PPX Group Research Articles

Impacts of different pancreatic resection ranges on endocrine function in Suncus murinus.

Surgical intervention involving the pancreas can lead to impaired glucose tolerance and other types of endocrine dysfunction. The scope of pancreatectomy and whether it includes the ventral pancreas are the key factors in the development of postoperative diabetes. The ventral and dorsal pancreases are almost separated in Suncus murinus (S. murinus). To investigate the effects of different extents of pancreatic resection on endocrine function in S. murinus. Eight-week-old male S. murinus shrews were randomly divided into three experimental groups according to different pancreatic resection ranges as follows: ventral pancreatectomy (VPx) group; partial pancreatectomy (PPx) group; subtotal pancreatectomy (SPx) group; and a sham-operated group. Postprandial serum insulin, glucagon-like peptide-1 (GLP-1), pancreatic polypeptide (PP), and somatostatin (SST) levels, as well as food intake, weight, blood glucose, and glucose tolerance were regularly measured for each animal. S. murinus treated with PPx and SPx suffered from varying degrees of impaired glucose tolerance, but only a small proportion of the SPx group developed diabetes. Only S. murinus in the SPx group showed a significant decrease in food intake accompanied by severe weight loss, as well as a significant increase in postprandial serum GLP-1 levels. Postprandial serum PP levels decreased in both the VPx and PPx groups, but not in the SPx group. Postprandial serum SST levels decreased in both VPx and PPx groups, but the decrease was marginal. Severe weight loss after pancreatectomy may be related to loss of appetite caused by compensatory elevation of GLP-1. PP and GLP-1 may play a role in resisting blood glucose imbalance.

Pramipexole protects against diabetic neuropathy: Effect on oxidative stress, TLR4/IRAK-1/TRAF-6/NF-κB and downstream inflammatory mediators

BackgroundDiabetic neuropathy (DN) is a serious microvascular complication and a major cause of morbidity and mortality in diabetes mellitus. It is characterized by neurodegeneration of terminal sensory nerve fibers with subsequent pain, loss of sensation, and paresthesia, thus compromising the quality of life of diabetic patients. It is considered the leading cause of non-traumatic amputations worldwide, reflecting the insufficiency of current therapies. Pramipexole (PPX) is a dopamine receptor agonist used for the treatment of Parkinson's disease. The current study aims to investigate the potential neuroprotective effect of PPX in an experimental model of DN. MethodsSprague Dawley rats were randomly assigned into five groups: normal control, Normal + PPX (1 mg/kg) group, STZ control, STZ + PPX (0.25 and 1 mg/kg/day for eight weeks). The neuroprotective effect of PPX in rats was evaluated in terms of sciatic nerve histological alterations, oxidative stress, and protein expression of TLR4/MyD88/IRAK-1/TRAF-6/NF-κB axis and downstream inflammatory mediators. ResultsPPX administration ameliorated histopathological signs of neuronal inflammation and apoptosis. Additionally, PPX attenuated STZ-induced sciatic nerve oxidative stress and downregulated neural tissue expression of TLR4, MyD88, IRAK-1, TRAF-6, NF-κB and downstream mediators (TNF-α, IL-1β and ICAM-1). ConclusionCollectively, the current study sheds light on PPX as a potential protective medication to alleviate neuropathy progression in diabetic patients. PPX neuroprotective effect can be attributed to modulating TLR4/ MyD88/IRAK-1/TRAF-6/ NF-κB axis signaling in nerve tissues with subsequent attenuation of oxidative stress and inflammation.

Clinical Outcomes with Prophylactic Corticosteroid Use for Axicabtagene Ciloleucel (axi-cel) in Patients with Relapsed/Refractory Large B-Cell Lymphoma (R/R LBCL): A Multicenter Analysis

Introduction: In Cohorts 1+2 of the ZUMA-1 Phase 1/2 study of axi-cel in R/R LBCL, 11% and 31% of patients (pts) experienced Grade ≥3 cytokine release syndrome (CRS) or neurologic evenets), respectively. To minimize the toxicities seen with axi-cel, a safety management cohort, Cohort 6 (N=40), was added to evaluate whether prophylactic (ppx) corticosteroids (CS) could decrease grade ≥ 3 CRS or ICANS. The 2-year update of ZUMA-1 Cohort 6 showed no grade ≥3 CRS and 15% grade ≥3 ICANS without any difference in objective response rate (ORR) or complete response rate (CR) when compared to cohorts 1+2 (Oluwole Blood 2022). The FDA had previously approved an update to the prescribing information for axi-cel to include use of ppx CS across all approved indications in January 2022. However, ppx CS is not a mandatory standard treatment and we sought to establish the clinical outcomes in the real-world practice. Methods: To assess the clinical outcomes of pts receiving ppx CS, we conducted a multicenter retrospective analysis of pts with R/R LBCL who were treated with axi-cel since the FDA approval of ppx CS in January 2022. Baseline characteristics, toxicities, and efficacy were compared between the no ppx and ppx CS groups. CRS and ICANS were graded based on ASTCT 2019 guidelines. Event-free survival (EFS) was defined as time from axi-cel infusion to progression, re-treatment, or death. Overall survival (OS) was defined as time from axi-cel infusion to death due to any cause. Results: A total of 66 pts at 5 centers received axi-cel between Jan 31, 2022, and June 20, 2023. Thirty-five (52%) pts received ppx CS, with a median age of 63 years (26-85 years). By histology, 75% (n=50) of the pts had DLBCL, 13.6% (n=9) had high grade B-cell lymphoma (HGBL), 9.1% (n=6) had transformed follicular lymphoma (TFL) and 1.5% (n=1) primary mediastinal LBCL (PMBCL). 59% of the pts (n=37) had IPI >2 and 66% (n=43) had stage III/IV disease. The baseline characteristics at the time of apheresis are shown in Table 1 and were comparable between the 2 groups, except for more HGBL, fewer prior lines of therapy and longer median time from apheresis to axi-cel infusion in the ppx CS group. Among the entire cohort, only 37% (n=25) met ZUMA-1 eligibility criteria at the time of lymphodepletion, and 67% (n=44) needed bridging therapy. Any grade CRS occurred in 88% (n=58) of the pts, with grade ≥2 CRS in 38% (n=25). Any grade ICANS occurred in 55% (n=37) of the pts, with grade ≥2 ICANS in 41% (n=27). Any grade ICANS was significantly lower in the ppx CS group than the no ppx group (45.7% vs 65.5%). The rates of any grade CRS, grade ≥2 CRS, grade ≥2 ICANS, the median time to CRS onset, ICANS onset, CRS duration, and ICANS duration were comparable between the 2 groups. Tocilizumab and steroids use was similar between two groups with a trend towards less ICU admission in patients in the ppx CS group. Overall, 14 (21%) pts developed infectious complications within 30 days of axi-cel infusion. The day 30 ORR was 84% and was comparable between the 2 groups (77% in the ppx group vs 93% in the no ppx group). The CR was 45.7% in ppx CS group compared to 65.5% in no ppx group. At a median follow up of 219 days (27-1178), 37 (56.1%) pts had progressed and 25 (37.9%) pts had died. The number of days to progress was significantly lower in the ppx CS arm. The median EFS and OS were not significant between the 2 groups. Conclusions: This multicenter retrospective study showed that the efficacy of treatment with axi-cel in R/R LBCL did not decrease with the use of ppx CS. No significant differences in efficacy or CAR-T-associated toxicities were noted in the 2 groups, potentially due to selective use with patients at presumed higher risk of severe CRS and ICANS. A larger dataset and longer follow-up is needed for risk-stratified analysis and the study is ongoing.

Addition of doxycycline to fluoroquinolones for bacterial prophylaxis in autologous stem cell transplantation for multiple myeloma.

e18732 Background: Autologous stem cell transplant (ASCT) is standard therapy for patients (pts) with multiple myeloma (MM), yet the risks of such treatment include neutropenic fever (NF) and bacteremia. Fluoroquinolones (FQs) are a mainstay of bacterial prophylaxis (ppx) of NF in ASCT at many transplant centers and reduce the incidence of bacteremia. Nevertheless, ppx regimens for ASCT are not standardized and variability exists even within single institutions. While antibacterial ppx decreases infections, antibiotic use can also cause toxicity, resistance, and microbiome disturbance. The addition of doxycycline (doxy) to FQs was previously linked to reduced NF and bacteremia when utilized for ppx in MM pts at our institution, leading some providers to incorporate doxy into their ppx regimens. However, our prior study introduced multiple confounders, including differing pre-transplant conditioning regimens between ppx groups. We sought to further compare the incidence of NF and bacteremia in MM pts receiving ppx with FQ alone and FQ-doxy during a time when ppx strategies varied but transplant conditioning was consistent between groups. Methods: This is a single institution retrospective review. We analyzed all medical charts in the ASCT database of MM pts treated at our institution between Jan 2016 and Dec 2021. The primary objective was to determine the effect of bacterial ppx on the rate of NF and bacteremia within 30 days of ASCT. Data was also collected on several pt characteristics. Results: Out of 341 pts with MM who underwent ASCT following melphalan (mel) conditioning, 121 received FQ (ciprofloxacin or levofloxacin) ppx and 220 received FQ-doxy ppx. Pt characteristics and outcomes of interest are shown in Table 1. NF developed in 71 (58.7%) and 103 (46.8%) pts in the FQ and FQ-doxy groups, respectively (p = 0.042). The odds of NF in FQ-doxy compared to FQ is 0.62 (95% CI 0.4, 0.97). Bacteremia developed in 7 (5.8%) and 6 (2.7%) pts of the FQ and FQ-doxy groups (p = 0.235). The odds of bacteremia in FQ-doxy compared to FQ is 0.46 (95% CI 0.15, 1.39). Documented bacteremia was infrequent, yet resistance profiles demonstrated FQ-resistant E. coli strains in the 7 total Gram-negative bacteremia cases and 5 extended-spectrum beta-lactamases. Conclusions: Overall, there were fewer cases of NF in the FQ-doxy ppx group than FQ, however there was no significant difference in the cases of bacteremia. This finding does not support the addition of doxy to FQ ppx at our institution and a future randomized controlled trial investigating appropriate ppx for ASCT is warranted. [Table: see text]

Anakinra (AKR) prophylaxis (ppx) in patients (pts) with relapsed/refractory multiple myeloma (RRMM) receiving orvacabtagene autoleucel (orva-cel).

2537 Background: Orva-cel is a B-cell maturation antigen–targeted chimeric antigen receptor (CAR) T cell therapy being evaluated in the phase 1/2 EVOLVE study (NCT03430011) in pts with RRMM who had at least 3 prior lines of therapy (Tx). We previously reported safety and efficacy in the phase 1 study and established the recommended dose (RD) of orva-cel as 600 × 106 CAR+ T cells (Mailankody et al, ASCO 2020). Cytokine release syndrome (CRS), a dominant toxicity of CAR T cell therapy, is mediated in part by IL-1. We explore the role of ppx with AKR, an IL-1 signaling inhibitor, on reducing the incidence of grade (G) ≥2 CRS after orva-cel treatment at the RD. Methods: Fourteen pts were enrolled sequentially for AKR ppx and treated with orva-cel at the RD. The non-AKR ppx control group comprised the remainder of the phase 1 pts receiving orva-cel at the RD (n = 19). The median follow-up (range) was 3.0 mo (1.8–6.2) for the AKR ppx group and 8.8 mo (5.3–12.2) for the non-AKR ppx group. AKR was administered as 100 mg SC the night before orva-cel infusion, 3 h before the infusion (Day 1), and q24 h on Days 2–5. Dosing was increased to q12 h if CRS developed. CRS was graded by Lee (2014) criteria. Tocilizumab (T) and steroids (S) were used per protocol-specified treatment management guidelines. Results: Disease characteristics and outcomes are shown in the table. In AKR ppx and non-AKR ppx groups, median number of prior regimens was 6 and 5, and bridging Tx was used in 57% and 68% of pts, respectively. The total frequency of CRS was similar in the 2 groups, but with less G 2 in the AKR ppx pts; relative risk (95% CI) = 0.54 (0.21, 1.38). No G ≥3 CRS was seen in either group. The incidence of neurological events (NE), G ≥3 infection, and macrophage activation syndrome/hemophagocytic lymphohistiocytosis (MAS/HLH) was similar. T and S use was numerically lower with AKR ppx. Orva-cel expansion kinetics were similar in the 2 groups. All pts had a 2-month efficacy assessment, with ORR in 100% of AKR ppx and 95% of non–AKR ppx pts. Conclusions: In this nonrandomized evaluation of AKR ppx with orva-cel treatment, the incidence of G ≥2 CRS was lower in pts receiving AKR ppx. The use of AKR ppx produced no adverse effect on the incidence of NE, infection, or MAS/HLH, nor on orva-cel expansion or disease response. These results warrant further study of AKR ppx in CAR T cell therapy. Clinical trial information: NCT03430011. [Table: see text]

Pramipexole attenuates 6-OHDA-induced Parkinson's disease by mediating the Nurr1/NF-κB pathway.

Neuroinflammation is the key factor associated with the progression of Parkinson's disease (PD). Pramipexole (PPX) has anti-inflammatory and antioxidant properties. This study explored the effects of PPX on PD and its related mechanisms. A PD rat model was established using 6-hydroxydopamine (6-OHDA). Thirty rats were divided into the following three groups: control, PD, and PD + PPX. The rats in the PD and PD + PPX groups were first administered 6-OHDA and then respectively treated with saline and PPX. Afterward, rotational behavior tests were performed to evaluate the efficiency of PPX. The level of tyrosine hydroxylase (TH) was measured using immunohistochemical staining. Subsequently, real-time quantitative PCR (RT-qPCR) and western blot were used to determine the expression of α-synuclein (α-syn), nuclear receptor subfamily 4 group A member 2 (Nurr1), and nuclear factor kappa B (NF-κB). PPX improved the motor behavior of PD rats caused by 6-OHDA. The number of TH-positive neurons in the PD group was significantly lower than that in the control group (P < 0.05), while PPX could rescue 6-OHDA-induced TH loss. RT-qPCR and western blot showed that Nurr1 expression was significantly downregulated in the PD group compared to that of the control group (P < 0.05), while after PPX treatment, its expression was significantly upregulated (P < 0.05). For α-syn and NF-κB, 6-OHDA significantly upregulated their expressions (P < 0.05), whereas PPX reversed them. PPX improved the motor behavior of PD through mediating the inflammatory response and regulating the Nurr1/NF-κB signaling pathway.

Impact of Primary Clostridium Difficile Prophylaxis in Thoracic Transplant Recipients

<h3>Purpose</h3> <i>Clostridium difficile</i> infection (CDI) is associated with increased morbidity and mortality after thoracic transplant. In response to a series of cases, our institution implemented primary CDI prophylaxis with oral vancomycin 125 mg twice daily. <h3>Methods</h3> We retrospectively reviewed all thoracic transplant recipients from January 2018 to March 2020. Exclusion criteria included postoperative antibiotics < 48 hours, history of CDI, less than 80% overlap of prophylaxis with antibiotics, and in-hospital mortality. Patients were categorized based on the receipt of oral vancomycin prophylaxis (OVP) or no prophylaxis (No PPX). The primary outcome, CDI during index hospitalization, was compared using Kaplan-Meier survival analysis. <h3>Results</h3> In total, we reviewed 164 thoracic transplant recipients. We excluded 55 patients for a final cohort of 109 patients. There were 63 lung and 46 heart transplant recipients. Twenty-two patients (20%) received prophylaxis and 87 patients (80%) did not. Baseline demographics and hospitalization or receipt of antibiotics within prior 90 days did not differ between groups. Median length of stay was 30 and 43 days in the No PPX and OVP groups, respectively (p=0.01). Post-transplant, more patients in the OVP group were mechanically ventilated greater than 72 hours (16% vs. 46%, p=0.003) or on ECMO (7% vs. 27%, p=0.006). Median duration of antibiotics was 18 and 28 days in the No PPX and OVP groups, respectively (p=0.002). OVP overlapped a median of 95% of antibiotic days and continued for a median of 4 days after antibiotic discontinuation. During hospitalization, CDI occurred in 6 patients (7%) in the No PPX arm and 0 patients in the OVP arm (p=0.35). CDI-free survival did not differ between groups based on the Kaplan-Meier survival analysis (p=0.16). <h3>Conclusion</h3> Despite a higher degree of post-transplant organ support and significantly longer duration of antibiotics and length of stay, the incidence of CDI trended lower with the use of OVP. Primary OVP should be investigated in larger cohorts.

Oropharyngeal candidiasis outcomes in renal transplant recipients receiving nystatin versus no antifungal prophylaxis.

To compare the incidence of oropharyngeal candidiasis (OC), or thrush, in renal transplant recipients receiving nystatin versus no antifungal prophylaxis. This was a single-center, retrospective, non-inferiority study of adult renal transplant recipients (RTRs) who received nystatin for 30days for OC prophylaxis (nystatin group) or no antifungal prophylaxis therapy (No PPX group). The primary outcome was the incidence of OC within 3months post-transplant. Secondary outcomes included time to OC occurrence and severity of OC. The pre-specified non-inferiority margin was 10%. The incidence of OC within 3months post-transplant among 257 RTRs was 7.8% (10/128) in the No PPX group and 4.7% (6/129) RTRs in the nystatin group, a risk difference of 3.2% (95% CI, -2.7% to 9.1%, non-inferiority P=.04). The median time to OC was 7.5days (IQR 6.3-34.3days) in the nystatin group and 9.5days (IQR 5.3-30.5days) in the No PPX group (P=.64). Esophageal candidiasis was observed in 10% (1/10) of RTRs with OC in the No PPX group compared to 16.7% (1/6) RTRs in the nystatin group (P=1.00). All RTRs with OC achieved symptom resolution with fluconazole and/or nystatin. Two patients in the No PPX group required readmission for decreased oral intake, and OC was diagnosed and treated during their hospital day. In this retrospective study of adult RTRs, the absence of antifungal prophylaxis demonstrated non-inferiority to 30-day nystatin prophylaxis at reducing the incidence of OC within 3months of transplant. OC prophylaxis may not be warranted after renal transplant.

Prophylactic treatment with transdermal deferoxamine mitigates radiation-induced skin fibrosis

Radiation therapy can result in pathological fibrosis of healthy soft tissue. The iron chelator deferoxamine (DFO) has been shown to improve skin vascularization when injected into radiated tissue prior to fat grafting. Here, we evaluated whether topical DFO administration using a transdermal drug delivery system prior to and immediately following irradiation (IR) can mitigate the chronic effects of radiation damage to the skin. CD-1 nude immunodeficient mice were split into four experimental groups: (1) IR alone (IR only), (2) DFO treatment for two weeks after recovery from IR (DFO post-IR), (3) DFO prophylaxis with treatment through and post-IR (DFO ppx), or (4) no irradiation or DFO (No IR). Immediately following IR, reactive oxygen species and apoptotic markers were significantly decreased and laser doppler analysis revealed significantly improved skin perfusion in mice receiving prophylactic DFO. Six weeks following IR, mice in the DFO post-IR and DFO ppx groups had improved skin perfusion and increased vascularization. DFO-treated groups also had evidence of reduced dermal thickness and collagen fiber network organization akin to non-irradiated skin. Thus, transdermal delivery of DFO improves tissue perfusion and mitigates chronic radiation-induced skin fibrosis, highlighting a potential role for DFO in the treatment of oncological patients.

Letermovir Prophylaxis in Patients at High Risk for CMV Disease Following Hematopoietic Cell Transplant

<h3>Objective</h3> Starting January 2018 all adult HCT recipients at Stanford University who were at high risk (HR) for CMV disease received Letermovir prophylaxis (LET PPX). HR included: (1) ATG containing regimen, (2) an umbilical cord blood (UBC) graft, or (3) a haplo-identical, (4) unrelated (URD) (5) mismatched-related donor (misM-RD). We performed a retrospective analysis of the impact of LET PPX on the impact of CMV compared to historical controls. <h3>Methods</h3> 629 adults HCT patients from Jan 2013 - May 2019 were analyzed. 76 of these patients received LET PPX. Plasma CMV PCR was performed weekly through D+100. Prior to 2018, UCB patients received valacyclovir 2000 mg TID. PET was started if viral load (VL) was > 400 copies/ml (2009-2012) or 400 IU/ml (2013-2019). CMV disease was defined by published criteria. <h3>Results</h3> • LET PPX was well-tolerated without hematopoietic/organ toxicity. • CMV viremia occurred during LET PPX in 71 % of patients which was comparable to 74% in the controls; however, 34% LET PPX (34%) were started on a different CMV-active agent compared to 50% of controls. In 52% of LET PPX patients viremia cleared without change of antiviral or disease. (Table 1) • Although median hospital stays were the same in the LET PPX and control groups, there was a trend to greater number of hospitalizations in the control group. • Median Day post-transplant of first detection of CMV viremia for patients who received PET/change in CMV-active agent was later in the LET PPX group (D+45) than in the controls (D+ 18) • 3 of 76 (3.9%) LET PPX developed disease compared with 48 of 553 controls (8.7%). None of 24 ATG patients on LET PPX developed disease compared to 23/235 controls. (Table 2) <h3>Conclusion</h3> • Compared to controls, LET prophylaxis decreased the burden of CMV. • Other analyses not shown: hospitalizations, transfusions, infections, GHVD, relapse, survival

Improvement in Quality of Life Outcomes and Bleeding Rates among Patients Switching from On-demand FVIII to Prophylactic BAY 94-9027 in the PROTECT VIII Study

Improvement in Quality of Life Outcomes and Bleeding Rates among Patients Switching from On-demand FVIII to Prophylactic BAY 94-9027 in the PROTECT VIII Study

The Role of Prophylactic Heart Failure Therapy in Duchenne Muscular Dystrophy

Purpose There is variable practice and debate surrounding prophylactic heart failure (HF) therapy in Duchenne Muscular Dystrophy (DMD) patients with normal systolic function . We sought to determine the impact of HF medications including ACE inhibitors and ARB on the development of moderate systolic dysfunction or death in a cohort of DMD patients. Methods We performed a retrospective cohort study of DMD patients followed at 17 centers across North America from 1/1/2005-12/31/2015. Inclusion criteria were normal systolic function on baseline echocardiogram (ejection fraction (EF) ≥ 55%) and age ≥ 9 years during the study. Moderate systolic dysfunction was defined as an EF≤40% or shortening fraction ≤21% if EF was not available. We compared the composite outcome of moderate systolic dysfunction or death in patients who started HF therapies before evidence of systolic dysfunction (PPX) vs those who did not (non-PPX) using a Cox proportional hazards regression model adjusting for baseline age. We also compared prophylaxis with ACE/ARB (ACE/ARB PPX) to non-PPX. Results 277 males with DMD and normal systolic function were included. Prophylactic HF medications were used in 70 patients (25%) which included ACE/ARB (44, 63%), beta blocker (26, 37%), aldosterone blockade (6, 9%) and digoxin (5, 7%). Medications began at a mean (SD) age of 13.6 (4) years. Mean baseline ages were 10.7 (4.2) and 9.9 (3.9) years in the PPX and non-PPX groups (p=0.16), while mean age to develop moderate systolic dysfunction was 18.6 (5.4) and 16.8 (4.0) in the PPX and non-PPX groups (p=.005). The risk of developing moderate systolic dysfunction or death was 50% lower in the PPX group compared to the non-PPX group (HR=0.50; p=.044) and 79% lower in the ACE/ARB PPX group (N=38) compared to the non-PPX group (HR=0.21; p=0.035) (Figure 1). Conclusion There is variability in the use and choice of prophylactic HF medications in boys with DMD. This cohort showed a benefit to introduction of ACE/ARBs prior to evidence of systolic dysfunction.

Vancomycin Prophylaxis (VAN PPx) for Intra-aortic Balloon Pump (IABP)

Vancomycin (VAN) has been used in some facilities to prevent intra-aortic balloon pump (IABP)-related infections. However, the data are scarce. Emergence of drug resistant organisms, costs and side effects of VAN are significant concerns. The use of VAN prophylaxis (PPx) for IABP was decided by the admitting physicians in our facility. A retrospective observational study of adults with an IABP at Memorial Hermann Hospital from 07/2012 until 3/2016 was conducted. Patients were excluded if they were treated with other antibiotics for more than 24 hours after the insertion or if they were less than 18 years old. All demographic data, clinical information, and the durations of VAN PPx and IABP were analyzed. Outcomes evaluated were all-cause mortality, fever, positive blood cultures, IABP site infections and IABP exchange. A total of 352 patients was identified; 154 patients were excluded due to concomitant use of antibiotic therapy (n = 135) and due to age <18 years old (N = 19). 198 patients were eligible; 55 (28 %) received VAN PPx and 143 (72 %) did not receive VAN. APACHE II score was significantly higher in VAN PPx group compared with non-PPx group (12 and 10, respectively P = 0.01). Non-VAN PPx group had more ST segment elevation myocardial infarction as the indication of IABP than VAN PPx group (50% vs. 16%, P = 0.01). Otherwise, no significant differences in the baseline characteristics were seen among the groups. All evaluated outcomes were NOT significantly different between VAN PPx and non-PPx groups. An event free Kaplan Meier (KM) curve was not different between the groups (Log Rank P = 0.514) (Figure 1). After propensity score matching with APACHE II score, no difference of outcomes were seen. 24 % of patients in PPx group had inadequate VAN trough levels (less than 10 mcg/mL). The rates of multi-resistant organisms or Clostridium difficile related infections were not significantly different between the groups. VAN PPx did not change patient outcomes nor prevent IABP infections. Frequent inadequate VAN levels were observed in VAN PPx group. Further larger studies are warranted to confirm the findings. Event free KM curve All authors: No reported disclosures.

Brincidofovir (BCV) Prophylaxis for Herpes Simplex Virus (HSV) and Varicella Zoster Virus (VZV) after Hematopoietic Cell Transplantation (HCT): Clinical Experience at Memorial Sloan-Kettering Cancer Center

Background: Hematopoietic cell transplant (HCT) patients are at risk for serious infections by Herpes simplex1/2 (HSV) and Varicella zoster(VZV). Current guidelines recommend prophylaxis (PPX) with acyclovir (ACV) during the peri-transplant period and continuing throughout the period of immunosuppression. Brincidofovir (BCV, CMX001) is a broad-spectrum nucleotide analog with in vitro activity against double stranded DNA (dsDNA) viruses including HSV and VZV. BCV is in Phase 3 development for the prevention of cytomegalovirus (CMV) infection post-HCT. At present, there is no clinical data to support the efficacy of BCV PPX for HSV/VZV post-HCT. At Memorial Sloan-Kettering Cancer Center (MSK) from 2010 to June 2015, approximately 70 alloHCT recipients were treated with BCV for various indications. We examined rates of breakthrough HSV and VZV infections during administration of BCV.Methods: Retrospective review of alloHCT patients (pts) treated for ≥14 days with BCV, on protocols or emergency investigational new drug application (EIND) at MSK. Administration of concomitant (CON) ACV for HSV PPX during BCV treatment was at clinician discretion. CMX001-350 was an expanded access study of BCV for treatment of subjects with dsDNA viruses and limited or no therapeutic options. CMX001-202 was a placebo-controlled study of BCV as preemption of adenovirus (ADV) post-HCT. CMX001-304 is a currently ongoing open label study of BCV for preemption of ADV disease. After June 2011, all pts received BCV 200mg total weekly dose [100mg twice weekly (BIW) or 200mg weekly (QW)] for adult/adolescent pts and 4mg/kg total weekly dose (2mg/kg BIW or 4mg/kg QW) for pediatric pts. Patients enrolled on CMX-304 through June 16, 2015 are included in this analysis. Based on CON ACV PPX during BCV treatment, 3 patient groups were identified: 1) No CON ACV PPX (group A); 2) Partial CON ACV PPX (group B); and 3) CON ACV PPX (group 3). Diagnosis of HSV or VZV infection was based on viral culture or PCR and clinical symptoms. Data was extracted from medical, pharmacy, and microbiology records.Results: Of 55 alloHCT pts who received BCV ≥14 days, 27 (49%) were treated on CMX001-350, 1 (2%) on CMX001-202, 12 (22%) on CMX001-304 and 15 (27%) under EIND. The median age was 53 years (range, 3-69). Thirty nine (71%) pts received T-cell depleted allografts, 9 (16%) cord blood, and 7 (13%) conventional allografts. BCV started a median of 85 days [Interquartile range (IQR), 59.5-209.5] post-HCT. The primary indication for BCV was: ACV resistant HSV in 2 (4%) pts, disseminated VZV in 1 (2%) pts, CMV in 28 (51%) pts, ADV in 21 (38%) pts and other dsDNA viruses (BK polyoma virus, Human herpesvirus 6, John Cunningham virus) in 3 (5%) pts. Thirty one (56%) pts received BCV 100mg BIW. Among 35 pts in group A, duration of BCV was a median of 39 days (IQR, 29.5-78). One pt in group A received concomitant anti-CMV antivirals for 12 days. Among 13 pts in group B, the median duration of BCV monotherapy was 23 days (IQR, 13-40). Two pts in group B had brief concomitant exposure to anti-CMV antivirals. Among 7 patients in group C, the median duration of BCV treatment was 71 days (IQR, 40-132) (Table 1).Two pts developed HSV infections during BCV treatment. For one pt, the primary indication for BCV was ACV resistant HSV. The pt initially responded to BCV with resolution of oral lesions. During his treatment with BCV, he had intermittent oral ulcers and oral cultures positive for HSV. The second pt developed breakthrough HSV infection during interruption of BCV for severe diarrhea related to graft versus-host disease. There were no breakthrough VZV infections. For one pt, the primary indication for BCV was disseminated VZV. The pt had complete resolution of VZV and no further VZV reactivation during BCV treatment.Conclusions: 1) During 2,806 patient-days of BCV monotherapy in highly immunosuppressed HCT pts, there were no VZV infections and only 2 breakthrough HSV infections. 2) BCV treatment interruptions and impaired gastrointestinal absorption likely explain the breakthrough HSV infections. 3) Our retrospective analysis in this heterogeneous cohort of sick alloHCT recipients supports that BCV administration at doses currently studied for CMV prevention is likely effective for prophylaxis of HSV/VZV in HCT. [Display omitted] DisclosuresOff Label Use: Brincidofovir (CMX001) for the efficacy of prophylaxis for Herpes simples 1/2 and Varicella zoster..

The urinary bladder carcinogen propoxur does not produce genotoxic effects in the urinary bladder of Wistar male rats

Propoxur (PPX) is a carbamate insecticide which induced urinary bladder cancer in Wistar rats when fed at 5000ppm in Altromin 1321 diet (1321). In the present investigation, PPX was studied for induction of several key events related to modes of action (MOA) of carcinogenicity in urinary bladders (UBs). Wistar rats were administered the compound for 28 days at 8000ppm in Provini Liba SA 3883 diet, which is similar to the 1321 diet. o-Anisidine HCl (AH) was used as a genotoxic UB carcinogenic comparator, and trisodium nitrilotriacetate (NTA) as an epigenetic UB carcinogen comparator. Along with the non-dosed control and three test substance groups (PPX, AH, NTA), four more groups were additionally fed 2% ammonium chloride (AC) in the diet to acidify the urine, since 1321 was reported to increase urinary pH. AC did acidify the urine, as expected, although the 3883 diet itself did not increase pH values above 8. In the alkaline comet assay, AH produced DNA single strand breaks (SSBs) in the UB urothelium (UBU) irrespective of AC administration, whereas PPX and NTA did not. In the nucleotide 32P-postlabeling assay (NPL), AH produced DNA adducts irrespective of AC administration, whereas PPX and NTA did not. Routine (H&E) histopathology evaluation of the UBU did not reveal any hyperplasia or evidence of luminal microprecipitates or calculi in any of the groups. Assessment of UBU proliferation as measured by immunohistochemistry of proliferating cell nuclear antigen, revealed that NTA and NTA plus AC increased the replicating fraction (RF). Also AH plus AC, but not AH alone, increased the RF of UBU, whereas PPX groups were not significantly different from controls. Thus, the results reveal no evidence for DNA SSBs, binding, or alteration of DNA synthesis in the UBU by PPX, while demonstrating UBU DNA damage by AH and showing that NTA does not damage DNA, but causes increased UBU proliferation. The findings are in accord with a genotoxic MOA for AH, and an epigenetic MOA for NTA. The MOA of PPX does not involve genotoxicity and may be specific to the 1321 diet.

Pramipexole for Chinese people with primary restless legs syndrome: a 12-week multicenter, randomized, double-blind study

BackgroundRestless legs syndrome (RLS) often responds to agents that enhance dopamine neurotransmission. The present 12-week study aimed to evaluate the efficacy and adverse events of pramipexole (PPX) for the treatment of adult, Chinese people with primary RLS. MethodsA total of 204 Chinese people with RLS were randomly assigned to receive either the placebo or PPX (flexibly titrated from 0.25 mg to 0.75 mg), 2 h to 3 h before bedtime for 12 weeks. The primary measuring outcomes were the International RLS Study Group Rating Scale (IRLS) and the Clinical Global Impressions-Improvement (CGI-I) scale. The secondary outcome was adverse events. ResultsOne hundred and ninety participants completed the study. At 12 weeks, the adjusted mean (SE) change from baseline was greater for PPX (vs placebo) for the IRLS score (−13.2 ± 0.7 vs −9.4 ± 0.6; p < 0.01), and (−12.1 ± 0.6 vs −8.3 ± 0.6; p < 0.01) at the end of one month follow-up after treatment. The CGI-I rating of “very much improved” or “much improved” in the percentage of participants (61.8% vs 34.3%; p < 0.01), and (51.0% vs 26.5%; p < 0.01) after week 12, and one month follow-up of treatment, respectively. The proportion of adverse events was 60.8% in the PPX group and 45.1% in the placebo group. No deaths related to PPX treatment were recorded. ConclusionsIn summary, the present study showed that PPX is efficacious and well tolerated in Chinese people with primary RLS.

Efficacy of Pramipexole for Treatment of Apathy in Parkinson’s Disease

Background: Apathy occurs frequently in patients with Parkinson’s disease (PD), and has a negative impact on activities of daily living through loss of motivation. Pramipexole (PPX), which shows preferential affinity for D3 dopamine receptor in the mesolimbic system, is thought to influence mood and motivation. Therefore, we conducted an open-label case-control study to examine the effect of PPX on apathy in PD. Methods: We studied 36 PD patients (mean age, 70.4 ± 8.1 years), who had been treated only with L-DOPA. PPX was added to L-DOPA treatment in 24 patients (PPX group) and other 12 patients continued with L-DOPA alone (non-PPX group). The study period was 8 weeks. Apathy was assessed using the revised apathy scale for Japanese. Motor function was assessed with part III of the Unified Parkinson’s Disease Rating Scale (UPDRS). Results: Seventeen of 36 patients (47%) were diagnosed as having apathy. In the PPX group, apathy scale significantly improved from 17.3 to 13.8 at week 8 (p

Pramipexole and pergolide in the treatment of depression in Parkinson's disease: a national multicentre prospective randomized study

An 8-month multicentre prospective randomized study aimed at comparing the effects of dopamine receptor agonists pramipexole (PPX; Mirapexin) and pergolide (PRG; Permax) as add-on to L-dopa therapy on depression [Montgomery and Asberg Depression Rating Scale (MADRS)] in 41 non-demented patients (25 men, 16 women) suffering from both mild or moderate depression and advanced Parkinson's disease (PD). The assessment was performed by a blinded independent observer. Motor symptoms (UPDRS III), motor complications (UPDRS IV), activities of daily living (UPDRS II and VI) and depressive symptoms as measured by Self - Rating Depression Scale by Zung were evaluated in an open-label design. The average value of Zung scores decreased significantly in both groups with no statistical difference between both groups. A significant decrease in the average value of MADRS scores was present only in the PPX group. The average UPDRS scores decreased significantly with no statistical difference between both groups at the comparable average total daily dose of both preparations. In both cases, the total daily dose of L-dopa decreased significantly but the decrease was statistically more pronounced in the PRG group. Our results demonstrate the antidepressant effect of PPX in patients with PD while we can't make any conclusions with regard to antidepressant effect of PRG.

Endogenous gastrin stimulates regeneration of remnant pancreas after partial pancreatectomy.

The purpose of this study was to evaluate the effect of endogenous gastrin on pancreatic regeneration after a partial pancreatectomy in the rat. Sixty rats were divided into 6 groups. Groups I and II received sham operation (splenectomy only), and groups III, IV, V, and VI received both 66% partial pancreatectomy (PPx) and splenectomy. Endogenous hypergastrinemia was induced in groups II, IV, and VI by gavage of Lansoprozole (LSP) for three weeks. In groups V and VI, gastrin receptor blocker, L365,260, was given continuously using an osmotic minipump. Following three weeks of treatment, PPx alone increased the pancreatic weight and protein content, but not RNA or DNA content (Group III). In the PPx groups, the pancreatic weight, and contents of protein, RNA, and DNA were significantly increased in the LSP treated rats (Group IV). This effect was abolished by L365,260 (Group VI). This results suggest that endogenous gastrin specifically stimulates regeneration of the remnant pancreas after partial pancreatectomy in rat. Induction of endogenous hypergastrinemia may be useful in patients following pancreatic resection for the prevention and treatment of pancreatic insufficiency.