Intravenous Days Research Articles

Acute Bacterial Skin and Skin Structure Infections: Advantages and Disadvantages of Early Discharge and Outpatient Parenteral Antibiotic Therapy

Acute bacterial skin and skin structure infections (ABSSSI) can require long periods of antibiotic therapy. If an ABSSSI is treated while a person is in hospital, this may lead to an extended hospital stay of days or even weeks, even if the patient is in a stable enough medical condition to be discharged to their home environment. As such, inpatient treatment of an ABSSSI can incur high costs for the hospital and tie up beds that could be used for other patients. Michael Wilke from Inspiring-health GmbH, Munich, Germany, and the Medical School Hamburg, Germany, discussed with the EMJ how early discharge may be viable for patients who are medically stable and can either return to the hospital for daily treatment with intravenous (IV) infusions or are able to, reliably, take oral antibiotics. Also available are the long-acting antibiotics oritavancin and dalbavancin. The latter is administered only once via IV infusion. While the cost per dose of dalbavancin is more expensive than most oral or daily/twice daily IV antibiotic regimens, its use can facilitate early discharge, leading to reduced hospital stays and offset cost savings. Due to the administration schedule, the use of long-acting antibiotics circumvents issues with daily medication adherence.

Direct Comparison of Chol-siRNA Polyplexes and Chol-DsiRNA Polyplexes Targeting STAT3 in a Syngeneic Murine Model of TNBC.

RNA interference (RNAi) molecules have tremendous potential for cancer therapy but are limited by insufficient potency after intravenous (IV) administration. We previously found that polymer complexes (polyplexes) formed between 3′-cholesterol-modified siRNA (Chol-siRNA) or DsiRNA (Chol-DsiRNA) and the cationic diblock copolymer PLL[30]-PEG[5K] greatly increase RNAi potency against stably expressed LUC mRNA in primary syngeneic murine breast tumors after daily IV dosing. Chol-DsiRNA polyplexes, however, maintain LUC mRNA suppression for ~48 h longer after the final dose than Chol-siRNA polyplexes, which suggests that they are the better candidate formulation. Here, we directly compared the activities of Chol-siRNA polyplexes and Chol-DsiRNA polyplexes in primary murine 4T1 breast tumors against STAT3, a therapeutically relevant target gene that is overexpressed in many solid tumors, including breast cancer. We found that Chol-siSTAT3 polyplexes suppressed STAT3 mRNA in 4T1 tumors with similar potency (half-maximal ED50 0.3 mg/kg) and kinetics (over 96 h) as Chol-DsiSTAT3 polyplexes, but with slightly lower activity against total Stat3 protein (29% vs. 42% suppression) and tumor growth (11.5% vs. 8.6% rate-based T/C ratio) after repeated IV administration of equimolar, tumor-saturating doses every other day. Thus, both Chol-siRNA polyplexes and Chol-DsiRNA polyplexes may be suitable clinical candidates for the RNAi therapy of breast cancer and other solid tumors.

1577. Particle Characterization of Nebulized Liposomal Amphotericin B and Its Use in the Treatment of Murine Pulmonary Aspergillosis

BackgroundImmunocompromised patients are very susceptible to pulmonary aspergillosis causing 50% mortality with present treatments, indicating a need for improved therapy. To address this, we standardized a nebulization method for effectively delivering liposomal amphotericin B (AmBisome®, AmBi) into lungs of Aspergillus fumigatus-infected mice.MethodsAmBi particle characterization was done with a Cascade particle impactor and a Schuco S5000 nebulizer containing 1.33 mg/mL AmBi. For in vivo studies, AmBi was nebulized (neb) into a 12 compartment chamber (one mouse/compartment), following immunosuppression with 28 mg/kg triamcinolone IP (d-3, -1, +1). Mice were challenged d0 with 9 x 106A. fumigatus (ATCC#13073) and 4 hours post-challenge, divided into 5 groups (n = 12/gp): 5 days of 20 min/day neb AmBi (Gp1), 5 days of 10 min/day neb AmBi (Gp2), 20 min/day neb AmBi days 0, 1, 3, 5, 7 (Gp 3), 5 days of intravenous(IV) AmBi 7.5 mg/kg/day (Gp4) and IV PBS (Gp5). Seven mice/gp were monitored for survival to d21 and lungs, livers, kidneys, spleens (5 mice/gp) analyzed for mean amphotericin B µg/g and CFU/g.Results87% of neb AmBi particles were between 0.43 mm to 3.3 mm allowing for drug penetration into 1°, 2° and terminal bronchi, bronchioles, and alveoli. This resulted in very good protection, with 20 min daily neb treatments (Gp1) giving 100% survival and 10 min daily neb treatments producing 71% survival (Gp2). There were no survivors in the PBS gp (P < 0.02 vs. Gp1 and Gp2). Every other day neb AmBi or daily IV AmBi was less effective (43% survival). In addition, neb AmBi for 20 min (Gp1) yielded significantly lower fungal burden in lungs vs. all other AmBi treatments (P < 0.02). While drug was detected in lungs of mice given 20 min of neb AmBi (2.6 µg/g), there was no drug detected in livers, kidneys or spleens of any mice given neb AmBi. In comparison, with IV AmBi, drug was detected in the lungs (7 µg/g), livers (204 µg/g), kidneys (38 µg/g), and spleens (114 µg/g).ConclusionDaily AmBi nebulization was an effective and potentially less nephrotoxic treatment for murine pulmonary aspergillosis since it achieved significantly lower tissue fungal burden and much better survival vs. daily IV AmBi, without delivering drug to the kidneys.Disclosures All authors: No reported disclosures.

Abstract P3045: The ELP-VEGF Fusion Protein Is Bioavailable After Subcutaneous Administration And Prevents Increased Blood Pressure In Response To Placental Ischemia

Preeclampsia is often characterized by high circulating levels of sFlt-1 and low VEGF and PlGF. VEGF supplementation therapy has shown promise in preclinical models, however rapid plasma clearance hampers the use of VEGF as a therapeutic. We fused human VEGF-A 121 with the Elastin-like Polypeptide (ELP) protein carrier. The objective of this study was to test the pharmacokinetics and therapeutic efficacy of ELP-VEGF when given via intravenous (IV) and subcutaneous (SC) administration routes.Fluorescently labeled ELP-VEGF was administered via daily IV (5 mg/kg/day) or SC injection (50 mg/kg/day). Plasma levels were determined by direct fluorescence measurement, and whole-body fluorescence imaging was used to determine total tissue clearance rates. The ability of SC delivered ELP-VEGF to modulate blood pressure was tested in a rat model of placental ischemia.When administered via IV injection, ELP-VEGF cleared from the plasma with an average daily half-life of 2.17±1.14 h. SC injected ELP-VEGF was absorbed into the blood and peaked within 2 hours of each injection. Tissue levels peaked 2h after each injection and remained elevated prior to the next injection, resulting in accumulation and high whole-body bioavailability. In pregnant rats, placental ischemia induced an increase in mean arterial pressure (108 ±11 vs. 122±13 mmHg, p=0.024). Daily SC injection of ELP-VEGF (50 mg/kg/day) completely prevented placental ischemia-induced increases in blood pressure (107±11 vs. 109±9 mmHg, p=ns). These results demonstrate that ELP-VEGF is bioavailable via clinically relevant administration routes and is a promising candidate agent for preeclampsia therapy.

Phlebitis after Parenteral Iron Sucrose Administration in Postpartum Women

Introduction: Multiple studies in industrialized countries indicate that postpartum anemia affects 20-50% of patients immediately after delivery (Barroso F et al Eur J Obstet Gynecol Reprod Biol 2011; Bergmann RL et al Eur J Obstet Gynecol Reprod Biol 2010; Urquizu IBX et al Med Clin (Barc) 2016). A growing body of literature suggests that intravenous (IV) iron improves time to anemia recovery in postpartum patients (Breymann C et al. Int J Gynaecol Obstet. 2008; Seid MH et al, Am J Obstet Gynecol 2008). We therefore developed recommendations for the use of IV iron on our Labor and Delivery (L&D) service to treat postpartum anemia. Three months after initiation of the IV iron recommendations, we performed an audit to assess its use.Methods: The UCSF pharmacy identified medical record numbers for obstetrical patients given IV iron sucrose 5/1/17 - 10/31/17, which spans 3 months pre-release of the IV iron protocol through the first 3 months after protocol release. Seventy-one patients were identified and their charts were individually reviewed to determine the dose and number of IV iron infusions received, interval between infusions when more than one infusion was given, the IV location for each infusion, and whether phlebitis was reported. Phlebitis was considered to have occurred if a physician or nursing note indicated that the patient had pain, swelling or erythema in an arm correlating to documented site of IV iron infusion. This study was conducted under UCSF Institutional Review Board approval number 17-22831.Results: Patients received 100 mg, 200 mg, or 300 mg of iron sucrose per infusion. Each infusion was administered over 30-90 minutes and patients received 1, 2, or 3 IV iron infusions. Venofer® is the only IV iron sucrose product received by patients in this study. The overall incidence of phlebitis was 9.9% (7 of 71 patients), higher than expected based on the previously published safety data and the published experience using IV iron sucrose in the postpartum setting (Breymann C et al. Eur J Clin Invest. 2000; Westad S et al. Acta Obstet Gynecol Scand. 2008). In addition, we found an increase in phlebitis incidence with increasing number of IV infusions: phlebitis was seen in 2 of 18 (11%) patients who received 2 iron infusions on consecutive days via a single IV site, while patients who received 300 mg iron sucrose on 3 consecutive days (5 out of 16 patients; Table 1) had a 31% incidence of phlebitis. Importantly, the phlebitis incidence was 50% for the 10 patients who received 3 infusions of 300 mg iron sucrose at a single IV site. Interestingly, in 6 patients who received 3 infusions of 300 mg iron sucrose on 3 consecutive days but had their peripheral IV re-sited between infusions, none developed phlebitis. No phlebitis was reported in 37 patients who received a single infusion of iron sucrose (100 - 300 mg dose range). Of the 7 phlebitis cases, 3 patients were readmitted to the hospital for evaluation and treatment. Three patients returned to our OB clinic or to L&D Triage for evaluation. One patient communicated her symptoms by telephone encounter.Discussion. IV iron safety analyses have historically focused on dose limitations and the risk for infusion reaction and anaphylaxis. We identified an increasing incidence of post-infusion phlebitis with increasing number of infusions of daily iron sucrose in patients admitted to our L&D service, an adverse event not previously highlighted in published safety literature for iron sucrose. We found the phlebitis events to be clinically significant for the patient, and to result in increased healthcare utilization post-infusion. It is our opinion that this adverse effect deserves attention because of the patient discomfort, inconvenience, and increased healthcare resource utilization. Physicians treating patients for iron-deficiency anemia, including hospitalists, hematologist, and OB-Gyn providers, should be aware of post-infusion phlebitis as a possible complication of iron sucrose therapy. Based on our findings, we recommend against daily IV iron sucrose infusions through a single peripheral venous access site. In addition, other formulations that allow for complete iron replacement in a single infusion session offer a convenience advantage to doctor and patient and may minimize the risk of phlebitis we observed with serial daily iron infusions. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Phase 1 Trial of Inotuzumab in Combination with CVP (Cyclophosphamide, Vincristine, Prednisone) for Relapsed/ Refractory CD22+ Acute Leukemia (SWOG 1312)

The prognosis of patients (pts) with relapsed/ refractory acute lymphoblastic leukemia (ALL) remains poor and novel therapies are needed. The anti-CD22 immunoconjugate inotuzumab ozogamicin (INO) has demonstrated promising results in both phase 2 and 3 trials (Kantarjian et al. Lancet Oncology 2012; 13(4): 403-11). Pre-clinical studies have demonstrated superior anti-tumor activity when INO is co-administered with cyclophosphamide (C), vincristine (V), and prednisone (P). In this study, SWOG 1312, we assess the safety of INO in combination with CVP and determine the maximum tolerated dose (MTD) of INO in this regimen for patients with relapsed or refractory (R/R) CD22+ acute leukemia (B-ALL, mixed phenotype, and Burkitts). Here, we present our toxicity results.Methods: Pts were treated at limited SWOG institutions from Apr 2014 to present. INO was supplied by Pfizer and an IND was approved by the FDA. The protocol was reviewed and approved by each institutional review board. Eligibility criteria included: age > 18 years (yrs), > 20% blasts expressing CD22, R/R CD22+ acute leukemia (B-ALL, mixed phenotype, or Burkitts), and adequate organ function. All pts received treatment with C (750 mg/m2) intravenous (IV) Day 1, V (1.4 mg/m2) (max 2 mg) IV Day 1, P (100 mg) orally Days 1-5 and IO (dose escalated as in Table 1) IV Days 1, 8, and 15. Each cycle was 28 days, and a maximum of 6 cycles could be administered. Dose escalation was performed using a standard 3x3 design; with the plan to treat 12 pts once the MTD was defined. Dose limiting toxicities (DLTs) were considered: (1) > Grade 4 non-hematologic toxicities with the exception of nausea, vomiting and toxicities secondary to neutropenia and sepsis; (2) prolonged myelosuppression [absolute neutrophil count (ANC) < 500/ uL or platelet count < 25,000/uL] in a bone marrow with < 5% blasts and no evidence of leukemia that lasts > 35 days beyond the most recent dose of IO; (3) any grade 3 non-hematologic toxicity (excluding peripheral neuropathy, hyperglycemia, and toxicities secondary to neutropenia, thrombocytopenia, and sepsis) that does not resolve to Grade 2 or better by 7 days beyond the most recent dose of IO; (4) any > Grade 3 elevation in SGOT/ SGPT or bilirubin lasting ≥ 7 days; (5) any IO-related toxicity resulting in permanent discontinuation of IO.Results: As of 7/14/2016, 24 pts have been enrolled: 2 pts were ineligible and 3 pts are currently receiving treatment and are not evaluable for toxicity. Of the 19 evaluable pts, the median age was 49 yrs (range 21-75), 10 (53%) were male, and the median WBC at registration was 9.4 K/uL (range 0.9-59.6). All pts had B-ALL. The median time from initial diagnosis to registration was 774 days. Five pts were in 1st relapse, 8 in 2nd relapse, 3 in 3rd relapse, 1 in 4th relapse, and 2 pts were primary refractory. Five pts had received prior allogeneic hematopoietic stem cell transplant (AHSCT); 7 pts had poor risk cytogenetics (Ph+, -7, +8, complex, or hypodiploid). One death occurred during treatment and was attributed to pneumonia. Grade 3-4 hematologic toxicity related to treatment was common: neutropenia (11 pts), thrombocytopenia (7 pts), and anemia (6 pts). Grade 3-4 non-hematologic toxicities were almost exclusively febrile neutropenia. One DLT occurred at Dose Level 3: prolonged myelosuppression. No cases of hepatic veno-occlusive disease (VOD) occurred during treatment, and 1 pt experienced Grade 3 alkaline phosphatase at Dose Level 1. Three pts proceeded to AHSCT after study treatment; 1 pt developed VOD post AHSCT however, this fully resolved. Currently, 3 pts have been enrolled to Dose Level 4.Conclusion: The combination of CVP/IO is well tolerated and only 1 significant hepatic event (which subsequently resolved) was observed despite a heavily pre-treated group of patients. Further toxicity results and dose escalation will be presented at the meeting. Response data will also be presented if enrollment is complete. [Display omitted] DisclosuresAdvani:Pfizer: Consultancy, Research Funding. Othus:Glycomimetics: Consultancy; Celgene: Consultancy. Erba:Pfizer: Consultancy; Juno: Research Funding; Gylcomimetics: Other: DSMB; Agios: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Astellas: Research Funding; Agios: Research Funding; Juno: Research Funding; Daiichi Sankyo: Consultancy; Celator: Research Funding; Gylcomimetics: Other: DSMB; Pfizer: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Sunesis: Consultancy; Seattle Genetics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Ariad: Consultancy; Novartis: Consultancy, Speakers Bureau; Celator: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Pfizer: Consultancy; Celgene: Consultancy, Speakers Bureau; Jannsen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Gylcomimetics: Other: DSMB; Pfizer: Consultancy; Sunesis: Consultancy; Ariad: Consultancy; Celator: Research Funding; Jannsen: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Ariad: Consultancy; Astellas: Research Funding; Astellas: Research Funding; Celator: Research Funding; Agios: Research Funding; Agios: Research Funding; Juno: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Juno: Research Funding; Gylcomimetics: Other: DSMB; Astellas: Research Funding; Jannsen: Consultancy, Research Funding; Ariad: Consultancy.

A Phase II Study of Dasatinib and Dexamethasone As Primary Therapy Followed By Hematopoietic Cell Transplantation for Adults with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: CALGB Study 10701 (Alliance)

Background:Potent inhibitors of BCR-ABL1have improved remission results and altered post-remission therapy for Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Dasatinib plus dexamethasone followed by hematopoietic cell transplantation (HCT) promises high response rates, reduced toxicity, and durable remissions.Methods:We conducted a Phase II trial at 17 U.S. centers with the primary objective being to estimate the 3-year overall survival and disease-free survival of patients with Ph+ ALL treated with dasatinib and dexamethasone for remission induction and intensification, central nervous system (CNS) prophylaxis, consolidation with reduced-intensity conditioning (RIC) allogeneic HCT, autologous HCT, or etoposide and cytarabine, and dasatinib-based maintenance. Eligible patients had untreated Ph+ ALL, were ≥18 years old, and had normal cardiac function. Induction (Course I) used dasatinib 140 mg oral daily and dexamethasone 10 mg/m2/day oral or intravenous (IV) days 1-7. For patients with ≤20% blasts in the Course I, Day 15 bone marrow biopsy, intensification (course II) continued daily dasatinib with another 7 days of dexamethasone. Those with >20% lymphoblasts also received vincristine (VCR) and daunorubicin (DNR). Patients (n=3) not in CR/CRi after Course II received a second induction (Course III) with dasatinib, cyclophosphamide, VCR, DNR, and dexamethasone. After Course II or III, CNS prophylaxis (Course IV) consisted of IV VCR and IV, oral, and intrathecal methotrexate (MTX). Dasatinib was restarted at serum [MTX] <0.05 microM. Course V consisted of HCT or chemotherapy. Patients aged 18-70 years with an HLA-matched donor underwent RIC allogeneic HCT; otherwise they underwent autologous HCT. Allogeneic HCT conditioning used fludarabine 30 mg/m2/day IV day -7 through -3, alemtuzumab 20 mg/day IV day -7 through -3, and melphalan 140 mg/m2 once on day -2. GVHD prophylaxis with tacrolimus began day -2. Patients undergoing autologous HCT received etoposide 10 mg/kg/day (age >65 years, 5 mg/kg/day) continuous IV for 4 days and cytarabine 2 g/m2 (age >65 years, 1 g/m2) IV every 12 hours for 8 doses (EA) then G-CSF for mobilization. Autologous HCT conditioning used melphalan 100 mg/m2/day on days -2 and -1. Patients >70 years or unable to undergo HCT received EA alone. Dasatinib maintenance (Course VI) began on day 30 of Course V and continued for 12 months and until 2 consecutively negative bone marrow BCR-ABL1RT-PCR assays 3 months apart or until relapse. Dasatinib levels were measured on day 15 of induction.Results:Sixty-six patients enrolled from 12/15/2010 to 11/14/2014; 65 received dasatinib and are evaluable. Median age was 60 years (22-87); 49% were male. Median presenting WBC count was 23.1 x 103/ul (0.3-453.6). No deaths occurred during induction or intensification. CR or CRi occurred 31 patients (48%) by Day 15 of induction and in 62 patients overall (95%; CR 86%). Median dasatinib levels in serum and CSF on Day 15 of induction were 30.3 ng/mL (<3-308) and 0.29 ng/mL (<0.2-1.37), respectively suggesting approximately 1% of plasma dasatinib penetrates into the CSF, less than the unbound fraction (6%). Fifty-four patients started Course IV, 38 Course V, and 37 Course VI. Fourteen patients continue on protocol therapy. Of 38 patients receiving Course V, 22 had allogeneic HCT, 6 had autologous HCT, and 10 had EA chemotherapy. Median age of allogeneic HCT recipients was 61 years (31-69). Robust autologous stem cell mobilization was observed [median CD34+ cell count, 90 x 106/kg (31-166, n=6)]. Dasatinib maintenance was feasible after allogeneic HCT, autologous HCT, and chemotherapy alone with no missed doses in 59%, 83%, and 63% of cycles, respectively. Ten patients have relapsed with one isolated CNS relapse. No relapses have occurred after allogeneic HCT with 3 relapses after autologous HCT and one after Course V EA alone. Median follow up for survivors is 22.8 months (longest, 51 months). There have been 23 deaths: 5 treatment-related (4 after allogeneic HCT, 1 after course V EA), 16 disease-related and 2 unrelated.Conclusions:Dasatinib with dexamethasone yields CR rates comparable to those reported with tyrosine kinase inhibitors combined with conventional chemotherapy. Post-remission therapy with reduced-intensity allogeneic HCT, autologous HCT, or chemotherapy followed by dasatinib maintenance is feasible. Survival follow up is maturing. DisclosuresStock:Sigma-Tau: Honoraria, Research Funding; Royalties for a chapter in Up to Date: Patents & Royalties; ADC Therapeutics: Honoraria; Amgen: Honoraria; Gilead Sciences: Honoraria. Beumer:Bristol-Myers Squibb: Research Funding. Stone:Abbvie: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Consultancy; Juno Therapeutics: Consultancy; Karyopharm: Consultancy; Sunesis Pharmaceuticals: Consultancy; Agios: Consultancy; Amgen: Consultancy; Celator: Consultancy; Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy; Jansen: Consultancy; Merck: Consultancy; ONO: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Xenetic Biosciences: Consultancy. Larson:Bristol-Myers Squibb: Consultancy; Astellas: Consultancy, Research Funding.

Reinforcing effectiveness of nicotine in nonhuman primates: effects of nicotine dose and history of nicotine self-administration.

Despite the high prevalence of nicotine use in humans, robust nicotine self-administration has been difficult to demonstrate in laboratory animals. A parametric analysis of nicotine self-administration was conducted to study its reinforcing effects in nonhuman primates. Adult rhesus macaques (N = 6) self-administered intravenous (IV) nicotine (0.001-0.1mg/kg) under a fixed-ratio (FR)1 schedule of reinforcement during daily 90-min sessions. Next, the demand function relating drug intake and response cost was determined by increasing the FR across sessions during the availability of each of several unit doses of nicotine (0.0032-0.032mg/kg/inj). The reinforcing effects of 0.01mg/kg/inj cocaine and 1g banana-flavored food pellets were also determined under similar testing conditions. Finally, the nicotine demand function was re-determined after approximately 8months of daily IV nicotine self-administration. IV nicotine self-administration followed an inverted U-shaped pattern, with the peak number of injections maintained by 0.0032mg/kg/inj. Self-administration of each reinforcer (food pellets, IV cocaine, and IV nicotine) decreased as FR size increased. Application of the exponential model of demand showed that demand elasticity for nicotine was (1) dose-dependent and lowest for 0.0032mg/kg/inj; (2) for 0.0032 mg/kg/inj,similar to that of food pellets and significantly higher than cocaine; and (3) decreased after 8months of daily nicotine self-administration. These data show that, though high levels of nicotine self-administration can be achieved under simple FR schedules in nonhuman primates, its reinforcing effectiveness is dose-related but limited and may increase over time.

WS14.4 Does exercise participation affect FEV1 and the number of IV antibiotic days over 5 years in adults with CF?

Objectives Exercise participation is important in the treatment of people with CF (PWCF) and is part of the Association of Chartered Physiotherapists in CF, Standards of Care 2011. The importance of exercise is widely recognised in health and disease. Not all PWCF are able to include exercise in their treatment regime due to lifestyle, personal choice or other factors. In this pilot study we aim to determine the impact of exercise on FEV 1 over time and the number of intravenous (IV) antibiotic days, for a sample of the Wessex CF service. Methods Data was retrospectively taken from the notes of 24 PWCF over a 5 year period. 12 were people identified as regularly taking part in moderate–intense exercise (group 1) compared to 12 patients who do not (group 2). Best FEV 1 was recorded for 2010 and 2014 along with number of IV days. Results The characteristics of the groups were similar [male/female 8/4 vs 8/4; mean age 30.83 (SD 6.13) and 30.33 (SD 8.51); mean lung function 3.05 L (SD 1.05) and 2.5 L (SD 1.14) respectively]. There was no difference in change in FEV1 from 2010 to 2014 between the two groups ( p = 0.74). However there was a difference between the days of IV's required each year to maintain this between the groups [mean 109 days/year (SD 72.49) as opposed to 238.6 (SD 119.71), p = 0.007]. Conclusion There was a small but insignificant decline in FEV 1 in both groups over 5 years. However, considerably more days of IV antibiotics were required to achieve this in those who exercised less often. Further study is required to analyse these findings in more detail due to the limitations of this initial design.

Extensive hidradenitis suppurativa (HS) Hurly stage III disease treated with intravenous (IV) linezolid and meropenem with rapid remission

A 57-year-old woman with Hurley Stage 3 hidradenitis suppurativa (HS) and multiple co-morbidities is presented. She had failed multiple antibiotic therapies and etanercept. She had end stage renal disease and was on dialysis. Her HS was put into remission with one month of daily IV treatment with 1.2 grams linezolid and 1 gram of meropenem, administered daily through her dialysis shunt. Unfortunately, her disease flared again two weeks after the cessation of the IV treatment. Nevertheless, more conventional therapy was then able to maintain her disease at a level that was significantly improved over baseline prior to the IV treatment. This case highlights above all a primary etiology of HS is stimulus of immune system's over-reaction in HS to the bacterial microbiome. If antibiotics are administered to a patient with stage 3 HS powerful enough to wipe out the bacterial biome, the immune system having no target retreats, permanent scarring in its wake and retreats to a certain but hardly permanent normalcy.

Sustained neuroprotection from a single intravitreal injection of PGJ₂ in a nonhuman primate model of nonarteritic anterior ischemic optic neuropathy.

Prostaglandin J₂ (PGJ₂) is neuroprotective in a murine model of nonarteritic anterior ischemic optic neuropathy (NAION). After assessing for potential toxicity, we evaluated the efficacy of a single intravitreal (IVT) injection of PGJ₂ in a nonhuman primate model of NAION (pNAION). We assessed PGJ₂ toxicity by administering it as a single high-dose intravenous (IV) injection, consecutive daily high-dose IV injections, or a single IVT injection in one eye of five adult rhesus monkeys. To assess efficacy, we induced pNAION in one eye of five adult male rhesus monkeys using a laser-activated rose bengal induction method. We then injected the eye with either PGJ₂ or phosphate-buffered saline (PBS) intravitreally immediately or 5 hours post induction. We performed a clinical assessment, optical coherence tomography, electrophysiological testing, fundus photography, and fluorescein angiography in all animals prior to induction and at 1 day, 1 week, 2 weeks, and 4 weeks after induction. Following analysis of the first eye, we induced pNAION in the contralateral eye and then injected either PGJ₂ or PBS. We euthanized all animals 5 weeks after final assessment of the fellow eye and performed both immunohistochemical and light and electron microscopic analyses of the retina and optic nerves. PGJ₂ caused no permanent systemic toxicity regardless of the amount injected or route of delivery, and there was no evidence of any ocular toxicity with the dose of PGJ₂ used in efficacy studies. Transient reduction in the amplitudes of the visual evoked potentials and the N95 component of the pattern electroretinogram (PERG) occurred after both IV and IVT administration of high doses of PGJ₂; however, the amplitudes returned to normal in all animals within 1 week. In all eyes, a single IVT dose of PGJ₂ administered immediately or shortly after induction of pNAION resulted in a significant reduction of clinical, electrophysiological, and histological damage compared with vehicle-injected eyes (P = 0.03 for both VEP and PERG; P = 0.05 for axon counts). In nonhuman primates, PGJ₂ administered either intravenously or intravitreally produces no permanent toxicity at even four times the dose given for neuroprotection. Additionally, a single IVT dose of PGJ₂ is neuroprotective when administered up to 5 hours after induction of pNAION.

Post-Transplantation Cyclophosphamide Following Busulfan and Fludarabine Myeloablative Conditioning Prevents Severe Acute and Chronic Graft-Versus-Host Disease and Minimizes Duration Of Immunosuppression: Results Of a Multi-Institutional Trial In Patients With High-Risk Hematologic Malignancies

IntroductionAllogeneic blood or marrow transplantation (alloBMT) involves a multi-faceted platform with each component having significant implications for the overall success of the transplant. However, the optimal transplantation platform is unknown. We combined two promising approaches, intravenous (IV) busulfan (Bu)/fludarabine (Flu) myeloablative conditioning and high-dose, post-transplantation cyclophosphamide (PTCy) graft-versus-host disease (GVHD) prophylaxis, in a multi-institutional trial for patients receiving HLA-matched related or unrelated bone marrow allografts. We hypothesized that this transplantation platform could prevent severe acute and chronic GVHD, while shortening the duration of post-grafting immunosuppression, having low treatment-related toxicity, and providing effective disease control. MethodsBusulfan was given in daily IV doses which were adjusted based on measured pharmacokinetics. Fludarabine was given at 40 mg/m2/day. PTCy (50 mg/kg/day in IV daily dosing) was administered as sole GVHD prophylaxis on days +3 and +4 after infusion of unmanipulated bone marrow. Forty-five (49%) patients received HLA-matched related allografts, while 47 (51%) received HLA-matched unrelated allografts. Seventy-three (79%) patients were transplanted for myeloid diseases, including 53 (58%) with acute myelogenous leukemia and 13 (14%) with myelodysplastic syndrome. Fifteen (16%) patients had acute lymphocytic leukemia. Sixty-seven (73%) patients were in morphologic complete remission (CR) at the time of alloBMT, and the remaining twenty-five (27%) patients had active disease. Eighteen (20%) patients had evidence of minimal residual disease. Twenty-five (27%) patients were males who received allografts from females. The primary endpoint of the study was the cumulative incidence of grade III-IV acute GVHD. Pre-defined secondary endpoints included chronic GVHD, non-relapse mortality, event-free and overall survival, and use and duration of systemic immunosuppressants beyond the originally planned two days of PTCy. GVHD was scored centrally by an independent reviewer. ResultsThe median follow-up was 595 days (1.6 years) for all patients and 794 days (2.2 years) for patients who were alive at last follow-up. The cumulative incidence (CI) of grade II-IV and III-IV acute GVHD were 51% and 15%, respectively, at two years. The CI of chronic GVHD was 14% at two years. Thirty-five percent of all patients and 39% of patients alive at last follow-up never required immunosuppression for any reason beyond day +4 post-transplant. Corticosteroid use occurred in 61% of all patients and 60% of patients alive at last follow-up. A median 98 days (range 10-1221) elapsed from first initiation to final cessation of corticosteroids. Immunosuppression beyond corticosteroids was used for 50% of all patients and 52% of patients alive at last follow-up. A median 167.5 days (range 1-1156) elapsed from first initiation to final cessation of secondary immunosuppression. A calcineurin inhibitor was required for any reason in 45% of patients. Only 16% of patients required additional immunosuppression beyond corticosteroids and/or a second systemic immunosuppressant. Seventy-two percent of patients alive at last follow-up were off all immunosuppression at one year.Non-relapse mortality was 9% and 16% at 100 days and one year, respectively. Event-free survival and overall survival were 62% and 67% at two years and were 80% and 79% at two years for patients in CR without MRD at the time of alloBMT. Multivariate Bayesian analysis showed that having an unrelated donor, being in CR without MRD, and having a higher nucleated cell count all had beneficial effects on EFS. ConclusionMyeloablative IV Bu/Flu conditioning followed by single-agent GVHD prophylaxis with PTCy results in low rates of severe acute and chronic GVHD and effective disease control for patients with high-risk hematologic malignancies undergoing HLA-matched alloBMT even from unrelated donors. Moreover, the use of post-grafting immunosuppression beyond day +4 was not required in a significant subset of patients and was rapidly tapered in others. This study confirms the efficacy of PTCy after myeloablative conditioning and provides further support for future randomized studies comparing PTCy against other GVHD prophylactic approaches. Disclosures:Off Label Use: post-transplantation cyclophosphamide as graft-versus-host disease prophylaxis. Luznik:Otsuka Pharmaceutical: Research Funding.

Pharmacokinetics, pharmacodynamics and metabolism of a novel anticancer agent for prostate cancer

The objective of these studies was to examine the murine pharmacokinetics, pharmacodynamics and metabolism of (3-(1H-indol-2-yl)phenyl)(1H-indol-2-yl)methanone (Indole 15), a novel tubulin inhibitor for the treatment of cancer. We developed HPLC and LC/MS/MS assays to quantitate Indole 15 and characterize its metabolites in vivo. Pharmacokinetic studies were performed after intravenous (IV), oral (PO) and subcutaneous (SC) administration of 10 mg/kg doses to male ICR mice. Urine and fecal samples were also collected over a 72-h period to identify metabolites. Pharmacodynamic studies were conducted by monitoring the tumor size change during a period of two weeks in PC-3 tumor bearing mice after daily IV administration of Indole 15 at doses of 0, 10, 50, 100 and 150 mg/kg. The pooled plasma concentration data after administration via different dose routes was simultaneously fitted by a two-compartmental model. Indole 15 was moderately well absorbed after PO and SC administration, with a bioavailable fraction of 0.27 and 0.72, respectively. The steady state volume distribution (Vss) and clearance (CL) were estimated to be 7.0 l/kg and 4.36 l/h/kg, respectively. The mean data of PC-3 tumor growth in mice was fitted well by a transduction model using fixed plasma pharmacokinetics as a driving function. Analysis of the metabolites in mice indicated that the compound undergoes extensive oxidative metabolism with subsequent sulfation. These studies demonstrate that favorable pharmacokinetic and pharmacodynamic properties of Indole 15 offer hope for achieving pharmacological activity in early clinical trials.

Development of a Population Pharmacokinetics‐Based Sampling Schedule to Target Daily Intravenous Busulfan for Outpatient Clinic Administration

Therapeutic drug monitoring of daily intravenous (IV) busulfan currently requires hospital admission. Population pharmacokinetic modeling and determination of an optimal pharmacokinetic sampling schedule over 6 hours could allow for personalizing these busulfan doses in the outpatient clinic. A retrospective evaluation of daily IV busulfan pharmacokinetics was conducted in 37 adults. SPK and NONMEM software were used to estimate the population pharmacokinetic parameters. Subsequent to model building, the area under the concentration-time curve (AUC) was computed using NONMEM. A 1-compartment model best fit the data. The optimal 6-hour outpatient sampling schedule was constructed using a simulation approach that sought to minimize scaled mean squared error for the clearance and volume parameters for each simulated individual. The best sampling times were 2.75, 3, 3.25, 5.5, 5.75, and 6 hours from the start of a 3-hour infusion. With these sampling times, the maximum a posteriori (MAP) Bayesian estimation was superior to maximum likelihood estimation with more samples. An individual patient's busulfan AUC and pharmacokinetic parameters may be accurately estimated with an outpatient sampling schedule that is used in conjunction with MAP Bayesian estimation, with a parameter prior based on population pharmacokinetic modeling. Prospective validation of this approach is needed.

Abstract 4776: Prophylactic Intravenous Magnesium Sulphate in Addition to Oral Beta Blockade does not Prevent Atrial Arrhythmias after Cardiac Surgery

Background Atrial arrhythmias (AA) affect up to 40% of patients following cardiac surgery. The best strategy for prevention of AA remains undetermined, however, beta blocker (BB) administration is the standard of care at many centers (including ours). Although there is now compelling evidence demonstrating the utility of magnesium sulphate (MgSO4) for treatment of AA, the effectiveness of MgSO4 for prophylaxis of AA remains controversial. This study is the largest randomized, placebo-controlled trial of intravenous (IV) MgSO4 for the prevention of AA following cardiac surgery. Methods Eligible patients requiring either coronary artery bypass graft surgery (CABG), or valve surgery ± CABG, were randomized to receive either 5g IV MgSO4, or placebo upon removal of the crossclamp, followed by daily infusions of IV MgSO4 or placebo over 4 hours, from the day of surgery until post-operative day 4. All patients were treated according to an established protocol with oral BB (atenolol). Patients were monitored by continuous telemetry for the first 5 post-operative days. The primary endpoint was an AA lasting ≥ 30 minutes, or requiring treatment because of hemodynamic compromise. Results Table 1 summarizes the results. There was no difference in the incidence of AA between patients who received IV MgSO4 or those who received placebo. Conclusions In patients proactively treated with atenolol using an established protocol, the addition of daily IV MgSO4 infusions for 5 days post-operatively did not reduce the incidence of clinically important AA following cardiac surgery. Results For Primary Outcome (Post-Operative AA)

Phase I study of oxaliplatin (Ox), irinotecan (Irino), and capecitabine (Cape) in patients with solid tumors

2111 Background: The combination of Ox, Irino and Cape has high potential for activity in gastrointestinal malignancies. Methods: Patients (pts) had solid tumors not amenable to curative therapy. Treatment: Ox intravenous (IV) days 1,8,15,22, followed by Irino IV days 1,8,15,22, and Cape orally bid Monday-Friday weeks1–4, repeated every 6 weeks. Primary endpoints: maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetic (PK) analysis. Response assessed q 2 cycles. Results: (see table) 22 pts enrolled: 13 males; median age 60, range 38–80; 11 colorectal cancer (ca); median 2 prior regimens. DLT at initial dose level 1A led to a protocol amendment lowering Cape dose. Peak SN38 concentrations of 10 ng/ml exceeded the IC50 doses reported for KB and L1210 tumor cells (0.37 and 3.6 ng/ml) (Kaneda, Cancer Res 1990). The mean peak ultrafilterable platinum was 0.75 +/- 0.17 μg/ml, exceeding the 0.5 μg/ml Ox concentration at which antitumor activity was observed against colon cancer using a hu...

Phase I Clinical Trial of Recombinant Human Endostatin Administered as a Short Intravenous Infusion Repeated Daily

To perform a phase I trial of recombinant human endostatin (rhEndostatin; EntreMed, Rockville, MD) given as a daily 20-minute intravenous (IV) injection in adult patients with refractory solid tumors. The daily dose was increased from 15 to 240 mg/m(2) by a factor of 100% in cohorts of three patients. In the absence of dose-limiting toxicity, uninterrupted treatment was continued until the tumor burden increased by more than 50% from baseline. Correlative studies included dynamic contrast-enhanced magnetic resonance imaging of tumor blood flow, urinary vascular endothelial growth factor and basic fibroblast growth factor levels, rhEndostatin serum pharmacokinetics, and monitoring of circulating antibodies to rhEndostatin. There were no notable treatment related toxicities among 15 patients receiving a total of 50 monthly cycles of rhEndostatin. One patient with a pancreatic neuroendocrine tumor had a minor response and two patients showed disease stabilization. Linearity in the pharmacokinetics of rhEndostatin was indicated by dose-proportionate increases in the area under the curve for the first dose and the peak serum concentration at steady state. Daily systemic exposure to rhEndostatin in patients receiving 240 mg/m(2)/d was approximately 50% lower than that provided by the therapeutically optimal dose in preclinical studies. rhEndostatin administered as a 20-minute daily IV injection at doses up to 240 mg/m(2) showed no significant toxicities. Evidence of clinical benefit was observed in three patients. Due to high variability between the peak and trough serum concentrations associated with the repeated short IV infusion schedule, daily serum drug levels only briefly exceeded concentrations necessary for in vitro antiangiogenic effects.

Pharmacokinetics of intravenous recombinant human granulocyte colony‐stimulating factor (rhG‐CSF) in children receiving myelosuppressive cancer chemotherapy: Clearance increases in relation to absolute neutrophil count with repeated dosing

Limited evidence suggests increased efficacy of rhG-CSF by subcutaneous (SQ) compared with intravenous (IV) administration. To examine the possibility that rapid elimination of IV rhG-CSF could substantially shorten the duration of systemic exposure and could explain a difference in pharmacodynamics, we characterized the pharmacokinetic profile of IV rhG-CSF for comparison to that previously reported for SQ administration. Twelve children were randomly assigned to receive 10 or more days of IV rhG-CSF at dosages of 5 or 10 μg/kg a day beginning 24 hr after chemotherapy. Enzyme-linked immunosorbent assay (ELISA) was used to measure rhG-CSF concentrations in timed serum samples on days 1 and 10. Pharmacokinetic parameters were estimated by nonlinear, least squares regression. All serum concentration-time profiles were best described by a two-compartment model of elimination. Mean t1/2β values ranged from 3.68 ± 0.86 to 22.4 ± 12.0 hr. ANC was correlated with log CLT (r = 0.72, P < 0.05), and inversely with log dose-adjusted AUC (r = −0.75, P < 0.05) and log dose-adjusted Cmax (r = −0.65, P < 0.05). Estimated duration of serum rhG-CSF concentrations above 1 ng/ml exceeded 24 hr for all but the 5 μg/kg cohort on day 1. Pharmacokinetic parameters of IV rhG-CSF are similar to those previously reported for SQ administration in children treated with myelosuppressive cancer chemotherapy. Daily IV administration should be suitable alternative route of administration in this patient population. Am. J. Hematol. 54:124–130, 1997 © 1997 Wiley-Liss, Inc.

Etoposide in Acute Nonlymphocytic Leukemia

Previously untreated patients with acute nonlymphocytic leukemia (ANLL) aged 15 to 70 years were randomized to either cytosine arabinoside 100 mg/m2/d continuous intravenous (IV) infusion days 1 through 7, daunorubicin 50 mg/m2/d IV days 1 through 3 (7-3), or the same drugs intensified with etoposide 75 mg/m2/d IV days 1 through 7 (7-3-7) as induction therapy. Patients achieving complete remission (CR) received two courses of consolidation therapy (5-2 or 5-2-5) followed by maintenance therapy. Of 264 eligible patients, CR occurred in 56% of 7-3 and 59% of 7-3-7 patients; 7-3-7 significantly improved remission duration (P = .01). The median remission duration was 12 months for 7-3 and 18 months for 7-3-7. Survival was similar when the two arms were compared overall. Subset analysis performed to identify patients with the most benefit showed that etoposide significantly prolonged remission duration in younger patients (less than 55 years) with a median of 12 months for 7-3 and 27 months for 7-3-7 (P = .01). Survival appeared to be prolonged with 7-3-7 in patients aged less than 55 years, with a median of 9 months for 7-3 as compared with 17 months for 7-3-7 (P = .03). In older patients (aged greater than or equal to 55 years), 7-3-7 was more toxic, with significantly more severe [World Health Organization (WHO) grade 3 or 4] stomatitis (P = .02) and no additional clinical benefit. Hematologic toxicity for induction courses was similar, with granulocytopenia less than 0.5 x 10(9)/L for a median of 16 days per course for 7-3 and 15 days for 7-3-7. Hematologic toxicity was more severe for 5-2-5 consolidation courses (P = .003). Induction and consolidation therapy intensified with etoposide resulted in significantly improved remission duration but not survival.

Etoposide in acute nonlymphocytic leukemia. Australian Leukemia Study Group

Previously untreated patients with acute nonlymphocytic leukemia (ANLL) aged 15 to 70 years were randomized to either cytosine arabinoside 100 mg/m2/d continuous intravenous (IV) infusion days 1 through 7, daunorubicin 50 mg/m2/d IV days 1 through 3 (7–3), or the same drugs intensified with etoposide 75 mg/m2/d IV days 1 through 7 (7–3–7) as induction therapy. Patients achieving complete remission (CR) received two courses of consolidation therapy (5–2 or 5–2–5) followed by maintenance therapy. Of 264 eligible patients, CR occurred in 56% of 7– 3 and 59% of 7–3–7 patients; 7–3–7 significantly improved remission duration (P = .01). The median remission duration was 12 months for 7–3 and 18 months for 7–3–7. Survival was similar when the two arms were compared overall. Subset analysis performed to identify patients with the most benefit showed that etoposide significantly prolonged remission duration in younger patients (less than 55 years) with a median of 12 months for 7–3 and 27 months for 7–3–7 (P = .01). Survival appeared to be prolonged with 7–3–7 in patients aged less than 55 years, with a median of 9 months for 7–3 as compared with 17 months for 7–3–7 (P = .03). In older patients (aged greater than or equal to 55 years), 7–3–7 was more toxic, with significantly more severe [World Health Organization (WHO) grade 3 or 4] stomatitis (P = .02) and no additional clinical benefit. Hematologic toxicity for induction courses was similar, with granulocytopenia less than 0.5 x 10(9)/L for a median of 16 days per course for 7–3 and 15 days for 7–3–7. Hematologic toxicity was more severe for 5–2–5 consolidation courses (P = .003). Induction and consolidation therapy intensified with etoposide resulted in significantly improved remission duration but not survival.