the disease had an especially severe course, complicated by frequent infections, making routine treatment difficult. Amyloidosis was diagnosed in the 5(th) year of the disease based on a rectal biopsy. Since the disease onset the boy has been taking prednisolone and sequentially cyclosporine A, methotrexate, chlorambucil, etanercept, and cyclophosphamide. Clinical and laboratory remission was observed after treatment with tocilizumab. After 42 months of treatment with tocilizumab the boy's condition is good. There is no pain or joint edema, and no signs of nephrotic syndrome.

  10. CD80 antigen expression as a predictor of ex vivo chemosensitivity in chronic lymphocytic leukemia. (United States)

    Kivekäs, Ilkka; Hulkkonen, Janne; Hurme, Mikko; Vilpo, Leena; Vilpo, Juhani


    We investigated the correlation between expression of 31 surface membrane antigens and chemosensitivity of peripheral blood mononuclear cells from 36 patients with CLL. The sensitivity of CLL cells to nine drugs (2'-chlorodeoxyadenosine, cisplatin, chlorambucil, cyclosporin A, doxorubicin, fludarabine, prednisolone, verapamil and vincristine) and two types of irradiation (gamma and UV-irradiation) was determined from dose-response curves of 4-day cultures ex vivo. The results indicated that the CLL cases responding to purine analogs (2'-chlorodeoxyadenosine and fludarabine) can be identified according to CD80 expression: all resistant cases had low or negative CD80 expression. No other correlations were revealed. CD80 may be a surrogate chemosensitivity marker for purine analogs. PMID:11916516

  11. Validation of a flow cytometric acridine orange micronuclei methodology in rats. (United States)

    Criswell, K A; Krishna, G; Zielinski, D; Urda, G A; Juneau, P; Bulera, S; Bleavins, M R


    Our laboratory has previously reported a flow cytometric acridine orange method for detection of micronucleus (MN) in the rat using cyclophosphamide as a test compound. To replace the manual method of scoring and satisfy Good Laboratory Practice (GLP) requirements, an extensive validation of the flow method was required. Therefore, manual scoring and flow cytometric determination of MN were compared using vincristine, chlorambucil, methotrexate, and doxorubicin compounds known to induce MN formation with various mechanisms of action. 1,2-Dimethylhydrazine (1,2-DH), a compound with negative or equivocal MN findings also was evaluated. The flow method consistently demonstrated dose- and time-dependent responses for MN production at all concentrations of vincristine, methotrexate, clorambucil, and doxorubicin. In contrast, manual scoring of slides failed to detect an increase in MN at the lowest doses of doxorubicin (1mg/kg) at 24 or 48 h, and methotrexate at 48 h, or any dose of methotrexate (50, 100, or 250 mg/kg) at 24h. Additionally, a dose-response for methotrexate at 48 h, and chlorambucil at 24 h were missed using manual scoring. For 1,2-DH, the flow method showed a low level (< 1.4-fold) increase in MN at all doses and times. In contrast, the manual method showed five-seven-fold increases at 24 h, but a < two-fold increase at 48 h in the highest dose only. These data may suggest that the flow method has a greater sensitivity and possibly accuracy than manual scoring. Significant decreases in polychromatic erythrocytes (PCE) were seen using both methods at approximately the same dose for all compounds. However, absolute flow cytometric PCE values were consistently higher than manual. Additional cytotoxicity parameters obtained by the flow method allowed a more complete assessment of cytotoxicity than PCE alone. Furthermore, data reported here combined with improved throughput, shortened data turnaround and reporting times, and possibly better precision due to

  12. Xantogranuloma necrobiótico solitário sem paraproteinemia Necrobiotic xanthogranuloma without paraproteinemia

    Directory of Open Access Journals (Sweden)

    Danielle Mazziero Macedo


    Full Text Available O xantogranuloma necrobiótico é doença crônica granulomatosa e xantomatosa, caracterizada por pápulas e placas infiltradas, eritematosas e amareladas, preferencialmente localizadas na região periorbital. É comum associar-se com paraproteinemia e risco aumentado para malignidades hematológicas e linfoproliferativas. Sua patogênese permanece desconhecida. Agentes alquilantes, como clorambucil e melfalan, podem ser utilizados no tratamento com sucesso variável. Relata-se um exemplo dessa rara doença em paciente com lesão única e sem paraproteinemia.Necrobiotic xanthogranuloma is a chronic granulomatous and xantomathous disease, characterized by indurated, nontender, yellowish and erythematous nodules and plaques especially located on the periorbital region. It is commonly associated with paraproteinemia and an increased risk for hematological and lymphoproliferative malignancies. Its pathogenesis remains unclear. Alkylating agents, such as chlorambucil and melphalan may be used to treat the disease with variable success. We report a case of this rare disease in a patient with a solitary tumor and without paraproteinemia.

  13. Multilayer nanoparticles with a magnetite core and a polycation inner shell as pH-responsive carriers for drug delivery (United States)

    Guo, Miao; Yan, Yu; Liu, Xiaozhou; Yan, Husheng; Liu, Keliang; Zhang, Hongkai; Cao, Youjia


    Nanocarriers with multilayer core-shell architecture were prepared by coating a superparamagnetic Fe3O4 core with a triblock copolymer. The first block of the copolymer formed the biocompatible outermost shell of the nanocarrier. The second block that contains amino groups and hydrophobic moiety formed the inner shell. The third block bound tightly onto the Fe3O4 core. Chlorambucil (an anticancer agent) and indomethacin (an anti-inflammation agent), each containing a carboxyl group and a hydrophobic moiety, were loaded into the amino-group-containing inner shell by a combination of ionic and hydrophobic interactions. The release rate of the loaded drugs was slow at pH 7.4, mimicking the blood environment, whereas the release rate increased significantly at acidic pH, mimicking the intracellular conditions in the endosome/lysosome. This can be attributed to the disruption of the ionic bond caused by protonation of the carboxylate anion of the drugs and the swelling of the inner shell caused by protonation of the amino groups.

  14. A Trimodal Closomer Drug-Delivery System Tailored with Tracing and Targeting Capabilities. (United States)

    Sarma, Saurav J; Khan, Aslam A; Goswami, Lalit N; Jalisatgi, Satish S; Hawthorne, M Frederick


    The construction and application of a unique monodisperse closomer drug-delivery system (CDDS) integrating three different functionalities onto an icosahedral closo-dodecaborane [B12 ](2-) scaffold is described. Eleven B-OH vertices of [closo-B12 (OH)12 ](2-) were used to attach eleven copies of the anticancer drug chlorambucil and the targeting vector glucosamine through a bifurcating lysine linker. The remaining twelfth vertex was used to attach a fluorescent imaging probe. The presence of multiple glucosamine units offered a monodisperse and highly water-soluble CDDS with a high payload of therapeutic cargo. This array enhanced the penetration of the drug into cancer cells by exploiting the overexpression of GLUT-1 receptors present on cancer cells. About 15-fold enhancement in cytotoxicity was observed for CDDS-1 against Jurkat cells, compared to CDDS-2, which lacks the GLUT-1 targeting glucosamine. A cytotoxicity comparison of CDDS-1 against colorectal RKO cells and its GLUT-1 knock-out version confirmed that GLUT-1 mediates endocytosis. Using fluorescent markers both CDDS-1 and -2 were traced to the mitochondria, a novel target for alkylating agents.

  15. A chromosomal translocation causing multiple abnormalities including open eyelids at birth and glomerulonephritis. (United States)

    Guarnieri, Mary H; Cacheiro, Nestor L; Rudofsky, Ulrich H; Montgomery, Jeffry C; Collins, Doris N; Flaherty, Lorraine A


    We have characterized the phenotype of a mouse with a t(2;13) reciprocal translocation induced by chlorambucil. It results in abnormal eyelid formation as well as a series of neurological, physiological, and immunological abnormalities. This mutant has been termed T(2;13)1Fla/+. T(2;13)1Fla/+ mice exhibit open eyelids at birth, a dilute coat color, hyperactivity, and occasional circling and stargazing activity. At 1-6 months, T(2;13)1Fla/+ mice show signs of immune complex-mediated glomerulonephritis and die prematurely. Additionally, double-stranded DNA autoantibodies have been found in sera of T(2;13)1Fla/+ mice. Cytogenetic analysis situated the translocation breakpoint at the proximal end of Chromosome (chr) 2 at band A2, and on Chr 13 at band A4. The mutant phenotype completely correlated with the presence of the translocation. Additional genetic studies have mapped the mutation and translocation breakpoint to Chr 13 between D13Mit16 and D13Mit64, and to Chr 2 proximal to D2Mit5. By fluorescent in situ hybridization (FISH), the position of this mutation/translocation on Chr 13 has been mapped to a region less than 1cM from D13Mit61. PMID:12226706

  16. Current treatment of the inflammatory myopathies. (United States)

    Dalakas, M C


    Among the main concerns regarding the current therapy for the inflammatory myopathies are a lack of adequate controlled trials, a lack of objective means to reliably measure muscle strength, lack of natural history data, consideration of polymyositis, dermatomyositis, and inclusion-body myositis as a homogeneous group of inflammatory myopathies, and reliance on nonspecific markers for determining prognosis and assessing response to therapies. Prednisone remains the drug of choice in treating these disorders, although a controlled trial has never been undertaken to study its efficacy. Among the steroid-sparing agents, azathioprine, methotrexate, cyclosporine, and chlorambucil are used with invariably low to moderate success. There are no results of controlled trials to indicate whether one of these drugs is superior to another. Intravenous immunoglobulin, which is very expensive, was shown in a controlled trial to be effective in steroid-resistant dermatomyositis not only in dramatically improving muscle strength and skin rash but also in resolving the underlying immunopathology. Controlled trials of intravenous immunoglobulin in patients with polymyositis and inclusion-body myositis are under way. Inclusion-body myositis has emerged as a common inflammatory myopathy that is predictably disabling and resistant to most therapies.

  17. Cutaneous xanthomas with concurrent demodicosis and dermatophytosis in a cat. (United States)

    Vogelnest, L J


    Multiple cutaneous xanthomas, associated with fasting hyperlipidaemia, are described in a 9-month-old domestic long-haired cat. A severely pruritic, papular, and crusting dermatitis affecting the head and neck, initially diagnosed as lesions of the eosinophilic granuloma complex, progressively developed on the head and pinnae. Pruritus was controlled with administration of prednisolone and chlorambucil. Repeat histological examination confirmed the diagnosis of cutaneous xanthoma and concurrent mild demodicosis. Marked fasting hypercholesterolaemia, hypertriglyceridaemia and transient hyperglycaemia were subsequently confirmed. Treatment for hyperlipidaemia and xanthomas with a low-fat diet (Hill's Feline r/d) and the previously unreported treatment for feline demodicosis of daily oral milbemycin were commenced. Multiple pink, alopecic plaques and papules gradually regressed, however pruritus recurred if immunosuppressive treatment was reduced, and well-demarcated areas of alopecia developed on the head, limbs and trunk, despite negative skin scrapings for demodex mites. Fungal culture of hair samples yielded Microsporum canis. All cutaneous lesions resolved with the addition of griseofulvin to the treatment regimen. Concurrent corneal ulceration and keratoconjunctivitis sicca ultimately resolved with treatment, including topical cyclosporin. Diabetes mellitus developed 6 months after resolution of skin lesions. No cutaneous or ocular abnormalities were present 6 months later with continued low-fat diet and insulin administration, although transient recurrence of papules and pruritus occurred after inadvertent access to a fatty meal. An underlying primary hyperlipidaemia was suspected, causing pruritic xanthomas. This may represent the first report of concurrent cutaneous xanthomas, demodicosis and dermatophytosis in a cat.

  18. Blinding Bilateral Hyperviscosity Retinopathy in a 43-Year-Old Nigerian Male with Lymphoplasmacytic Lymphoma: A Case Report and Management Challenges

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    Abdulkabir A. Ayanniyi


    Full Text Available Lymphoplasmacytic lymphomas are rare and may present with uncommon and devastating symptoms. We report a case of a 43-year-old male who presented with bleeding gums and sudden onset of bilateral blindness but was not on anticoagulants and had no family history of bleeding disorder. He had bilateral hyperpigmented infraorbital skin lesions, visual acuities (VA of hand motion in both eyes (blindness, round and sluggish pupils, and bilateral diffuse and extensive retinal haemorrhages obliterating the retinal details with central visual field defects. The optical coherence tomography revealed retinal haemorrhage, oedema, detachment, and diffuse photoreceptors damage. Investigations revealed elevated ESR and β2 microglobulin, monoclonal peak on serum protein electrophoresis, high IG with lambda restriction on serum, and urine immunofixation with increased lymphocytes and plasma cells in the bone marrow. A diagnosis of lymphoplasmacytic lymphoma complicated by blinding hyperviscosity retinopathy was made. In the absence of an aphaeresis machine, he received four cycles of manual exchange blood transfusion (EBT and commenced with chlorambucil/prednisolone due to difficulty in obtaining blood for continued EBT. His general condition and VA has improved and he is stable for more than six months into treatment.

  19. The cell transmembrane pH gradient in tumors enhances cytotoxicity of specific weak acid chemotherapeutics. (United States)

    Kozin, S V; Shkarin, P; Gerweck, L E


    The extracellular pH is lower in tumor than in normal tissue, whereas their intracellular pH is similar. In this study, we show that the tumor-specific pH gradient may be exploited for the treatment of cancer by weak acid chemotherapeutics. i.v.-injected glucose substantially decreased the electrode estimated extracellular pH in a xenografted human tumor while its intracellular pH, evaluated by (31)P magnetic resonance spectroscopy, remained virtually unchanged. The resulting increase in the average cell pH gradient caused a parallel increase in tumor growth delay by the weak acid chlorambucil (CHL). Regardless of glucose administration, the effect of CHL was significantly greater in tumors preirradiated with a large dose of ionizing radiation. This suggests that CHL was especially pronounced in radioresistant hypoxic cells possessing a larger transmembrane pH gradient. These results indicate that the naturally occurring cell pH gradient difference between tumor and normal tissue is a major and exploitable determinant of the uptake of weak acids in the complex tumor microenvironment. The use of such drugs may be especially effective in combination with radiation.

  20. The effect of immunosuppressants on experimental infection with Fasciola hepatica. (United States)

    Corba, J; Spaldonová, R


    Results are presented on the effect of immunosuppressive substances such as chlorambucil, cyclophosphamide, azathioprine, amethopterine and a cortizone derivate of betamethasone, on the development of Fasciola hepatica in the rat. The suppression of the immune response of the host to immunosuppressants was reflected in an earlier start of migration of the flukes to the common bile duct, and in an earlier onset of egg production as compared with that in the controls. Of the substances employed, cyclophosphamide and betamethasone were the most effective ones within the period from week 2--6 p.i., which is the time during which the migration of the flukes in the liver parenchyma is highest. Pathological changes in the liver of the animals were less marked than those of the infected controls. Evidence was obtained on an increased pathogenicity of infective larval flukes causing a higher mortality of the hosts in comparison with that of the control animals. On the other hand, the administration of immunosuppressants did neither influence the total number of developed flukes nor the appearance of eosinophilia in the peripheral blood of the treated animals.

  1. Diffuse pulmonary infiltrates in an old man with chronic lymphocytic leukemia

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    Alireza Hosseinnezhad


    Full Text Available An 82-year-old man known case of chronic lymphocytic leukemia (CLL presented with fever and weakness. He had never received any treatment for his CLL in the past. On admission he was found to be in mild respiratory distress with bilateral crackles and had markedly elevated white blood count (WBC (137 K/uL with 93% lymphocytes. His respiratory status deteriorated necessitating noninvasive ventilatory support. Chest computed tomography (CT scan revealed bilateral diffuse ground glass opacities, so broad spectrum antibiotic therapy was initiated. Despite that, he remained febrile and cultures were all negative. Chest x-rays showed progressive worsening of diffuse alveolar opacities. Bronchoalveolar lavage (BAL was negative for infectious etiologies, however flow cytometry of the fluid was consistent with CLL. Chemotherapy with chlorambucil was started. Although most of the pulmonary infiltrates in CLL patients are due to infectious causes, leukemic cells infiltration should be considered as well in CLL patients with respiratory symptoms who do not respond appropriately to standard antimicrobial regimen.

  2. Coumarin-containing-star-shaped 4-arm-polyethylene glycol: targeted fluorescent organic nanoparticles for dual treatment of photodynamic therapy and chemotherapy. (United States)

    Gangopadhyay, Moumita; Singh, Tanya; Behara, Krishna Kalyani; Karwa, S; Ghosh, S K; Singh, N D Pradeep


    Single component fluorescent organic polymeric nanoparticles (NPs) have been synthesized based on a star shaped 4-arm PEG containing coumarin chromophore for the concomitant employment of photodynamic therapy (PDT) and chemotherapy synergistically to wipe out tumour cells with a high efficiency. Polymeric NPs are emerging as the most promising nanoparticulates in the area of drug delivery systems due to their ability to overcome the disadvantages like premature and imprecise control over the drug release, lack of loading capacity etc. Among polymeric NPs, star shaped branched polymers have attracted great attention mainly due to their multiple functionalization properties. Hence, herein we have made use of a multi-arm PEG, functionalized with a targeting unit biotin and a coumarin fluorophore for site-specific and image guided synergic treatment of cancer cells. The anticancer drug chlorambucil is released by the coumarin chromophore in a photocontrolled manner. In addition to that, coumarin also generated singlet oxygen upon irradiation with UV/vis light (≥365 nm) with a moderate quantum yield of ∼0.37. In vitro application of thus prepared organic polymeric nanoparticles (PEG-Bio-Cou-Cbl) in the HeLa cell line shows a reduction of cell viability by up to ∼5% in the case of a combined treatment of PDT and chemotherapy whereas analogous organic polymeric NPs without the chemotherapeutic drug (PEG-Bio-Cou) result in ∼49% cell viability by means of PDT process only.

  3. Bing and Neel Syndrome

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    S. Jennane


    Full Text Available Introduction. We report the case of a Bing and Neel syndrome revealed by an isolated left ptosis. Case Report. a 57-year-old man was followed up since October 2003 for a typical Waldenström’s macroglobulinemia. A first complete remission was obtained with chlorambucil. In August 2004, he relapsed. A second complete remission was obtained with RFC chemotherapy regimen (rituximab, fludarabine, and cyclophosphamide. In October 2009, the patient presented with an isolated left ptosis revealing a Bing and Neel syndrome. The diagnosis was suspected on MRI and confirmed by the detection in the CSF of a monoclonal IgM similar to the one found in the plasma. A quite good partial remission has been obtained after one course of RDHAP (rituximab, dexamethasone, cytarabine, and cisplatin and 3 courses of RDHOx (rituximab, dexamethasone, cytarabine, and oxaliplatin, in addition to ten intrahectal chemotherapy injections. The treatment was followed by intensification and autologous stem cell transplantation. At D58, the patient died due to a septic shock. Conclusion. BNS is a rare and potentially treatable complication of WM. It should be considered in patients with neurologic symptoms and a history of WM.

  4. Bing and neel syndrome. (United States)

    Jennane, S; Doghmi, K; Mahtat, E M; Messaoudi, N; Varet, B; Mikdame, M


    Introduction. We report the case of a Bing and Neel syndrome revealed by an isolated left ptosis. Case Report. a 57-year-old man was followed up since October 2003 for a typical Waldenström's macroglobulinemia. A first complete remission was obtained with chlorambucil. In August 2004, he relapsed. A second complete remission was obtained with RFC chemotherapy regimen (rituximab, fludarabine, and cyclophosphamide). In October 2009, the patient presented with an isolated left ptosis revealing a Bing and Neel syndrome. The diagnosis was suspected on MRI and confirmed by the detection in the CSF of a monoclonal IgM similar to the one found in the plasma. A quite good partial remission has been obtained after one course of RDHAP (rituximab, dexamethasone, cytarabine, and cisplatin) and 3 courses of RDHOx (rituximab, dexamethasone, cytarabine, and oxaliplatin), in addition to ten intrahectal chemotherapy injections. The treatment was followed by intensification and autologous stem cell transplantation. At D58, the patient died due to a septic shock. Conclusion. BNS is a rare and potentially treatable complication of WM. It should be considered in patients with neurologic symptoms and a history of WM. PMID:22988532

  5. Outcome of advanced chronic lymphocytic leukemia following different first-line and relapse therapies: a meta-analysis of five prospective trials by the German CLL Study Group (GCLLSG) (United States)

    Cramer, Paula; Isfort, Susanne; Bahlo, Jasmin; Stilgenbauer, Stephan; Döhner, Hartmut; Bergmann, Manuela; Stauch, Martina; Kneba, Michael; Lange, Elisabeth; Langerbeins, Petra; Pflug, Natali; Kovacs, Gabor; Goede, Valentin; Fink, Anna-Maria; Elter, Thomas; Fischer, Kirsten; Wendtner, Clemens-Martin; Hallek, Michael; Eichhorst, Barbara


    To evaluate the effect of first-line and subsequent therapies, the outcome of 1,558 patients with chronic lymphocytic leukemia from five prospective phase II/III trials conducted between 1999 and 2010 was analyzed. The 3-year overall survival rate was higher after first-line treatment with chemoimmunotherapies such as fludarabine/cyclophosphamide/rituximab (87.9%) or bendamustine/rituximab (90.7%) compared to chemotherapies without an antibody (fludarabine/cyclophosphamide: 84.6%; fludarabine: 77.5%; chlorambucil: 77.4%). Furthermore, the median overall survival was longer in patients receiving at least one antibody-containing regimen in any treatment line (94.4 months) compared to the survival in patients who never received an antibody (84.3 months, P24 months after first-line therapy repeated the first-line regimen. Among 315 patients requiring treatment ≤24 months after first-line therapy, cyclophosphamide/doxorubicin/vincristine/prednisone with or without rituximab as well as alemtuzumab were the most commonly used therapies. In these early relapsing patients, the median overall survival was shorter following therapies containing an anthracycline and/or three or more cytotoxic agents (e.g. cyclophosphamide/doxorubicin/vincristine/prednisone or fludarabine/cyclophosphamide/mitoxantrone, 30.0 months) compared to single agent chemotherapy (e.g. fludarabine; 39.6 months) and standard chemoimmunotherapy (e.g. fludarabine/cyclophosphamide/rituximab: 61.6 months). In conclusion, the analysis confirms the superior efficacy of chemoimmunotherapies in patients with chronic lymphocytic leukemia. Moreover, the use of aggressive chemo(immuno)therapy combinations in patients with an early relapse does not offer any benefit when compared to less intensive therapies. Trial identifier: NCT00281918, ISRCTN75653261, ISRCTN36294212, NCT00274989 and NCT00147901. PMID:26315931

  6. Current trends in the management of ocular symptoms in Adamantiades-Behçet’s disease

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    Fouad R Zakka


    Full Text Available Fouad R Zakka,1 Peter Y Chang,1 Gian P Giuliari,1 C Stephen Foster1,21Massachusetts Eye Research and Surgery institution (MERSI, Cambridge, Massachusetts, USA; 2Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USAAbstract: Adamantiades-Behçet’s disease (ABD is a multisystemic vasculitic disease. It is most prevalent in the Eastern Mediterranean countries and the Eastern region of Asia. Its effect on the eye can range from mild to debilitating, resulting in total blindness. A necrotizing and obliterative vasculitis affects both arteries and veins of organs. Recurrent attacks of uveitis, oral aphthous ulcers, skin lesions, and genital ulcers are common. Topical and systemic corticosteroids have been the mainstay in the treatment of ocular inflammation for many years; however, due to the several known side effects of corticosteroids and thanks to scientific advances, more novel approaches to ABD treatment have been emerging. Antimetabolites such as methotrexate and azathioprine have been utilized with the latter showing positive results. Chlorambucil has been utilized effectively for ocular manifestations of ABD. Interferon alpha has shown encouraging results in the management of refractory ocular inflammation associated with ABD, either alone or in combination with other immunosuppressive agents. Surgical interventions to deal with complications from ABD can be safely done if adequate control of inflammation is achieved peri-operatively. Early detection and aggressive treatment, when needed, have proven to be essential in the management of this relentlessly explosive disease.Keywords: Adamantiades-Behçet’s disease, Behçet’s disease, ocular inflammation, uveitis, immunomodulatory therapy, immunosuppressive therapy

  7. Treatment of steroid resistant nephrotic syndrome in children

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    Kari Jameela


    Full Text Available Achieving remission in children with Steroid-Resistant Nephrotic Syndrome (SRNS could be difficult. Many immunosuppressive drugs are used with variable success rates. We have studied the response of children with SRNS who presented to our pediatric′s renal unit between 2002 and 2007 to various modalities of therapy. We included patients with no response to pred-nisolone (60 mg/M 2 /day after four weeks of therapy; all the patients had renal biopsy and follow-up duration for at least one year. We excluded patients with congenital nephrotic syndrome, lupus, or sickle cell disease. There were 31 (23 girls and 8 boys with F: M= 2.9:1; the mean age at presentation was 4.2 ± 3.2 children who fulfilled the inclusion criteria. The mean duration of follow up was 3.1 ± 1.6 years. Twenty children (65% achieved partial (6 children or complete (14 children remission. There were 16 children treated with cyclophosphamide either oral or intra-venous, and only 4 of them (25% achieved remission. Seven children received oral chlorambucil, and only2 of them (28.5% achieved remission; none of the children experienced side effects. Fifteen children received cyclosporine, and only eight of them (53% achieved remission. Six children developed gum hypertrophy and one had renal impairment, which was reversible after discontinuing the drug. Mycophonelate mofetil (MMF was used as the last option in 5 children, and 2 of them achieved complete remission. One child developed a systemic cytomegalovirus (CMV infection which indicated discontinuing the drug. Fourteen (45% children needed more than one immunosuppressive therapy. Three children progressed to end stage renal failure and required dialysis. We conclude that SRNS in children is a difficult disease with significant morbidity. However, remission is achievable with cyclosporine and other immunosuppressive agents. Treatment should be individualized according to the underlying histopathology, and clinical and social

  8. Comparison of in vitro and in vivo clastogenic potency based on benchmark dose analysis of flow cytometric micronucleus data. (United States)

    Bemis, Jeffrey C; Wills, John W; Bryce, Steven M; Torous, Dorothea K; Dertinger, Stephen D; Slob, Wout


    The application of flow cytometry as a scoring platform for both in vivo and in vitro micronucleus (MN) studies has enabled the efficient generation of high quality datasets suitable for comprehensive assessment of dose-response. Using this information, it is possible to obtain precise estimates of the clastogenic potency of chemicals. We illustrate this by estimating the in vivo and the in vitro potencies of seven model clastogenic agents (melphalan, chlorambucil, thiotepa, 1,3-propane sultone, hydroxyurea, azathioprine and methyl methanesulfonate) by deriving BMDs using freely available BMD software (PROAST). After exposing male rats for 3 days with up to nine dose levels of each individual chemical, peripheral blood samples were collected on Day 4. These chemicals were also evaluated for in vitro MN induction by treating TK6 cells with up to 20 concentrations in quadruplicate. In vitro MN frequencies were determined via flow cytometry using a 96-well plate autosampler. The estimated in vitro and in vivo BMDs were found to correlate to each other. The correlation showed considerable scatter, as may be expected given the complexity of the whole animal model versus the simplicity of the cell culture system. Even so, the existence of the correlation suggests that information on the clastogenic potency of a compound can be derived from either whole animal studies or cell culture-based models of chromosomal damage. We also show that the choice of the benchmark response, i.e. the effect size associated with the BMD, is not essential in establishing the correlation between both systems. Our results support the concept that datasets derived from comprehensive genotoxicity studies can provide quantitative dose-response metrics. Such investigational studies, when supported by additional data, might then contribute directly to product safety investigations, regulatory decision-making and human risk assessment. PMID:26049158

  9. Stability of solutions of antineoplastic agents during preparation and storage for in vitro assays. General considerations, the nitrosoureas and alkylating agents. (United States)

    Bosanquet, A G


    In vitro drug sensitivity of tumour biopsies is currently being determined using a variety of methods. For these chemosensitivity assays many drugs are required at short notice, and this in turn means that the drugs must generally be stored in solution. There are, however, a number of potential problems associated with dissolving and storing drugs for in vitro use, which include (a) drug adsorption; (b) effects of freezing; (c) drug stability under the normal conditions of dilution and setting up of an in vitro assay; and (d) insolubility of drugs in normal saline (NS) or phosphate-buffered saline (PBS). These problems are considered in general, and some recommendations for use of solutions of drugs in in vitro assays are suggested. The nitrosoureas and alkylating agents are also investigated in greater detail in this respect. The nitrosoureas are found to be very labile in PBS at pH 7, with 5% degradation (t0.95) occurring in 10-50 min at room temperature. These values are increased about 10-fold on refrigeration and about 5- to 10-fold on reduction of the pH of the medium to pH 4-5. At pH 7 and room temperature, t0.95 is observed in under 1 h with the alkylating agents nitrogen mustard, chlorambucil, melphalan, 2,5-diaziridinyl-3,6-bis(2-hydroxyethylamino)-1,4-benzoquinone (BZQ), dibromodulcitol, dibromomannitol, treosulphan, and procarbazine. Of the other alkylating agents, 4-hydroperoxycylophosphamide (sometimes used in vitro in place of cyclophosphamide), busulphan, dianhydrogalactitol, aziridinylbenzoquinone (AZQ), and dacarbazine have a t0.95 of between 2 and 24 h, while ifosfamide and pentamethylmelamine are both stable in aqueous solution for greater than 7 days. About half the drugs studied in detail have been stored frozen in solution for in vitro use, although very little is known about their stability under these conditions.

  10. Clinical utility and patient considerations in the use of ofatumumab in chronic lymphocytic leukemia

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    Frustaci AM


    Full Text Available Anna Maria Frustaci, Alessandra Tedeschi, Paola Picardi, Roberto Cairoli, Marco MontilloDepartment of Hematology, Niguarda Cancer Center, Niguarda Ca' Granda Hospital, Milan, Italy Abstract: Treatment aim for chronic lymphocytic leukemia has been radically changed over the past years from providing only a palliative approach to reaching disease eradication and improving survival. Ofatumumab is a monoclonal humanized antibody with peculiar in vitro and in vivo properties, at present approved for double fludarabine and alemtuzumab refractory chronic lymphocytic leukemia. Its efficacy in this subset of patients, who typically have an unfavorable prognosis, facilitated its use in different Phase II and III trials. Ofatumumab as single agent or combined with chemotherapeutic or biologic agents, led to sundry results in the setting of both previously treated or untreated patients. Its role in maintenance therapy is also under investigation. Further advances concerning ofatumumab administration as first line therapy in combination with chlorambucil, came recently from the COMPLEMENT 1 study. Results from this trial will open the door to new perspectives of its use in treatment-naïve patients. Ofatumumab was well tolerated in almost all the studies, with the main adverse events relating mostly to infusion reaction. Hematologic toxicity, especially neutropenia, was also common. A significant improvement in patients' quality of life was reported following ofatumumab treatment and this was mainly due to its effect on constitutional symptoms. Nevertheless, some concerns remain regarding the long-term efficacy of the drug in terms of response duration and survival. The real strength of this drug needs to be confirmed by further studies and direct comparative trials. Keywords: ofatumumab, chronic lymphocytic leukemia, refractory, alemtuzumab, fludarabine, high risk

  11. Multidrug resistance-associated protein gene overexpression and reduced drug sensitivity of topoisomerase II in a human breast carcinoma MCF7 cell line selected for etoposide resistance. (United States)

    Schneider, E; Horton, J K; Yang, C H; Nakagawa, M; Cowan, K H


    A human breast cancer cell line (MCF7/WT) was selected for resistance to etoposide (VP-16) by stepwise exposure to 2-fold increasing concentrations of this agent. The resulting cell line (MCF7/VP) was 28-, 21-, and 9-fold resistant to VP-16, VM-26, and doxorubicin, respectively. MCF7/VP cells also exhibited low-level cross-resistance to 4'-(9-acridinylamino)-methanesulfon-m-anisidide, mitoxantrone, and vincristine and no cross-resistance to genistein and camptothecin. Furthermore, these cells were collaterally sensitive to the alkylating agents melphalan and chlorambucil. DNA topoisomerase II levels were similar in both wild-type MCF7/WT and drug-resistant MCF7/VP cells. In contrast, topoisomerase II from MCF7/VP cells appeared to be 7-fold less sensitive to drug-induced cleavable complex formation in whole cells and 3-fold less sensitive in nuclear extracts than topoisomerase II from MCF7/WT cells. Although this suggested that the resistant cells may contain a qualitatively altered topoisomerase II, no mutations were detected in either the ATP-binding nor the putative breakage/resealing regions of either DNA topoisomerase II alpha or II beta. In addition, the steady-state intracellular VP-16 concentration was reduced by 2-fold in the resistant cells, in the absence of detectable mdr1/P-gp expression and without any change in drug efflux. In contrast, expression of the gene encoding the MRP was increased at least 10-fold in resistant MCF7/VP cells as compared to sensitive MCF7/WT cells. These results suggest that resistance to epipodophyllotoxins in MCF7/VP cells is multifactorial, involving a reduction in intracellular drug concentration, possibly as a consequence of MRP overexpression, and an altered DNA topoisomerase II drug sensitivity. PMID:7903202

  12. Purine analog-like properties of bendamustine underlie rapid activation of DNA damage response and synergistic effects with pyrimidine analogues in lymphoid malignancies.

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    Nobuya Hiraoka

    Full Text Available Bendamustine has shown considerable clinical activity against indolent lymphoid malignancies as a single agent or in combination with rituximab, but combination with additional anti-cancer drugs may be required for refractory and/or relapsed cases as well as other intractable tumors. In this study, we attempted to determine suitable anti-cancer drugs to be combined with bendamustine for the treatment of mantle cell lymphoma, diffuse large B-cell lymphoma, aggressive lymphomas and multiple myeloma, all of which are relatively resistant to this drug, and investigated the mechanisms underlying synergism. Isobologram analysis revealed that bendamustine had synergistic effects with alkylating agents (4-hydroperoxy-cyclophosphamide, chlorambucil and melphalan and pyrimidine analogues (cytosine arabinoside, gemcitabine and decitabine in HBL-2, B104, Namalwa and U266 cell lines, which represent the above entities respectively. In cell cycle analysis, bendamustine induced late S-phase arrest, which was enhanced by 4-hydroperoxy-cyclophosphamide, and potentiated early S-phase arrest by cytosine arabinoside (Ara-C, followed by a robust increase in the size of sub-G1 fractions. Bendamustine was able to elicit DNA damage response and subsequent apoptosis faster and with shorter exposure than other alkylating agents due to rapid intracellular incorporation via equilibrative nucleoside transporters (ENTs. Furthermore, bendamustine increased the expression of ENT1 at both mRNA and protein levels and enhanced the uptake of Ara-C and subsequent increase in Ara-C triphosphate (Ara-CTP in HBL-2 cells to an extent comparable with the purine analog fludarabine. These purine analog-like properties of bendamustine may underlie favorable combinations with other alkylators and pyrimidine analogues. Our findings may provide a theoretical basis for the development of more effective bendamustine-based combination therapies.

  13. Anomalous cross-linking by mechlorethamine of DNA duplexes containing C-C mismatch pairs. (United States)

    Romero, R M; Mitas, M; Haworth, I S


    Nitrogen mustards such as mechlorethamine have previously been shown to covalently cross-link DNA through the N7 position of the two guanine bases of a d[GXC].d[GYC] duplex sequence, a so-called 1,3 G-G-cross-link, when X-Y = C-G or T-A. Here, we report the formation of a new mechlorethamine cross-link with the d[GXC].d[GYC] fragment when X-Y is a C-C mismatch pair. Mechlorethamine cross-links this fragment preferentially between the two mismatched cytosine bases, rather than between the guanine bases. The cross-link also forms when one or both of the guanine bases of the d[GCC].d[GCC] fragment are replaced by N7-deazaguanine, and, more generally, forms with any C-C mismatch, regardless of the flanking base pairs. Piperidine cleavage of the cross-link species containing the d[GCC].d[GCC] sequence gives DNA fragments consistent with alkylation at the mismatched cytosine bases. We also provide evidence that the cross-link reaction occurs between the N3 atoms of the two cytosine bases by showing that the formation of the C-C cross-link is pH dependent for both mechlorethamine and chlorambucil. Dimethyl sulfate (DMS) probing of the cross-linked d[GCC].d[GCC] fragment showed that the major groove of the guanine adjacent to the C-C mismatch is still accessible to DMS. In contrast, the known minor groove binder Hoechst 33258 inhibits the cross-link formation with a C-C mismatch pair flanked by A-T base pairs. These results suggest that the C-C mismatch is cross-linked by mechlorethamine in the minor groove. Since C-C pairs may be involved in unusual secondary structures formed by the trinucleotide repeat sequence d[CCG]n, and associated with triplet repeat expansion diseases, mechlorethamine may serve as a useful probe for these structures. PMID:10090751

  14. Management of idiopathic nephrotic syndrome in childhood

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    Peco-Antić Amira


    Full Text Available The management of idiopathic nephrotic syndrome (INS in children includes immunosuppressive and symptomatic treatment. The response to corticosteroid therapy is the best prognostic marker of the disease. The majority of children with INS (about 85% are steroid-sensitive as they normalize proteinuria within 4 weeks of daily, oral prednisone administration. The most of steroid-sensitive patients (94% has minimal change of nephrotic syndrome, while the majority (80.5%-94.4% of those who are steroid-resistant has focal segmental glomerulosderosis or mesangioproliferative glomerulonephritis. Initial therapy of INS consists of 60 mg/m2/day prednisone daily for 4 weeks followed by 40 mg/m2 on alternate days for 4 weeks, thereafter decreasing alternate day therapy every month by 25% over the next 4 months. Thus, the overall duration of the initial cortico-steroids course is 6 months that may be significantly protective against the future development of frequent relapses. Approximately 30% of patients experience only one attack and are cured after the first course of therapy; 10-20% have only 3 or 4 steroid-responsive episodes before permanent cure; the remaining 40-50% of patients are frequent relapsers, or steroid-dependent. Standard relapse therapy consists of 60 mg/m2/ day prednisone until urine is protein free for at least 3 days, followed by 40 mg/m2 on alternate days for 4 weeks. The treatment of frequent-relapses and steroid-dependent INS includes several different regimens: maintenance (6 months alternate steroid therapy just above steroid threshold (0.1-0.5 mg/kg/ 48h, levamisole, alkylating agents (cyclophosphamide or chlorambucil or cyclosporine. The worse prognosis is expected in steroid-resistant patients who are the most difficult to treat. Renal biopsy should be performed in them. At present, there is no consensus on therapeutic regimen for steroid-resistant patients. The following immunosuppressive drugs have been used with varying

  15. Acometimento pulmonar na doença de Behçet: uma boa experiência com o uso de imunossupressores Pulmonary involvement in Behcet's disease: a positive single-center experience with the use of immunosuppressive therapy

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    Alfredo Nicodemos Cruz Santana


    well as the survival, of patients with BD-related pulmonary involvement. METHODS: A retrospective review of our experience with pulmonary manifestations in patients with BD treated at our institution between January 1, 1988 and April 30, 2006. The clinical, radiological, treatment and survival data were obtained from medical charts. RESULTS: We identified 9 patients with BD-related pulmonary involvement. The mean age was 34 ± 11.5 years, and 7 of the patients were male. The radiological findings were as follows: pulmonary artery aneurysm (PAA in 8 patients; pulmonary embolism in 3 (translating to an incidence of 5.11 cases/100 patient-years; alveolar hemorrhage in one; and pulmonary hypertension in one. The treatment consisted of immunosuppression with prednisone plus chlorambucil (or cyclophosphamide or mycophenolate mofetil in all patients, with partial or complete resolution of the PAAs. One patient with a PAA and pulmonary hypertension also received sildenafil and warfarin, with good clinical and tomographic response (the first report in the English literature. In our sample, the mean duration of the follow-up period was 6.52 years. The three-year survival rate was 88.8%, as was the five-year survival rate. CONCLUSIONS: Patients with BD-related pulmonary involvement can present good survival with immunosuppressive therapy, and BD should be borne in mind as a possible cause of pulmonary hypertension and alveolar hemorrhage.

  16. 儿童原发性肾病综合症治理方案%Management strategy for idiopathic nehprotic syndrome in children

    Institute of Scientific and Technical Information of China (English)

    CHIU Man-chun


    Corticosteroid, alkylating agents, like cyclophosphamide and chlorambucil, have been used to treat idiopathic nephrotic syndrome for more than fifty years, changing the outcome of these children. However, with long-term use of steroid, especially high dosages, they have unbeara-ble side effects. Newer agents like cyclosporine A, levamisole, taerolimus, mycophenolate mofefil, have been used to spare those unwanted side effects. In the choice of drugs, the benefits obtained will have to be evaluated against possible side effects, with drug cost also taken into consideration. Though most steroid sensitive nephrotie children may run a relapsing course, have a good prognosis with many becoming non-relapsers or infrequent relapsers in adulthood, the treatment approach should aim at using the minimal amount of drug required to keep patient in remission to tie them over child-hood. As for steroid resistant nephrotie syndrome children, especially for focal segmental glomerulo-sclerosis (FSGS) , because of possible grave prognosis of going into end-stage renal failure, more ag-gressive approach should be adopted, including the use of strong immunosuppressants, such as, cy-closporine, tacrolimus, or mycophenolate mofetil if necessary. The long-term goals of treatment, other than those of physical and medical conditions, should also consider the growth, education, and psychological impact of the disease and side effects of drugs on the child, especially during an adoles-cent period,so an to allow them having normal development into adulthood.%皮质激素、烷基化物如环磷酰胺、苯丁酸氮芥用于原发性肾病综合症近50年,改变了肾病综合症儿童的预后.然而,长期使用激素,尤其较高剂量却引起严重副作用.较新药物如环孢A、左旋咪唑、他克莫司、霉酚酸酯可免去不少激素副作用.在选择药物时,应衡量及平衡效益与副作用,并考虑药物价格.虽然大部份肾病综合症儿童都会复发,然而

  17. Encefalitis por virus San Luis en la Ciudad de Buenos Aires durante el brote de dengue 2009 Saint Louis encephalitis virus in Buenos Aires city during the outbreak of dengue in 2009

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    Horacio López


    Full Text Available Se presenta un paciente de 80 años de edad, residente en la Ciudad de Buenos Aires, con diagnóstico serológico para el virus de la encefalitis de San Luis (SLE durante el brote de dengue ocurrido entre enero y mayo de 2009. Presentaba leucemia linfoide crónica en tratamiento con clorambucilo, cáncer de próstata tratado con hormonoterapia y radioterapia, e imágenes óseas compatibles con metástasis. El estudio del líquido cefalorraquídeo demostró pleocitosis con predominio de mononucleares y proteinorraquia elevada. El resultado de los cultivos para bacterias, hongos y micobacterias, así como el PCR en LCR para herpes virus, HSV, CMV y EBV, fue negativo. Se detectaron anticuerpos IgM para virus SLE tanto en LCR como en muestra de suero, con seroconversión IgG por neutralización en cultivos celulares y resultados negativos para los demás Flavivirus con circulación en Argentina. Se revisan evidencias sobre la presencia de virus de San Luis en nuestro país, y se señala la importancia de la confirmación diagnóstica y el estudio de otros Flavivirus en casos sospechosos de dengue con presentación grave o atípica. Este trabajo remarca la necesidad de fortalecer tanto la vigilancia epidemiológica del virus SLE, como el control vectorial para prevenir las diferentes infecciones transmitidas por mosquitos y conocer su efecto en Salud Pública en la Argentina.We report the case of a male, 80-year-old resident in the City of Buenos Aires, with a diagnosis of St. Louis encephalitis (SLE during a countrywide dengue outbreak, from January to May 2009. The patient had a chronic lymphocytic leukemia treated with chlorambucil, prostate cancer (hormone therapy and radiotherapy and images consistent with bone metastases. Cerebrospinal fluid examination showed pleocytosis with a predominance of mononuclear cells and high protein concentration. Bacteria, fungi and mycobacteria cultures, as well as the PCR for herpes virus, HSV, CMV and EBV, were

  18. Gateways to clinical trials. (United States)

    Bayés, M; Rabasseda, X; Prous, J R


    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, This issue focuses on the following selection of drugs: Abiraterone acetate, acyline, adalimumab, adenosine triphosphate, AEE-788, AIDSVAX gp120 B/B, AK-602, alefacept, alemtuzumab, alendronic acid sodium salt, alicaforsen sodium, alprazolam, amdoxovir, AMG-162, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, aminophylline hydrate, anakinra, anecortave acetate, anti-CTLA-4 MAb, APC-8015, aripiprazole, aspirin, atazanavir sulfate, atomoxetine hydrochloride, atorvastatin calcium, atrasentan, AVE-5883, AZD-2171; Betamethasone dipropionate, bevacizumab, bimatoprost, biphasic human insulin (prb), bortezomib, BR-A-657, BRL-55730, budesonide, busulfan; Calcipotriol, calcipotriol/betamethasone dipropionate, calcium folinate, capecitabine, capravirine, carmustine, caspofungin acetate, cefdinir, certolizumab pegol, CG-53135, chlorambucil, ciclesonide, ciclosporin, cisplatin, clofarabine, clopidogrel hydrogensulfate, clozapine, co-trimoxazole, CP-122721, creatine, CY-2301, cyclophosphamide, cypher, cytarabine, cytolin; D0401, darbepoetin alfa, darifenacin hydrobromide, DASB, desipramine hydrochloride, desloratadine, desvenlafaxine succinate, dexamethasone, didanosine, diquafosol tetrasodium, docetaxel, doxorubicin hydrochloride, drotrecogin alfa (activated), duloxetine hydrochloride, dutasteride; Ecallantide, efalizumab, efavirenz, eletriptan, emtricitabine, enfuvirtide, enoxaparin sodium, estramustine phosphate sodium, etanercept, ethinylestradiol, etonogestrel, etonogestrel/ethinylestradiol, etoposide, exenatide; Famciclovir, fampridine, febuxostat, filgrastim, fludarabine phosphate, fluocinolone acetonide, fluorouracil, fluticasone propionate