Percutaneous thrombin injection with a distal embolic protection device for treatment of a common carotid artery pseudoaneurysm.

Carotid artery pseudoaneurysm is a rare complication from placement of an internal jugular triple lumen catheter. Endovascular stenting is the favored treatment option in the setting of traumatic carotid injury. In other parts of the body, specifically the femoral artery, thrombin injection has become the standard of care. We intend to show that effective management of carotid pseudoaneurysms can also be achieved with thrombin injection after placement of a distal embolic protection device.

Bioinformatic and experimental fishing for artemisinin-interacting proteins from human nasopharyngeal cancer cells.

Determining interacting cellular partners of drugs by chemical proteomic techniques is complex and tedious. Most approaches rely on activity-based probe profiling and compound-centric chemical proteomics. The anti-malarial artemisinin also exerts profound anti-cancer activity, but the mechanisms of action are incompletely understood. In the present investigation, we present a novel approach to identify artemisinin-interacting target proteins. Our approach overcomes usual problems in traditional fishing procedures, because the drug was attached to a surface without further chemical modification. The proteins identified effect among others, cell cycle arrest, apoptosis, inhibition of angiogenesis, disruption of cell migration, and modulation of nuclear receptor responsiveness. Furthermore, a bioinformatic approach confirmed experimentally identified proteins and suggested a large number of other interacting proteins. Theoretically predicted interaction partners may serve as a starting point to complete the whole set of proteins binding artemisinin.

2,3-diphenyl-1,4-naphthoquinone: a potential chemotherapeutic agent against Trypanosoma cruzi.

Chagas disease, caused by Trypanosoma cruzi, is a widespread infection in Latin America. Currently, only 2 partially effective and highly toxic drugs, i.e., benznidazole and nifurtimox, are available for the treatment of this disease, and several efforts are underway in the search for better chemotherapeutic agents. Here, we have determined the trypanocidal activity of 2,3-diphenyl-1 ,4-naphthoquinone (DPNQ), a novel quinone derivative. In vitro, DPNQ was highly cytotoxic at a low, micromolar concentration (LD50 = 2.5 microM) against epimastigote, cell-derived trypomastigote, and intracellular amastigote forms of T. cruzi, but not against mammalian cells (LD50 = 130 microM). In vivo studies on the murine model of Chagas disease revealed that DPNQ-treated animals (3 doses of 10 mg/kg/day) showed a significant delay in parasitemia peak and higher (up to 60%) survival rate 70 days post-infection, when compared with the control group (infected, untreated). We also observed a 2-fold decrease in parasitemia between the control group (infected, untreated) and the treated group (infected, treated). No apparent drug toxicity effects were noticed in the control group (uninfected, treated). In addition, we determined that DPNQ is the first competitive inhibitor of T. cruzi lipoamide dehydrogenase (TcLipDH) thus far described. Our results indicate that DPNQ is a promising chemotherapeutic agent against T. cruzi.

Early sildenafil dose optimization and personalized instruction improves the frequency, flexibility, and success of sexual intercourse in men with erectile dysfunction.

We investigated the effect of early sildenafil dose optimization and personalized instructions on sexual intercourse success in 1109 men beginning sildenafil therapy for erectile dysfunction. In phase 1 (4 weeks), patients followed the instructions contained in the sildenafil (50 mg) sample pack and had 1.4 sexual intercourse attempts per week with 82% success. Patients (17%) had a second intercourse attempt (80% successful): 58% occurred within 4 h, 20% within 5-8 h, and 22% within 9-24 h of the first attempt. In phase 2 (4 weeks), sildenafil was adjusted as needed (53% to 100 mg, and 2% to 25 mg), and investigators provided personalized instructions to facilitate patient success. Sexual intercourse attempts increased to 1.7 per week, with 91% success, and 18% were followed by a second attempt, of which 91% were successful. Most patients requested the 100-mg dose, which helped improve sexual intercourse frequency, flexibility and success.

Development and validation of the Self-Esteem And Relationship (SEAR) questionnaire in erectile dysfunction.

Development and validation of a patient-reported measure of psychosocial variables in men with erectile dysfunction (ED) is described. Literature review, focus groups, and medical specialists identified 86 potential items. Redundant, ambiguous, or low item-to-total correlation items were removed. Data from 98 men reporting diagnosed ED and 94 controls assisted in final item selection and psychometric evaluation. Treatment responsiveness was evaluated in 93 men with ED in a 10-week open-label trial of sildenafil citrate (Viagra). The 14 chosen items resolved into two domains: Sexual Relationship (eight items) and Confidence (six items), the latter comprising Self-Esteem (four items) and Overall Relationship (two items) subscales. The resulting Self-Esteem And Relationship (SEAR) questionnaire demonstrated validity and reliability. The intervention study demonstrated responsiveness to beneficial treatment with significant improvement in scores (P=0.0001). The SEAR questionnaire possesses strong psychometric properties that support its validity and reliability for measuring sexual relationship, confidence, and particularly self-esteem.

Quality of life, mood, and sexual function: a path analytic model of treatment effects in men with erectile dysfunction and depressive symptoms.

Erectile dysfunction (ED) is commonly associated with depressed mood and diminished quality of life (QoL), but few studies have investigated the causal associations involved. Therefore, we evaluated the correlation between several measures of mood, QoL, and sexual function in a retrospective analysis of a sample of depressed men (n=152), with ED enrolled in a clinical trial of sildenafil citrate (VIAGRA). Strong correlations were observed at baseline among measures of erectile function (EF), mood, and overall QoL. Significant treatment effects were observed on all three domains, with significant interactions between changes in mood and QoL. Based on multiple regression and path analysis, a model was developed in which EF changes were associated with improved mood and quality of sexual life, which resulted in improved partner satisfaction, family life, and overall life satisfaction. These data suggest that QoL changes associated with ED therapy may be mediated by changes in sexual function, mood, and family relationships.

Relationship between patient self-assessment of erectile dysfunction and the sexual health inventory for men.

BACKGROUND: The Sexual Health Inventory for Men (SHIM) has been shown to possess favorable statistical properties in diagnosing the presence and severity of erectile dysfunction (ED). However, the SHIM has not been compared with patient self-assessment of ED. OBJECTIVE: This article describes an independent-validation study examining the correlation and agreement between the SHIM and patient self-assessment of ED with respect to the severity of ED at baseline and after treatment, and in terms of change from baseline. METHODS: The study population consisted of 247 male outpatients with ED participating in a multicenter, double-blind, placebo-controlled, flexible-dose (25-100 mg/d) Phase IIIb clinical trial in which they were randomized equally to sildenafil citrate or placebo. Patients assessed their degree of ED as severe, moderate, minimal/mild, or no problem at baseline and after 12 weeks of treatment. They also responded to the 5 questions on the SHIM, after which their degree of ED was calculated based on the SHIM total score. RESULTS: In general, the SHIM and the single-item self-assessment question produced similar descriptive profiles of the severity of ED. Kendall tau-b correlations were 0.66 (95% CI, 0.58-0.74) at baseline, 0.86 (95% CI, 0.82-0.90) after treatment, and 0.72 (95% CI, 0.67-0.77) for change from baseline. Agreement between instruments, measured by the weighted kappa statistic, mirrored the correlations at baseline and after treatment. As expected, both measures correlated moderately with improvement in erections and treatment satisfaction of both patient and partner. CONCLUSION: The moderate-to-high correlation and agreement between the SHIM and patient self-assessment of ED validate the SHIM for use in the diagnostic classification of ED severity.

Efficacy of sildenafil citrate for the treatment of erectile dysfunction in men taking serotonin reuptake inhibitors.

OBJECTIVE: This study was an evaluation of whether sildenafil citrate is effective for the treatment of erectile dysfunction in men taking concomitant serotonin-reuptake-inhibiting antidepressants. METHOD: A retrospective subanalysis of combined data from 10 phase II/III double-blind, placebo-controlled, fixed- and flexible-dose trials (12-26 weeks) identified a group of men with erectile dysfunction receiving 5 to 200 mg/day of sildenafil (N=65) or placebo (N=33) and concomitant serotonin-reuptake-inhibiting antidepressants. Efficacy was measured by responses to questions from the International Index of Erectile Function on ability to achieve erection, ability to maintain erection, ejaculation frequency, orgasm frequency, and sexual desire. RESULTS: Patients with erectile dysfunction receiving sildenafil and concomitant serotonergic antidepressants had significantly greater improvements in ability to achieve and maintain an erection, frequency of ejaculation, and orgasm frequency than did patients receiving placebo, without increased sexual desire. CONCLUSIONS: Sildenafil significantly improved erectile dysfunction in patients taking concomitant serotonergic antidepressants.

Characterization of radial forces in Z stents.

RATIONAL AND OBJECTIVES: The purpose of this study was to evaluate the effects of variation in design parameters on the resultant radial force. We evaluated the influence of wire gauge, leg length, and number of bends on the radial force produced by z stents and compared these with radial forces produced by commercial stents. A second goal was to develop an engineering model for predicting radial forces generated by z stents. METHODS: Z stents were fashioned by hand using stainless steel wire and solder that connected the ends. The radial force was measured as a function of wire gauge, vessel diameter, leg length, and number of bends and compared with the theoretical values of radial force calculated by combining Castigliano's theorem and the law of Laplace. RESULTS: Theoretically predicted radial forces were within 8% of each observed value of radial force up to 70% spring compression. CONCLUSIONS: These results suggest that the z-stent model can be used to build custom stents with preselected values of radial force for clinical use. In addition, they can be used to design model investigational stents made of similar materials and surface areas to test the effects of radial force on biological response.

Patient and partner satisfaction with Viagra (sildenafil citrate) treatment as determined by the Erectile Dysfunction Inventory of Treatment Satisfaction Questionnaire.

OBJECTIVES: To assess the efficacy and safety of Viagra (sildenafil citrate) in male outpatients with erectile dysfunction and patient and partner satisfaction with treatment using the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS). METHODS: A total of 247 patients with erectile dysfunction of broad-spectrum etiology were treated in a randomized, double-blind, parallel-group, multicenter study conducted at outpatient clinics. Patients receiving oral sildenafil (25, 50, and 100 mg) were compared with patients receiving placebo during a 12-week period. The principal efficacy measures were responses to question 3 (ability to achieve an erection) and question 4 (ability to maintain an erection) on the International Index of Erectile Function and three global efficacy questions. Patient and partner satisfaction with treatment were assessed, for the first time, using the EDITS questionnaire. RESULTS: Efficacy scores for the International Index of Erectile Function questions and the global efficacy questions were significantly higher for patients receiving sildenafil than for those receiving placebo (P <0.001). Both patients and partners receiving sildenafil also had significantly higher EDITS scores than those receiving placebo (P <0.001). Adverse events were chiefly mild or moderate. Two patients receiving sildenafil and none receiving placebo discontinued treatment because of adverse events. CONCLUSIONS: Sildenafil was an effective, well-tolerated treatment for erectile dysfunction in an outpatient setting. Partner evaluations corroborated patient assessments. The results from the EDITS questionnaire indicated that after 12 weeks of receiving sildenafil both patients and partners reported higher levels of treatment satisfaction relative to placebo.

2- and 3-substituted 1,4-naphthoquinone derivatives as subversive substrates of trypanothione reductase and lipoamide dehydrogenase from Trypanosoma cruzi: synthesis and correlation between redox cycling activities and in vitro cytotoxicity.

Trypanothione reductase (TR) is both a valid and an attractive target for the design of new trypanocidal drugs. Starting from menadione, plumbagin, and juglone, three distinct series of 1,4-naphthoquinones (NQ) were synthesized as potential inhibitors of TR from Trypanosoma cruzi (TcTR). The three parent molecules were functionalized at carbons 2 and/or 3 by various polyamine chains. Optimization of TcTR inhibition and TcTR specificity versus human disulfide reductases was achieved with the 3,3'-[polyaminobis(carbonylalkyl)]bis(1,4-NQ) series 19-20, in which an optimum chain length was determined for inhibition of the trypanothione disulfide reduction. The most active derivatives against trypanosomes in cultures were also studied as subversive substrates of TcTR and lipoamide dehydrogenase (TcLipDH). The activities were measured by following NAD(P)H oxidation as well as coupling the reactions to the reduction of cytochrome c which permits the detection of one-electron transfer. For TcTR, 20(4-c) proved to be a potent subversive substrate and an effective uncompetitive inhibitor versus trypanothione disulfide and NADPH. Molecular modeling studies based on the known X-ray structures of TcTR and hGR were conducted in order to compare the structural features, dimensions, and accessibility of the cavity at the dimer interface of TcTR with that of hGR, as one of the putative NQ binding sites. TcLipDH reduced the plumbagin derivatives by an order of magnitude faster than the corresponding menadione derivatives. Such differences were not observed with the pig heart enzyme. The most efficient and specific subversive substrates of TcTR and TcLipDH exhibited potent antitrypanosomal activity in in vitro T. brucei and T. cruzi cultures. The results obtained here confirm that reduction of NQs by parasitic flavoenzymes is a promising strategy for the development of new trypanocidal drugs.

Trypanothione-dependent synthesis of deoxyribonucleotides by Trypanosoma brucei ribonucleotide reductase.

Trypanosoma brucei, the causative agent of African sleeping sickness, synthesizes deoxyribonucleotides via a classical eukaryotic class I ribonucleotide reductase. The unique thiol metabolism of trypanosomatids in which the nearly ubiquitous glutathione reductase is replaced by a trypanothione reductase prompted us to study the nature of thiols providing reducing equivalents for the parasite synthesis of DNA precursors. Here we show that the dithiol trypanothione (bis(glutathionyl)spermidine), in contrast to glutathione, is a direct reductant of T. brucei ribonucleotide reductase with a K(m) value of 2 mm. This is the first example of a natural low molecular mass thiol directly delivering reducing equivalents for ribonucleotide reduction. At submillimolar concentrations, the reaction is strongly accelerated by tryparedoxin, a 16-kDa parasite protein with a WCPPC active site motif. The K(m) value of T. brucei ribonucleotide reductase for T. brucei tryparedoxin is about 4 micrometer. The disulfide form of trypanothione is a powerful inhibitor of the tryparedoxin-mediated reaction that may represent a physiological regulation of deoxyribonucleotide synthesis by the redox state of the cell. The trypanothione/tryparedoxin system is a new system providing electrons for a class I ribonucleotide reductase, in addition to the well known thioredoxin and glutaredoxin systems described in other organisms.

Radiologic placement of a low profile implantable venous access port in a pediatric population.

PURPOSE: To evaluate the feasibility and complications of placement of a low-profile venous access port in the chest in children requiring long-term venous access. METHOD: A low-profile peripheral arm port (PAS port; Sims Deltec, St. Paul, MN, USA) was implanted in the chest in 22 children over a 4-year period. The mean age of the study group was 6 years (range: 9 months to 20 years). Ports were placed for the administration of chemotherapy, hyperalimentation and frequent blood sampling. Sonographic guidance was used to access the internal jugular or subclavian vein in each case. A review of all inpatient and outpatient charts was undertaken to assess catheter performance and complications. RESULTS: Access to the central venous circulation was successfully achieved in each case without complication. Ports remained implanted for 6579 catheter-days (mean: 299 days). Ten ports have been removed. Of three patients (13%) experiencing device-related infections (0.45 infections/1000 catheter days), two (9.1%) were unresponsive to antibiotics and removed (0.3 infections/1000 catheter days). One port was removed because of pain in the shoulder adjacent to the port implantation site. One port was removed because of difficult access. The final port was removed in order to place a dual-lumen catheter prior to bone marrow transplant. Twelve ports remain implanted. Aspiration occlusion occurred in four patients (18%). Deep venous thrombosis did not occur in any patient. CONCLUSION: Low-profile chest ports placed by interventional radiologists in the interventional radiology suite can be placed in children as safely as traditional chest ports placed in the operating room. The incidence of infection, venous thrombosis and aspiration occlusion is comparable to that of ports placed operatively.

(2,2':6',2"-Terpyridine)platinum(II) complexes are irreversible inhibitors of Trypanosoma cruzi trypanothione reductase but not of human glutathione reductase.

(2,2':6',2"-terpyridine)platinum(II) complexes possess pronounced cytostatic activities against trypanosomes and leishmania. As shown here, the complexes are irreversible inhibitors of trypanothione reductase (TR) from Trypanosoma cruzi, the causative agent of Chagas' disease. The most effective derivatives are the (4'-chloro-2, 2':6',2"-terpyridine)platinum(II) ammine and the (4-picoline)(4'-p-bromophenyl-2,2':6',2" -terpyridine)platinum(II) complexes which in the presence of NADPH inhibit TR with second-order rate constants of about 1.3 x 10(4) M(-1) s(-1). The modified enzyme species possess increased oxidase activities. The inhibition is not reversed upon dialysis or treatment with low-molecular-mass thiols. Kinetic and spectroscopic data suggest that Cys52 in the active site has been specifically altered. Inhibition of this key enzyme of parasite thiol metabolism probably contributes to the antitrypanosomal activity of the compounds. In contrast to the parasite enzyme, most (terpyridine)platinum complexes interact only reversibly with human glutathione reductase and an initial inhibition is completely abolished during the course of the assay.

Inactivation of Trypanosoma cruzi dihydrolipoamide dehydrogenase by leukocyte myeloperoxidase systems: role of hypochloride and nitrite related radicals.

Dihydrolipoamide dehydrogenase (LADH) from Trypanosoma cruzi, the causative agent of Chagas' disease, was inactivated by treatment with myeloperoxidase (MPO)-dependent systems. LADH lipoamide reductase and diaphorase activities decreased as a function of incubation time and composition of the MPO/H2O2/halide system, a transient increase preceding the loss of diaphorase activity. Iodide, bromide, thiocyanide and chloride were effective components of MPO/H2O2 or MPO/NADH systems. Catalase prevented LADH inactivation by the MPO/NADH/halide systems in agreement with H2O2 production by NADH-supplemented LADH. Thiol compounds (L-cysteine, N-acetylcysteine, penicillamine, N-(2-mercaptopropionylglycine) and Captopril prevented LADH inactivation by the MPO/H2O2/NaCl system and by NaOCl, thus supporting HOCl as agent of the MPO/H2O2/NaCl system. MPO/H2O2/NaNO2 and MPO/NADH/NaNO2 inactivated LADH, the reaction being prevented by MPO inhibitors and thiol compounds. T. cruzi LADH was affected by MPO-dependent systems like myocardial LADH, allowance being made for the variation of the diaphorase activity and the greater sensitivity of the T. cruzi enzyme to MPO/H2O2/halide systems.

Inactivation of Trypanosoma cruzi dihydrolipoamide dehydrogenase by leukocyte myeloperoxidase systems: role of hypochloride and nitrite related radicals

Dihydrolipoamide dehydrogenase (LADH) from Trypanosoma cruzi, the causative agent of Chagas' disease, was inactivated by treatment with myeloperoxidase (MPO)-dependent systems. LADH lipoamide reductase and diaphorase activities decreased as a function of incubation time and composition of the MPO/H2O2/halide system, a transient increase preceding the loss of diaphorase activity. Iodide, bromide, thiocyanide and chloride were effective components of MPO/H2O2 or MPO/NADH systems. Catalase prevented LADH inactivation by the MPO/NADH/halide systems in agreement with H2O2 production by NADH-supplemented LADH. Thiol compounds (L-cysteine, N-acetylcysteine, penicillamine, N-(2-mercaptopropionylglycine) and Captopril prevented LADH inactivation by the MPO/H2O2/NaCl system and by NaOCl, thus supporting HOCl as agent of the MPO/H2O2/NaCl system. MPO/H2O2/NaNO2 and MPO/NADH/NaNO2 inactivated LADH, the reaction being prevented by MPO inhibitors and thiol compounds. T. cruzi LADH was affected by MPO-dependent systems like myocardial LADH, allowance being made for the variation of the diaphorase activity and the greater sensitivity of the T. cruzi enzyme to MPO/H2O2/halide systems.