Browsing by Subject "Infusions, Intravenous"
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Item Open Access A Monoclonal Antibody for Malaria Prevention.(The New England journal of medicine, 2021-08) Gaudinski, Martin R; Berkowitz, Nina M; Idris, Azza H; Coates, Emily E; Holman, LaSonji A; Mendoza, Floreliz; Gordon, Ingelise J; Plummer, Sarah H; Trofymenko, Olga; Hu, Zonghui; Campos Chagas, Andrezza; O'Connell, Sarah; Basappa, Manjula; Douek, Naomi; Narpala, Sandeep R; Barry, Christopher R; Widge, Alicia T; Hicks, Renunda; Awan, Seemal F; Wu, Richard L; Hickman, Somia; Wycuff, Diane; Stein, Judy A; Case, Christopher; Evans, Brian P; Carlton, Kevin; Gall, Jason G; Vazquez, Sandra; Flach, Britta; Chen, Grace L; Francica, Joseph R; Flynn, Barbara J; Kisalu, Neville K; Capparelli, Edmund V; McDermott, Adrian; Mascola, John R; Ledgerwood, Julie E; Seder, Robert A; VRC 612 Study TeamBackground
Additional interventions are needed to reduce the morbidity and mortality caused by malaria.Methods
We conducted a two-part, phase 1 clinical trial to assess the safety and pharmacokinetics of CIS43LS, an antimalarial monoclonal antibody with an extended half-life, and its efficacy against infection with Plasmodium falciparum. Part A of the trial assessed the safety, initial side-effect profile, and pharmacokinetics of CIS43LS in healthy adults who had never had malaria. Participants received CIS43LS subcutaneously or intravenously at one of three escalating dose levels. A subgroup of participants from Part A continued to Part B, and some received a second CIS43LS infusion. Additional participants were enrolled in Part B and received CIS43LS intravenously. To assess the protective efficacy of CIS43LS, some participants underwent controlled human malaria infection in which they were exposed to mosquitoes carrying P. falciparum sporozoites 4 to 36 weeks after administration of CIS43LS.Results
A total of 25 participants received CIS43LS at a dose of 5 mg per kilogram of body weight, 20 mg per kilogram, or 40 mg per kilogram, and 4 of the 25 participants received a second dose (20 mg per kilogram regardless of initial dose). No safety concerns were identified. We observed dose-dependent increases in CIS43LS serum concentrations, with a half-life of 56 days. None of the 9 participants who received CIS43LS, as compared with 5 of 6 control participants who did not receive CIS43LS, had parasitemia according to polymerase-chain-reaction testing through 21 days after controlled human malaria infection. Two participants who received 40 mg per kilogram of CIS43LS and underwent controlled human malaria infection approximately 36 weeks later had no parasitemia, with serum concentrations of CIS43LS of 46 and 57 μg per milliliter at the time of controlled human malaria infection.Conclusions
Among adults who had never had malaria infection or vaccination, administration of the long-acting monoclonal antibody CIS43LS prevented malaria after controlled infection. (Funded by the National Institute of Allergy and Infectious Diseases; VRC 612 ClinicalTrials.gov number, NCT04206332.).Item Open Access A Trial of Itraconazole or Amphotericin B for HIV-Associated Talaromycosis.(N Engl J Med, 2018-03-16) Le, Thuy; Kinh, Nguyen Van; Cuc, Ngo TK; Tung, Nguyen LN; Lam, Nguyen T; Thuy, Pham TT; Cuong, Do D; Phuc, Pham TH; Vinh, Vu H; Hanh, Doan TH; Tam, Vu Van; Thanh, Nguyen T; Thuy, Tran P; Hang, Nguyen T; Long, Hoang B; Nhan, Ho T; Wertheim, Heiman FL; Merson, Laura; Shikuma, Cecilia; Day, Jeremy N; Chau, Nguyen VV; Farrar, Jeremy; Thwaites, Guy; Wolbers, Marcel; IVAP InvestigatorsBACKGROUND: Talaromyces marneffei infection is a major cause of human immunodeficiency virus (HIV)-related death in South and Southeast Asia. Guidelines recommend initial treatment with amphotericin B deoxycholate, but this drug has substantial side effects, a high cost, and limited availability. Itraconazole is available in oral form, is associated with fewer unacceptable side effects than amphotericin, and is widely used in place of amphotericin; however, clinical trials comparing these two treatments are lacking. METHODS: In this open-label, noninferiority trial, we randomly assigned 440 HIV-infected adults who had talaromycosis, confirmed by either microscopy or culture, to receive either intravenous amphotericin B deoxycholate (amphotericin) (219 patients), at a dose of 0.7 to 1.0 mg per kilogram of body weight per day, or itraconazole capsules (221 patients), at a dose of 600 mg per day for 3 days, followed by 400 mg per day, for 11 days; thereafter, all the patients received maintenance therapy with itraconazole. The primary outcome was all-cause mortality at week 2. Secondary outcomes included all-cause mortality at week 24, the time to clinical resolution of talaromycosis, early fungicidal activity, relapse of talaromycosis, development of the immune reconstitution inflammatory syndrome (IRIS), and the side-effect profile. RESULTS: The risk of death at week 2 was 6.5% in the amphotericin group and 7.4% in the itraconazole group (absolute risk difference, 0.9 percentage points; 95% confidence interval [CI], -3.9 to 5.6; P<0.001 for noninferiority); however, the risk of death at week 24 was 11.3% in the amphotericin group and 21.0% in the itraconazole group (absolute risk difference, 9.7 percentage points; 95% CI, 2.8 to 16.6; P=0.006). Treatment with amphotericin was associated with significantly faster clinical resolution and fungal clearance and significantly lower rates of relapse and IRIS than itraconazole. The patients who received amphotericin had significantly higher rates of infusion-related reactions, renal failure, hypokalemia, hypomagnesemia, and anemia than patients in the itraconazole group. CONCLUSIONS: Amphotericin was superior to itraconazole as initial treatment for talaromycosis with respect to 6-month mortality, clinical response, and fungicidal activity. (Funded by the Medical Research Council and others; IVAP Current Controlled Trials number, ISRCTN59144167 .).Item Open Access Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors.(The New England journal of medicine, 2016-09) Connolly, Stuart J; Milling, Truman J; Eikelboom, John W; Gibson, C Michael; Curnutte, John T; Gold, Alex; Bronson, Michele D; Lu, Genmin; Conley, Pamela B; Verhamme, Peter; Schmidt, Jeannot; Middeldorp, Saskia; Cohen, Alexander T; Beyer-Westendorf, Jan; Albaladejo, Pierre; Lopez-Sendon, Jose; Goodman, Shelly; Leeds, Janet; Wiens, Brian L; Siegal, Deborah M; Zotova, Elena; Meeks, Brandi; Nakamya, Juliet; Lim, W Ting; Crowther, Mark; ANNEXA-4 InvestigatorsBackground
Andexanet alfa (andexanet) is a recombinant modified human factor Xa decoy protein that has been shown to reverse the inhibition of factor Xa in healthy volunteers.Methods
In this multicenter, prospective, open-label, single-group study, we evaluated 67 patients who had acute major bleeding within 18 hours after the administration of a factor Xa inhibitor. The patients all received a bolus of andexanet followed by a 2-hour infusion of the drug. Patients were evaluated for changes in measures of anti-factor Xa activity and were assessed for clinical hemostatic efficacy during a 12-hour period. All the patients were subsequently followed for 30 days. The efficacy population of 47 patients had a baseline value for anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.5 IU per milliliter for those receiving enoxaparin) and had confirmed bleeding severity at adjudication.Results
The mean age of the patients was 77 years; most of the patients had substantial cardiovascular disease. Bleeding was predominantly gastrointestinal or intracranial. The mean (±SD) time from emergency department presentation to the administration of the andexanet bolus was 4.8±1.8 hours. After the bolus administration, the median anti-factor Xa activity decreased by 89% (95% confidence interval [CI], 58 to 94) from baseline among patients receiving rivaroxaban and by 93% (95% CI, 87 to 94) among patients receiving apixaban. These levels remained similar during the 2-hour infusion. Four hours after the end of the infusion, there was a relative decrease from baseline of 39% in the measure of anti-factor Xa activity among patients receiving rivaroxaban and of 30% among those receiving apixaban. Twelve hours after the andexanet infusion, clinical hemostasis was adjudicated as excellent or good in 37 of 47 patients in the efficacy analysis (79%; 95% CI, 64 to 89). Thrombotic events occurred in 12 of 67 patients (18%) during the 30-day follow-up.Conclusions
On the basis of a descriptive preliminary analysis, an initial bolus and subsequent 2-hour infusion of andexanet substantially reduced anti-factor Xa activity in patients with acute major bleeding associated with factor Xa inhibitors, with effective hemostasis occurring in 79%. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327 .).Item Open Access Association Between Thrombolytic Door-to-Needle Time and 1-Year Mortality and Readmission in Patients With Acute Ischemic Stroke.(JAMA, 2020-06) Man, Shumei; Xian, Ying; Holmes, DaJuanicia N; Matsouaka, Roland A; Saver, Jeffrey L; Smith, Eric E; Bhatt, Deepak L; Schwamm, Lee H; Fonarow, Gregg CImportance:Earlier administration of intravenous tissue plasminogen activator (tPA) in acute ischemic stroke is associated with reduced mortality by the time of hospital discharge and better functional outcomes at 3 months. However, it remains unclear whether shorter door-to-needle times translate into better long-term outcomes. Objective:To examine whether shorter door-to-needle times with intravenous tPA for acute ischemic stroke are associated with improved long-term outcomes. Design, Setting, and Participants:This retrospective cohort study included Medicare beneficiaries aged 65 years or older who were treated for acute ischemic stroke with intravenous tPA within 4.5 hours from the time they were last known to be well at Get With The Guidelines-Stroke participating hospitals between January 1, 2006, and December 31, 2016, with 1-year follow-up through December 31, 2017. Exposures:Door-to-needle times for intravenous tPA. Main Outcomes and Measures:The primary outcomes were 1-year all-cause mortality, all-cause readmission, and the composite of all-cause mortality or readmission. Results:Among the 61 426 patients treated with tPA within 4.5 hours, the median age was 80 years and 43.5% were male. The median door-to-needle time was 65 minutes (interquartile range, 49-88 minutes). The 48 666 patients (79.2%) who were treated with tPA and had door-to-needle times of longer than 45 minutes, compared with those treated within 45 minutes, had significantly higher all-cause mortality (35.0% vs 30.8%, respectively; adjusted HR, 1.13 [95% CI, 1.09-1.18]), higher all-cause readmission (40.8% vs 38.4%; adjusted HR, 1.08 [95% CI, 1.05-1.12]), and higher all-cause mortality or readmission (56.0% vs 52.1%; adjusted HR, 1.09 [95% CI, 1.06-1.12]). The 34 367 patients (55.9%) who were treated with tPA and had door-to-needle times of longer than 60 minutes, compared with those treated within 60 minutes, had significantly higher all-cause mortality (35.8% vs 32.1%, respectively; adjusted hazard ratio [HR], 1.11 [95% CI, 1.07-1.14]), higher all-cause readmission (41.3% vs 39.1%; adjusted HR, 1.07 [95% CI, 1.04-1.10]), and higher all-cause mortality or readmission (56.8% vs 53.1%; adjusted HR, 1.08 [95% CI, 1.05-1.10]). Every 15-minute increase in door-to-needle times was significantly associated with higher all-cause mortality (adjusted HR, 1.04 [95% CI, 1.02-1.05]) within 90 minutes after hospital arrival, but not after 90 minutes (adjusted HR, 1.01 [95% CI, 0.99-1.03]), higher all-cause readmission (adjusted HR, 1.02; 95% CI, 1.01-1.03), and higher all-cause mortality or readmission (adjusted HR, 1.02 [95% CI, 1.01-1.03]). Conclusions and Relevance:Among patients aged 65 years or older with acute ischemic stroke who were treated with tissue plasminogen activator, shorter door-to-needle times were associated with lower all-cause mortality and lower all-cause readmission at 1 year. These findings support efforts to shorten time to thrombolytic therapy.Item Open Access Continuous intravenous cimetidine decreases stress-related upper gastrointestinal hemorrhage without promoting pneumonia.(Crit Care Med, 1993-01) Martin, LF; Booth, FV; Karlstadt, RG; Silverstein, JH; Jacobs, DM; Hampsey, J; Bowman, SC; D'Ambrosio, CA; Rockhold, FWOBJECTIVES: To determine whether a continuous i.v. infusion of cimetidine, a histamine-2 (H2) receptor antagonist, is needed to prevent upper gastrointestinal (GI) hemorrhage when compared with placebo and if that usage is associated with an increased risk of nosocomial pneumonia. Due to the importance of this latter issue, data were collected to examine the occurrence rate of nosocomial pneumonia under the conditions of this study. DESIGN: A multicenter, double-blind, placebo-controlled study. INTERVENTIONS: Patients were randomized to receive cimetidine (n = 65) as an iv infusion of 50 to 100 mg/hr or placebo (n = 66). SETTING: Intensive care units in 20 institutions. PATIENTS: Critically ill patients (n = 131), all of whom had at least one acute stress condition that previously had been associated with the development of upper GI hemorrhage. MEASUREMENTS AND MAIN RESULTS: Samples of gastric fluid from nasogastric aspirates were collected every 2 hrs for measurement of pH and were examined for the presence of blood. Upper GI hemorrhage was defined as bright red blood or persistent (continuing for > 8 hrs) "coffee ground material" in the nasogastric aspirate. Baseline chest radiographs were performed and sputum specimens were collected from all patients, and those patients without clear signs of pneumonia (positive chest radiograph, positive cough, fever) at baseline were followed prospectively for the development of pneumonia while receiving the study medication. Cimetidine-infused patients experienced significantly (p = .009) less upper GI hemorrhage than placebo-infused patients: nine (14%) of 65 cimetidine vs. 22 (33%) of 66 placebo patients. Cimetidine patients demonstrated significantly (p = .0001) higher mean intragastric pH (5.7 vs. 3.9), and had intragastric pH values at > 4.0 for a significantly (p = .0001) higher mean percentage of time (82% vs. 41%) than placebo patients. Differences in pH variables were not found between patients who had upper GI hemorrhage and those patients who did not, although there was no patient in the cimetidine group who bled with a pH < 3.5 compared with 11 such patients in the placebo group. Also, the upper GI hemorrhage rate in patients with one risk factor (23%) was similar to that rate in patients with two or more risk factors (25%). Of the 56 cimetidine-infused patients and 61 placebo-infused patients who did not have pneumonia at baseline, no cimetidine-infused patient developed pneumonia while four (7%) placebo-infused patients developed pneumonia. CONCLUSIONS: The continuous i.v. infusion of cimetidine was highly effective in controlling intragastric pH and in preventing stress-related upper GI hemorrhage in critically ill patients without increasing their risk of developing nosocomial pneumonia. While the number of risk factors and intragastric pH may have pathogenic importance in the development of upper GI hemorrhage, neither the risk factors nor the intragastric pH was predictive. Therefore, short-term administration of continuously infused cimetidine offers benefits in patients who have sustained major surgery, trauma, burns, hypotension, sepsis, or single organ failure.Item Open Access Decongestion strategies and renin-angiotensin-aldosterone system activation in acute heart failure.(JACC Heart Fail, 2015-02) Mentz, Robert J; Stevens, Susanna R; DeVore, Adam D; Lala, Anuradha; Vader, Justin M; AbouEzzeddine, Omar F; Khazanie, Prateeti; Redfield, Margaret M; Stevenson, Lynne W; O'Connor, Christopher M; Goldsmith, Steven R; Bart, Bradley A; Anstrom, Kevin J; Hernandez, Adrian F; Braunwald, Eugene; Felker, G MichaelOBJECTIVES: The purpose of this study was to assess the relationship between biomarkers of renin-angiotensin-aldosterone system (RAAS) activation and decongestion strategies, worsening renal function, and clinical outcomes. BACKGROUND: High-dose diuretic therapy in patients with acute heart failure (AHF) is thought to activate the RAAS; and alternative decongestion strategies, such as ultrafiltration (UF), have been proposed to mitigate this RAAS activation. METHODS: This study analyzed 427 AHF patients enrolled in the DOSE-AHF (Diuretic Optimization Strategies in Acute Heart Failure) and CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) trials. We assessed the relationship between 2 markers of RAAS activation (plasma renin activity [PRA] and aldosterone) from baseline to 72 h and 96 h and decongestion strategy: high- versus low-dose and continuous infusion versus bolus furosemide for DOSE-AHF and UF versus stepped pharmacologic care for CARRESS-HF. We determined the relationships between RAAS biomarkers and 60-day outcomes. RESULTS: Patients with greater RAAS activation at baseline had lower blood pressures, lower serum sodium levels, and higher blood urea nitrogen (BUN) concentration. Continuous infusion furosemide and UF were associated with greater PRA increases (median: +1.66 vs. +0.66 ng/ml/h with continuous vs. bolus infusion, respectively, p = 0.021; +4.05 vs. +0.56 ng/ml/h with UF vs. stepped care, respectively, p = 0.014). There were no significant differences in RAAS biomarker changes with high- versus low-dose diuretic therapy (both: p > 0.5). Neither baseline log PRA nor log aldosterone was associated with increased death or HF hospitalization (hazard ratio [HR] for a doubling of 1.05; 95% confidence interval [CI]: 0.98 to 1.13; p = 0.18; and HR: 1.13; 95% CI: 0.99 to 1.28; p = 0.069, respectively). The change in RAAS biomarkers from baseline to 72 and 96 h was not associated with outcomes (both: p > 0.5). CONCLUSIONS: High-dose loop diuretic therapy did not result in RAAS activation greater than that with low-dose diuretic therapy. UF resulted in greater PRA increase than stepped pharmacologic care. Neither PRA nor aldosterone was significantly associated with short-term outcomes in this cohort. (Determining Optimal Dose and Duration of Diuretic Treatment in People With Acute Heart Failure [DOSE-AHF]; NCT00577135; Effectiveness of Ultrafiltration in Treating People With Acute Decompensated Heart Failure and Cardiorenal Syndrome [CARRESS]; NCT00608491).Item Open Access Development and initial testing of the stroke rapid-treatment readiness tool.(J Neurosci Nurs, 2014-10) Olson, DaiWai M; Cox, Margueritte; Constable, Mark; Britz, Gavin W; Lin, Cheryl B; Zimmer, Louise O; Fonarow, Gregg C; Schwamm, Lee H; Peterson, Eric DNo instruments are currently available to help health systems identify target areas for reducing door-to-needle times for the administration of intravenous tissue plasminogen activator to eligible patients with ischemic stroke. A 67-item Likert-scale survey was administered by telephone to stroke personnel at 252 U.S. hospitals participating in the "Get With The Guidelines-Stroke" quality improvement program. Factor analysis was used to refine the instrument to a four-factor 29-item instrument that can be used by hospitals to assess their readiness to administer intravenous tissue plasminogen activator within 60 minutes of patient hospital arrival.Item Open Access Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta-Analysis.(The New England journal of medicine, 2017-06) PRISM Investigators; Rowan, Kathryn M; Angus, Derek C; Bailey, Michael; Barnato, Amber E; Bellomo, Rinaldo; Canter, Ruth R; Coats, Timothy J; Delaney, Anthony; Gimbel, Elizabeth; Grieve, Richard D; Harrison, David A; Higgins, Alisa M; Howe, Belinda; Huang, David T; Kellum, John A; Mouncey, Paul R; Music, Edvin; Peake, Sandra L; Pike, Francis; Reade, Michael C; Sadique, M Zia; Singer, Mervyn; Yealy, Donald MBACKGROUND:After a single-center trial and observational studies suggesting that early, goal-directed therapy (EGDT) reduced mortality from septic shock, three multicenter trials (ProCESS, ARISE, and ProMISe) showed no benefit. This meta-analysis of individual patient data from the three recent trials was designed prospectively to improve statistical power and explore heterogeneity of treatment effect of EGDT. METHODS:We harmonized entry criteria, intervention protocols, outcomes, resource-use measures, and data collection across the trials and specified all analyses before unblinding. After completion of the trials, we pooled data, excluding the protocol-based standard-therapy group from the ProCESS trial, and resolved residual differences. The primary outcome was 90-day mortality. Secondary outcomes included 1-year survival, organ support, and hospitalization costs. We tested for treatment-by-subgroup interactions for 16 patient characteristics and 6 care-delivery characteristics. RESULTS:We studied 3723 patients at 138 hospitals in seven countries. Mortality at 90 days was similar for EGDT (462 of 1852 patients [24.9%]) and usual care (475 of 1871 patients [25.4%]); the adjusted odds ratio was 0.97 (95% confidence interval, 0.82 to 1.14; P=0.68). EGDT was associated with greater mean (±SD) use of intensive care (5.3±7.1 vs. 4.9±7.0 days, P=0.04) and cardiovascular support (1.9±3.7 vs. 1.6±2.9 days, P=0.01) than was usual care; other outcomes did not differ significantly, although average costs were higher with EGDT. Subgroup analyses showed no benefit from EGDT for patients with worse shock (higher serum lactate level, combined hypotension and hyperlactatemia, or higher predicted risk of death) or for hospitals with a lower propensity to use vasopressors or fluids during usual resuscitation. CONCLUSIONS:In this meta-analysis of individual patient data, EGDT did not result in better outcomes than usual care and was associated with higher hospitalization costs across a broad range of patient and hospital characteristics. (Funded by the National Institute of General Medical Sciences and others; PRISM ClinicalTrials.gov number, NCT02030158 .).Item Unknown Hydrostatic isolated limb perfusion with adeno-associated virus vectors enhances correction of skeletal muscle in Pompe disease.(Gene Ther, 2010-12) Sun, B; Li, S; Bird, A; Koeberl, DDGlycogen storage disease type II (Pompe disease; MIM 232300) stems from the inherited deficiency of acid-α-glucosidase (GAA; acid maltase; EC 3.2.1.20), which primarily involves cardiac and skeletal muscles. We hypothesized that hydrostatic isolated limb perfusion (ILP) administration of an adeno-associated virus (AAV) vector containing a muscle-specific promoter could achieve relatively higher transgene expression in the hindlimb muscles of GAA-knockout (GAA-KO) mice, in comparison with intravenous (IV) administration. ILP administration of AAV2/8 vectors encoding alkaline phosphatase or human GAA-transduced skeletal muscles of the hindlimb widely, despite the relatively low number of vector particles administered (1 × 10¹¹), and IV administration of an equivalent vector dose failed to transduce skeletal muscle detectably. Similarly, ILP administration of fewer vector particles of the AAV2/9 vector encoding human GAA (3 × 10¹⁰) transduced skeletal muscles of the hindlimb widely and significantly reduced glycogen content to, in comparison with IV administration. The only advantage for IV administration was moderately high-level transduction of cardiac muscle, which demonstrated compellingly that ILP administration sequestered vector particles within the perfused limb. Reduction of glycogen storage in the extensor digitorum longus demonstrated the potential advantage of ILP-mediated delivery of AAV vectors in Pompe disease, because type II myofibers are resistant to enzyme replacement therapy. Thus, ILP will enhance AAV transduction of multiple skeletal muscles while reducing the required dosages in terms of vector particle numbers.Item Unknown Infusion of Reconstituted High-Density Lipoprotein, CSL112, in Patients With Atherosclerosis: Safety and Pharmacokinetic Results From a Phase 2a Randomized Clinical Trial.(Journal of the American Heart Association, 2015-08-25) Tricoci, Pierluigi; D'Andrea, Denise M; Gurbel, Paul A; Yao, Zhenling; Cuchel, Marina; Winston, Brion; Schott, Robert; Weiss, Robert; Blazing, Michael A; Cannon, Louis; Bailey, Alison; Angiolillo, Dominick J; Gille, Andreas; Shear, Charles L; Wright, Samuel D; Alexander, John HBackground
CSL112 is a new formulation of human apolipoprotein A-I (apoA-I) being developed to reduce cardiovascular events following acute coronary syndrome. This phase 2a, randomized, double-blind, multicenter, dose-ranging trial represents the first clinical investigation to assess the safety and pharmacokinetics/pharmacodynamics of a CSL112 infusion among patients with stable atherosclerotic disease.Methods and results
Patients were randomized to single ascending doses of CSL112 (1.7, 3.4, or 6.8 g) or placebo, administered over a 2-hour period. Primary safety assessments consisted of alanine aminotransferase or aspartate aminotransferase elevations >3× upper limits of normal and study drug-related adverse events. Pharmacokinetic/pharmacodynamic assessments included apoA-I plasma concentration and measures of the ability of serum to promote cholesterol efflux from cells ex vivo. Of 45 patients randomized, 7, 12, and 14 received 1.7-, 3.4-, and 6.8-g CSL112, respectively, and 11 received placebo. There were no clinically significant elevations (>3× upper limit of normal) in alanine aminotransferase or aspartate aminotransferase. Adverse events were nonserious and mild and occurred in 5 (71%), 5 (41%), and 6 (43%) patients in the CSL112 1.7-, 3.4-, and 6.8-g groups, respectively, compared with 3 (27%) placebo patients. The imbalance in adverse events was attributable to vessel puncture/infusion-site bruising. CSL112 resulted in rapid (T(max)≈2 hours) and dose-dependent increases in apoA-I (145% increase in the 6.8-g group) and total cholesterol efflux (up to 3.1-fold higher than placebo) (P<0.001).Conclusions
CSL112 infusion was well tolerated in patients with stable atherosclerotic disease. CSL112 immediately raised apoA-I levels and caused a rapid and marked increase in the capacity of serum to efflux cholesterol. This potential novel approach for the treatment of atherosclerosis warrants further investigation.Clinical trial registration
URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01499420.Item Open Access Rapidly progressing mycotic aortic aneurysm masquerading as acute coronary syndrome.(The Canadian journal of cardiology, 2013-12) Chhabra, Lovely; Kruger, Mihaela A; Kuraganti, Gayatri; Eltibi, Rami; Mamidala, Suresh; Bajaj, Rishi; Belur, Akhila; Rapose, Alwyn; Hannan, JosephMycotic aortic aneurysms are rare. The most common cause of a mycotic aortic aneurysm is bacterial seeding in a diseased or injured aortic intima with subsequent arteritis. Because the clinical presentation of mycotic aortic aneurysms can be quite variable, the diagnosis hence can often be quite challenging. We herewith report an interesting case study in which the patient with a mycotic aortic aneurysm presented with the clinical picture masquerading as an acute coronary syndrome. The scenario reiterates the fact that despite the availability of accurate noninvasive imaging techniques, strong clinical suspicion might be imperative for the diagnosis of mycotic aneurysms.Item Open Access Renal Dysfunction and In-Hospital Outcomes in Patients With Acute Ischemic Stroke After Intravenous Thrombolytic Therapy.(Journal of the American Heart Association, 2019-10-09) Rao, Zhen-Zhen; Gu, Hong-Qiu; Wang, Xian-Wei; Xie, Xue-Wei; Yang, Xin; Wang, Chun-Juan; Zhao, Xingquan; Xian, Ying; Wang, Yi-Long; Li, Zi-Xiao; Xiao, Rui-Ping; Wang, Yong-Jun; Chinese Stroke Center Alliance investigatorsBackground The impact of estimated glomerular filtration rate (eGFR) on clinical short-term outcomes after stroke thrombolysis with tissue plasminogen activator remains controversial. Methods and Results We analyzed 18 320 ischemic stroke patients who received intravenous tissue plasminogen activator at participating hospitals in the Chinese Stroke Center Alliance between June 2015 and November 2017. Multivariate logistic regression models were used to evaluate associations between eGFR (<45, 45-59, 60-89, and ≥90 mL/min per 1.73 m2) and in-hospital mortality and symptomatic intracerebral hemorrhage, adjusting for patient and hospital characteristics and the hospital clustering effect. Of the 18 320 patients receiving tissue plasminogen activator, 601 (3.3%) had an eGFR <45, 625 (3.4%) had an eGFR 45 to 59, 3679 (20.1%) had an eGFR 60 to 89, and 13 415 (73.2%) had an eGFR ≥90. As compared with eGFR ≥90, eGFR values <45 (6.7% versus 0.9%, adjusted odds ratio, 3.59; 95% CI, 2.18-5.91), 45 to 59 (4.0% versus 0.9%, adjusted odds ratio, 2.00; 95% CI, 1.18-3.38), and 60 to 89 (2.5% versus 0.9%, adjusted odds ratio, 1.67; 95% CI, 1.20-2.34) were independently associated with increased odds of in-hospital mortality. However, there was no statistically significant association between eGFR and symptomatic intracerebral hemorrhage. Conclusions eGFR was associated with an increased risk of in-hospital mortality in acute ischemic stroke patients after treatment with tissue plasminogen activator. eGFR is an important predictor of poststroke short-term death but not of symptomatic intracerebral hemorrhage.Item Open Access Risks of intracranial hemorrhage among patients with acute ischemic stroke receiving warfarin and treated with intravenous tissue plasminogen activator.(JAMA, 2012-06) Xian, Y; Liang, L; Smith, EE; Schwamm, LH; Reeves, MJ; Olson, DM; Hernandez, AF; Fonarow, GC; Peterson, EDIntravenous tissue plasminogen activator (tPA) is known to improve outcomes in ischemic stroke; however, patients receiving long-term chronic warfarin therapy may face an increased risk for intracranial hemorrhage when treated with tPA. Although current guidelines endorse administering intravenous tPA to warfarin-treated patients if their international normalized ratio (INR) is 1.7 or lower, there are few data on safety of intravenous tPA in warfarin-treated patients in clinical practice.To determine the risk of symptomatic intracranial hemorrhage (sICH) among patients with ischemic stroke treated with intravenous tPA who were receiving warfarin vs those who were not and to determine this risk as a function of INR.Observational study, using data from the American Heart Association Get With The Guidelines-Stroke Registry, of 23,437 patients with ischemic stroke and with INR of 1.7 or lower, treated with intravenous tPA in 1203 registry hospitals from April 2009 through June 2011.Symptomatic intracranial hemorrhage. Secondary end points include life-threatening/serious systemic hemorrhage, any tPA complications, and in-hospital mortality.Overall, 1802 (7.7%) patients with stroke treated with tPA were receiving warfarin (median INR, 1.20; interquartile range [IQR], 1.07-1.40). Warfarin-treated patients were older, had more comorbid conditions, and had more severe strokes. The unadjusted sICH rate in warfarin-treated patients was higher than in non-warfarin-treated patients (5.7% vs 4.6%, P < .001), but these differences were not significantly different after adjustment for baseline clinical factors (adjusted odds ratio [OR], 1.01 [95% CI, 0.82-1.25]). Similarly, there were no significant differences between warfarin-treated and non-warfarin-treated patients for serious systemic hemorrhage (0.9% vs 0.9%; adjusted OR, 0.78 [95% CI, 0.49-1.24]), any tPA complications (10.6% vs 8.4%; adjusted OR, 1.09 [95% CI, 0.93-1.29]), or in-hospital mortality (11.4% vs 7.9%; adjusted OR, 0.94 [95% CI, 0.79-1.13]). Among warfarin-treated patients with INRs of 1.7 or lower, the degree of anticoagulation was not statistically significantly associated with sICH risk (adjusted OR, 1.10 per 0.1-unit increase in INR [95% CI, 1.00-1.20]; P = .06).Among patients with ischemic stroke, the use of intravenous tPA among warfarin-treated patients (INR ≤1.7) was not associated with increased sICH risk compared with non-warfarin-treated patients.Item Restricted Safety profile of L-arginine infusion in moderately severe falciparum malaria.(PLoS One, 2008-06-11) Yeo, Tsin W; Lampah, Daniel A; Gitawati, Retno; Tjitra, Emiliana; Kenangalem, Enny; Granger, Donald L; Weinberg, J Brice; Lopansri, Bert K; Price, Ric N; Celermajer, David S; Duffull, Stephen B; Anstey, Nicholas MBACKGROUND: L-arginine infusion improves endothelial function in malaria but its safety profile has not been described in detail. We assessed clinical symptoms, hemodynamic status and biochemical parameters before and after a single L-arginine infusion in adults with moderately severe malaria. METHODOLOGY AND FINDINGS: In an ascending dose study, adjunctive intravenous L-arginine hydrochloride was infused over 30 minutes in doses of 3 g, 6 g and 12 g to three separate groups of 10 adults hospitalized with moderately severe Plasmodium falciparum malaria in addition to standard quinine therapy. Symptoms, vital signs and selected biochemical measurements were assessed before, during, and for 24 hours after infusion. No new or worsening symptoms developed apart from mild discomfort at the intravenous cannula site in two patients. There was a dose-response relationship between increasing mg/kg dose and the maximum decrease in systolic (rho = 0.463; Spearman's, p = 0.02) and diastolic blood pressure (r = 0.42; Pearson's, p = 0.02), and with the maximum increment in blood potassium (r = 0.70, p<0.001) and maximum decrement in bicarbonate concentrations (r = 0.53, p = 0.003) and pH (r = 0.48, p = 0.007). At the highest dose (12 g), changes in blood pressure and electrolytes were not clinically significant, with a mean maximum decrease in mean arterial blood pressure of 6 mmHg (range: 0-11; p<0.001), mean maximal increase in potassium of 0.5 mmol/L (range 0.2-0.7 mmol/L; p<0.001), and mean maximal decrease in bicarbonate of 3 mEq/L (range 1-7; p<0.01) without a significant change in pH. There was no significant dose-response relationship with blood phosphate, lactate, anion gap and glucose concentrations. All patients had an uncomplicated clinical recovery. CONCLUSIONS/SIGNIFICANCE: Infusion of up to 12 g of intravenous L-arginine hydrochloride over 30 minutes is well tolerated in adults with moderately severe malaria, with no clinically important changes in hemodynamic or biochemical status. Trials of adjunctive L-arginine can be extended to phase 2 studies in severe malaria. TRIAL REGISTRATION: ClinicalTrials.gov NCT00147368.