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Preprocedural coronary computed tomography angiography in chronic total occlusion percutaneous coronary intervention: Insights from the PROGRESS-CTO registry.
Simsek, B, Jaffer, FA, Kostantinis, S, Karacsonyi, J, Koike, H, Doshi, D, Alaswad, K, Gorgulu, S, Goktekin, O, Khatri, J, et al
International journal of cardiology. 2022;:20-25
Abstract
BACKGROUND Preprocedural coronary computed tomography angiography (CCTA) can be useful in procedural planning for chronic total occlusion (CTO) percutaneous coronary intervention (PCI). METHODS We examined the clinical, angiographic and procedural characteristics and outcomes of cases with vs. without preprocedural CCTA in PROGRESS-CTO (NCT02061436). Multivariable logistic regression was used to adjust for confounding factors. RESULTS Of 7034 CTO PCI cases, preprocedural CCTA was used in 375 (5.3%) with increasing frequency over time. Patients with preprocedural CCTA had a higher prevalence of prior coronary artery bypass graft surgery (39% vs. 27%, p < 0.001) and angiographically unfavorable characteristics including higher prevalence of proximal cap ambiguity (52% vs. 33%, p < 0.001) and moderate/severe calcification (59% vs. 41%, p < 0.001) compared with those without CCTA. CCTA helped resolve proximal cap ambiguity in 27%, identified significant calcium not seen on diagnostic angiography in 18%, changed estimated CTO length by >5 mm in 10%, and was performed as part of initial coronary artery disease work up in 19%. CCTA cases had higher J-CTO (2.6 ± 1.2 vs. 2.3 ± 1.3, p < 0.001) and PROGRESS-CTO (1.3 ± 1.0 vs. 1.2 ± 1.0 p = 0.027) scores. After adjusting for potential confounders, cases with preprocedural CCTA had similar technical success (odds ratio [OR]: 1.18, 95% confidence interval [CI], 0.83-1.67) and incidence of major adverse cardiovascular events (OR: 1.47, 95% CI, 0.72-3.00). CONCLUSION Preprocedural CCTA was used in ~5% of CTO PCI cases. While CCTA may help with procedural planning, especially in complex cases, technical success and MACE were similar with or without CCTA.
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HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma.
Zein, J, Gaston, B, Bazeley, P, DeBoer, MD, Igo, RP, Bleecker, ER, Meyers, D, Comhair, S, Marozkina, NV, Cotton, C, et al
Proceedings of the National Academy of Sciences of the United States of America. 2020;(4):2187-2193
Abstract
Asthma resistance to glucocorticoid treatment is a major health problem with unclear etiology. Glucocorticoids inhibit adrenal androgen production. However, androgens have potential benefits in asthma. HSD3B1 encodes for 3β-hydroxysteroid dehydrogenase-1 (3β-HSD1), which catalyzes peripheral conversion from adrenal dehydroepiandrosterone (DHEA) to potent androgens and has a germline missense-encoding polymorphism. The adrenal restrictive HSD3B1(1245A) allele limits conversion, whereas the adrenal permissive HSD3B1(1245C) allele increases DHEA metabolism to potent androgens. In the Severe Asthma Research Program (SARP) III cohort, we determined the association between DHEA-sulfate and percentage predicted forced expiratory volume in 1 s (FEV1PP). HSD3B1(1245) genotypes were assessed, and association between adrenal restrictive and adrenal permissive alleles and FEV1PP in patients with (GC) and without (noGC) daily oral glucocorticoid treatment was determined (n = 318). Validation was performed in a second cohort (SARP I&II; n = 184). DHEA-sulfate is associated with FEV1PP and is suppressed with GC treatment. GC patients homozygous for the adrenal restrictive genotype have lower FEV1PP compared with noGC patients (54.3% vs. 75.1%; P < 0.001). In patients with the homozygous adrenal permissive genotype, there was no FEV1PP difference in GC vs. noGC patients (73.4% vs. 78.9%; P = 0.39). Results were independently confirmed: FEV1PP for homozygous adrenal restrictive genotype in GC vs. noGC is 49.8 vs. 63.4 (P < 0.001), and for homozygous adrenal permissive genotype, it is 66.7 vs. 67.7 (P = 0.92). The adrenal restrictive HSD3B1(1245) genotype is associated with GC resistance. This effect appears to be driven by GC suppression of 3β-HSD1 substrate. Our results suggest opportunities for prediction of GC resistance and pharmacologic intervention.
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Andecaliximab/GS-5745 Alone and Combined with mFOLFOX6 in Advanced Gastric and Gastroesophageal Junction Adenocarcinoma: Results from a Phase I Study.
Shah, MA, Starodub, A, Sharma, S, Berlin, J, Patel, M, Wainberg, ZA, Chaves, J, Gordon, M, Windsor, K, Brachmann, CB, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2018;(16):3829-3837
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Abstract
Purpose: Matrix metalloproteinase-9 (MMP9) is implicated in protumorigenic processes. Andecaliximab (GS-5745, a monoclonal antibody targeting MMP9) was evaluated as monotherapy and in combination with mFOLFOX6.Patients and Methods: Three dosages of andecaliximab monotherapy [200, 600, and 1800 mg i.v. every 2 weeks (q2w)] were investigated in patients with advanced solid tumors (n = 13 in a 3+3 design). After determining a recommended dose, patients with advanced HER2-negative gastric/gastroesophageal junction (GEJ) adenocarcinoma (n = 40) received 800 mg andecaliximab + mFOLFOX6 q2w. Pharmacokinetics, pharmacodynamics, safety, and efficacy were assessed.Results: Andecaliximab monotherapy demonstrated no dose-limiting toxicity (DLT) in any cohort, displaying target-mediated drug disposition at the lowest dose (200 mg) and linear pharmacokinetics at higher doses. Based on target engagement, recommended doses for further study are 800 mg q2w or 1,200 mg q3w. Maximal andecaliximab target binding, defined as undetectable andecaliximab-free MMP9 in plasma, was observed in the gastric/GEJ adenocarcinoma cohort. We observed no unusual toxicity, although there were four deaths on study not attributed to andecaliximab treatment. In first-line patients (n = 36), median progression-free survival (PFS) was 9.9 months [95% confidence interval (CI), 5-13.9 months], and the overall response rate (ORR) was 50%. Among all patients (n = 40), median PFS was 7.8 (90% CI, 5.5-13.9) months, and ORR was 48%, with a median duration of response of 8.4 months.Conclusions: Andecaliximab monotherapy achieved target engagement without DLT. Andecaliximab + mFOLFOX6 showed encouraging clinical activity without additional toxicity in patients with HER2-negative gastric/GEJ adenocarcinoma. A phase III study evaluating mFOLFOX6 ± andecaliximab in this setting is ongoing. Clin Cancer Res; 24(16); 3829-37. ©2018 AACR.
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A Phase II Study of the c-Met Inhibitor Tivantinib in Combination with FOLFOX for the Treatment of Patients with Previously Untreated Metastatic Adenocarcinoma of the Distal Esophagus, Gastroesophageal Junction, or Stomach.
Pant, S, Patel, M, Kurkjian, C, Hemphill, B, Flores, M, Thompson, D, Bendell, J
Cancer investigation. 2017;(7):463-472
Abstract
BACKGROUND This phase I/II study was designed to determine the maximum tolerated dose of tivantinib in combination with standard dose FOLFOX for the treatment of patients with advanced solid tumors and to evaluate the safety and efficacy of this combination for patients with previously untreated metastatic adenocarcinoma of the distal esophagus, gastroesophageal (GE) junction, or stomach. METHODS Patients with advanced solid tumors for which FOLFOX would be appropriate chemotherapy received escalating doses of tivantinib BID (days 1-14) in a standard 3 + 3 design in phase I. In phase II, patients with advanced GE cancer received standard FOLFOX day 1 and tivantinib (360 mg PO BID) days 1-14 of each 2-week cycle. Restaging occurred every four cycles. The primary phase II endpoint was response rate (RR). RESULTS Forty-nine patients were enrolled (15 on phase I and 34 on phase II). The expansion dose was established as tivantinib 360 mg BID in combination with FOLFOX. Thirty-two phase II patients were treated for a median of eight cycles (range, 1-38), with an overall RR of 38%. Treatment-related toxicities included neutropenia, fatigue, diarrhea, nausea, and peripheral neuropathy. Median progression-free survival (PFS) was 6.1 hmonths with a median time to progression of 7.0 months. Median overall survival was 9.6 months. Two patients remain on study at the time of this analysis. CONCLUSIONS The combination treatment of tivantinib plus FOLFOX in patients with advanced GE cancer showed a response and PFS in the range of historical controls for first-line FOLFOX therapy. However, two patients had extended time on study treatment (36 and 45 cycles) at the time of data cutoff.
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Evaluation of CYP3A-mediated drug-drug interactions with romidepsin in patients with advanced cancer.
Laille, E, Patel, M, Jones, SF, Burris, HA, Infante, J, Lemech, C, Liu, L, Arkenau, HT
Journal of clinical pharmacology. 2015;(12):1378-85
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Abstract
Two multicenter, single-arm, single-infusion, open-label studies were conducted to evaluate the effect of ketoconazole (a strong CYP3A inhibitor) or rifampin (a strong CYP3A inducer) daily for 5 days on the pharmacokinetics (PK) and safety of romidepsin (8 mg/m(2) intravenous 4-hour infusion for the ketoconazole study or a 14 mg/m(2) intravenous 4-hour infusion for the rifampin study) in patients with advanced cancer. Romidepsin coadministered with ketoconazole (400 mg) or rifampin (600 mg) was not bioequivalent to romidepsin alone. With ketoconazole, the mean romidepsin AUC and Cmax were increased by approximately 25% and 10%, respectively. With rifampin, the mean romidepsin AUC and Cmax were unexpectedly increased by approximately 80% and 60%, respectively; this is likely because of inhibition of active liver uptake. For both studies, romidepsin clearance and volume of distribution were decreased, terminal half-life was comparable, and median Tmax was similar. Overall, the safety profile of romidepsin was not altered by coadministration with ketoconazole or rifampin, except that a higher incidence and greater severity of thrombocytopenia was observed when romidepsin was given with rifampin. The use of romidepsin with rifampin and strong CYP3A inducers should be avoided. Toxicity related to romidepsin exposure should be monitored when romidepsin is given with strong CYP3A inhibitors.
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The use of a portable breath analysis device in monitoring type 1 diabetes patients in a hypoglycaemic clamp: validation with SIFT-MS data.
Walton, C, Patel, M, Pitts, D, Knight, P, Hoashi, S, Evans, M, Turner, C
Journal of breath research. 2014;(3):037108
Abstract
Monitoring blood glucose concentrations is a necessary but tedious task for people suffering from diabetes. It has been noted that breath in people suffering with diabetes has a different odour and thus it may be possible to use breath analysis to monitor the blood glucose concentration. Here, we evaluate the analysis of breath using a portable device containing a single mixed metal oxide sensor during hypoglycaemic glucose clamps and compare that with the use of SIFT-MS described in previously published work on the same set of patients. Outputs from both devices have been correlated with the concentration of blood glucose in eight volunteers suffering from type 1 diabetes mellitus. The results demonstrate that acetone as measured by SIFT-MS and the sensor output from the breath sensing device both correlate linearly with blood glucose; however, the sensor response and acetone concentrations differ greatly between patients with the same blood glucose. It is therefore unlikely that breath analysis can entirely replace blood glucose testing.
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Ayurvedic management of ulcerative colitis--a non-randomized observational clinical study.
Patel, KB, Patel, M, Mehta, CS, Gupta, S, Kessler, CS
Forschende Komplementarmedizin (2006). 2013;(2):144-7
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Pegaptanib 1-year systemic safety results from a safety-pharmacokinetic trial in patients with neovascular age-related macular degeneration.
, , Apte, RS, Modi, M, Masonson, H, Patel, M, Whitfield, L, Adamis, AP
Ophthalmology. 2007;(9):1702-12
Abstract
OBJECTIVE To characterize the safety, tolerability, and pharmacokinetics of the pegylated anti-vascular endothelial growth factor (VEGF) aptamer pegaptanib sodium in subfoveal choroidal neovascularization secondary to age-related macular degeneration (AMD). DESIGN Prospective 2-cohort study: (1) open-label cohort and (2) randomized, double-masked, uncontrolled multicenter trial. PARTICIPANTS In the combined cohorts, 147 subjects with any angiographic subtype of subfoveal choroidal neovascularization secondary to AMD and best-corrected visual acuities (VAs) in the study eye of 20/40 to 20/320 and in the fellow eye of 20/800 or better received pegaptanib sodium. INTERVENTION Subjects were randomized to receive intravitreous pegaptanib sodium (1 mg or 3 mg [3- and 10-fold higher than the 0.3-mg approved dose]) every 6 weeks for 54 weeks. MAIN OUTCOME MEASURES Safety assessments included blood chemistries, urinalyses, vital signs, electrocardiograms, serum antipegaptanib antibody assays, adverse events, VAs, and intraocular pressures. After the first, fourth, and eighth injections, serial blood samples were obtained for quantification of pegaptanib plasma concentrations. RESULTS No antipegaptanib immunoglobulin G (IgG) or IgM antibodies were detected. Few systemic adverse events were noted. Mild or moderate ocular adverse events related to the injection procedure were reported in most patients. Pegaptanib did not accumulate in plasma after multiple doses; systemic exposures were similar after the first, fourth, and eighth doses. The mean apparent terminal half-life was 10 days. Evaluation of blood pressure (BP) and urine protein, both of which are known to be affected by systemic VEGF inhibition, indicated no evidence of a pegaptanib treatment effect on these parameters. Mean BP at the end of year 1 remained below 140 mmHg (systolic) and 90 mmHg (diastolic), levels considered hypertension by the American College of Cardiology. CONCLUSIONS At doses up to 10-fold higher than the 0.3-mg dose approved for the treatment of AMD, pegaptanib sodium was well tolerated, with no detectable clinical evidence of systemic VEGF inhibition (i.e., no clinically meaningful changes in proteinuria or mean BP) and no clinically relevant ocular inflammation. Most ocular adverse events were related to the injection procedure itself and were mild or moderate in severity.
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A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema.
Cunningham, ET, Adamis, AP, Altaweel, M, Aiello, LP, Bressler, NM, D'Amico, DJ, Goldbaum, M, Guyer, DR, Katz, B, Patel, M, et al
Ophthalmology. 2005;(10):1747-57
Abstract
OBJECTIVE To evaluate the safety and efficacy of pegaptanib sodium injection (pegaptanib) in the treatment of diabetic macular edema (DME). DESIGN Randomized, double-masked, multicenter, dose-ranging, controlled trial. PARTICIPANTS Individuals with a best-corrected visual acuity (VA) between 20/50 and 20/320 in the study eye and DME involving the center of the macula for whom the investigator judged photocoagulation could be safely withheld for 16 weeks. INTERVENTION Intravitreous pegaptanib (0.3 mg, 1 mg, 3 mg) or sham injections at study entry, week 6, and week 12 with additional injections and/or focal photocoagulation as needed for another 18 weeks. Final assessments were conducted at week 36. MAIN OUTCOME MEASURES Best-corrected VA, central retinal thickness at the center point of the central subfield as assessed by optical coherence tomography measurement, and additional therapy with photocoagulation between weeks 12 and 36. RESULTS One hundred seventy-two patients appeared balanced for baseline demographic and ocular characteristics. Median VA was better at week 36 with 0.3 mg (20/50), as compared with sham (20/63) (P = 0.04). A larger proportion of those receiving 0.3 mg gained VAs of > or =10 letters (approximately 2 lines) (34% vs. 10%, P = 0.003) and > or =15 letters (18% vs. 7%, P = 0.12). Mean central retinal thickness decreased by 68 microm with 0.3 mg, versus an increase of 4 microm with sham (P = 0.02). Larger proportions of those receiving 0.3 mg had an absolute decrease of both > or =100 microm (42% vs. 16%, P = 0.02) and > or =75 microm (49% vs. 19%, P = 0.008). Photocoagulation was deemed necessary in fewer subjects in each pegaptanib arm (0.3 mg vs. sham, 25% vs. 48%; P = 0.04). All pegaptanib doses were well tolerated. Endophthalmitis occurred in 1 of 652 injections (0.15%/injection; i.e., 1/130 [0.8%] pegaptanib subjects) and was not associated with severe visual loss. CONCLUSIONS In this phase II trial, subjects assigned to pegaptanib had better VA outcomes, were more likely to show reduction in central retinal thickness, and were deemed less likely to need additional therapy with photocoagulation at follow-up.
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Clinical and bacteriological efficacy and safety of 5 and 7 day regimens of telithromycin once daily compared with a 10 day regimen of clarithromycin twice daily in patients with mild to moderate community-acquired pneumonia.
Tellier, G, Niederman, MS, Nusrat, R, Patel, M, Lavin, B
The Journal of antimicrobial chemotherapy. 2004;(2):515-23
Abstract
OBJECTIVES This study was conducted to investigate the potential equivalence in clinical efficacy and assess safety of a 5 or 7 day regimen of oral telithromycin (800 mg once daily) and a 10 day regimen of oral clarithromycin (500 mg twice daily) in treating community-acquired pneumonia (CAP). Bacteriological efficacy was also compared. METHODS This was a multicentre, randomized, double-blind, active-controlled study. Patients with mild to moderate CAP received telithromycin 800 mg once a day for 5 (n=193) or 7 (n=195) days or clarithromycin 500 mg twice a day for 10 days (n=187). In these groups, 159, 161 and 146 patients, respectively, completed the study. RESULTS At the post-therapy/test-of-cure evaluation, clinical cure rates (per-protocol clinical population) were 89.3% (5 days) and 88.8% (7 days) for telithromycin, and 91.8% for clarithromycin 10 days. Satisfactory bacteriological outcome rates (per-protocol bacteriological population) were 87.7% and 80.0% for 5 and 7 days of telithromycin, respectively, and 83.3% for 10 days of clarithromycin. Bacteriological eradication rates in the respective treatment groups were, for Streptococcus pneumoniae, 95.8% (23/24), 96.7% (29/30) and 88.5% (23/26); for Haemophilus influenzae, 88.0% (22/25), 84.0% (21/25) and 88.2% (15/17) and for Moraxella catarrhalis, 1/1, 4/5 and 3/4. Both telithromycin regimens demonstrated clinical efficacy against pneumococcal bacteraemia (19/19), atypical pathogens (9/9) and erythromycin-resistant S. pneumoniae isolates (5/5). Most treatment-emergent adverse events were mild to moderate in intensity with most commonly reported adverse events involving the gastrointestinal system. CONCLUSIONS Telithromycin 800 mg administered once a day for 5 or 7 days was as effective and safe as clarithromycin 500 mg administered twice a day for 10 days in treating patients with CAP caused by common respiratory pathogens, including macrolide-resistant isolates, and pneumococcal bacteraemia.