Evaluation of a primary antifungal prophylaxis protocol for preventing invasive mold infections after allogeneic hematopoietic stem cell transplantation.

INTRODUCTION: Invasive mold infections contribute to morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation. The optimal strategy for primary antifungal prophylaxis in this patient population remains uncertain. METHODS: Medical records of patients who underwent allogeneic hematopoietic stem cell transplantation between 1 January 2013 and 31 December 2017 were retrospectively reviewed. Adult patients were included if they received micafungin followed by fluconazole, with the option to escalate to voriconazole, for antifungal prophylaxis. The primary outcome was the incidence rate of proven or probable invasive mold infection. Secondary outcomes were time to invasive mold infection diagnosis, invasive mold infection-related mortality, and risk factors associated with invasive mold infection. RESULTS: Two hundred patients were included in the study, a majority of whom underwent matched unrelated (46%) or matched related (33%) donor transplants. The incidence rate of proven or probable invasive mold infection was 18.4 cases per 100 patient-years, with a one-year cumulative incidence of 14%. Median time to proven or probable invasive mold infection was 94 days post-transplant (IQR 26-178), with invasive mold infection-related mortality occurring in 18 (64%) of 28 patients diagnosed with invasive mold infection. Comparison of invasive mold infection-free survival by potential risk factors failed to show any significant differences. CONCLUSIONS: In this real-life cohort of allogeneic hematopoietic stem cell transplantation recipients, the incidence of proven or probable invasive mold infection was higher than expected based on previous literature. In the absence of standard guidance on anti-mold prophylaxis in this patient population and given that unique risk factors for invasive mold infection may differ between institutions, it is essential that centers performing allogeneic hematopoietic stem cell transplantation routinely monitor their antifungal prophylaxis strategies for effectiveness.

Minibeam radiation therapy enhanced tumor delivery of PEGylated liposomal doxorubicin in a triple-negative breast cancer mouse model.

BACKGROUND: Minibeam radiation therapy is an experimental radiation therapy utilizing an array of parallel submillimeter planar X-ray beams. In preclinical studies, minibeam radiation therapy has been shown to eradicate tumors and cause significantly less damage to normal tissue compared to equivalent radiation doses delivered by conventional broadbeam radiation therapy, where radiation dose is uniformly distributed. METHODS: Expanding on prior studies that suggested minibeam radiation therapy increased perfusion in tumors, we compared a single fraction of minibeam radiation therapy (peak dose:valley dose of 28 Gy:2.1 Gy and 100 Gy:7.5 Gy) and broadbeam radiation therapy (7 Gy) in their ability to enhance tumor delivery of PEGylated liposomal doxorubicin and alter the tumor microenvironment in a murine tumor model. Plasma and tumor pharmacokinetic studies of PEGylated liposomal doxorubicin and tumor microenvironment profiling were performed in a genetically engineered mouse model of claudin-low triple-negative breast cancer (T11). RESULTS: Minibeam radiation therapy (28 Gy) and broadbeam radiation therapy (7 Gy) increased PEGylated liposomal doxorubicin tumor delivery by 7.1-fold and 2.7-fold, respectively, compared to PEGylated liposomal doxorubicin alone, without altering the plasma disposition. The enhanced tumor delivery of PEGylated liposomal doxorubicin by minibeam radiation therapy is consistent after repeated dosing, is associated with changes in tumor macrophages but not collagen or angiogenesis, and nontoxic to local tissues. Our study indicated that the minibeam radiation therapy's ability to enhance the drug delivery decreases from 28 to 100 Gy peak dose. DISCUSSION: Our studies suggest that low-dose minibeam radiation therapy is a safe and effective method to significantly enhance the tumor delivery of nanoparticle agents.

Delayed Onset of Central Diabetes Insipidus With Ketamine Sedation: A Report of 2 Cases.

Ketamine is being prescribed with greater frequency due to an emphasis on multimodal analgesia. With increasing use, uncommon adverse effects associated with ketamine are likely to surface. Limited reports of transient central diabetes insipidus (DI) occurring early after initiation (ie, within 10 hours) of ketamine have been reported. We present 2 cases of delayed onset (32 hours or more after initiation), ketamine-induced, transient central DI in patients cannulated for venovenous extracorporeal membranous oxygenation. No other causes of central DI were determined based upon physical examination or laboratory data, and both patients responded to treatment with desmopressin/vasopressin. The Naranjo adverse drug reaction probability scale noted a probable causation for each case. These cases demonstrate the possibility of a rare but serious complication of ketamine. Improvement after discontinuation of ketamine and administration of desmopressin/vasopressin appear to support a drug-effect association.

Voxelotor: A Novel Treatment for Sickle Cell Disease.

OBJECTIVE: To review the pharmacological characteristics, clinical evidence, and place in therapy of voxelotor for the treatment of sickle cell disease (SCD). DATA SOURCES: A comprehensive literature search of PubMed (1966 to April 2020) was conducted. Key search terms included GBT440, sickle cell, and voxelotor. Other sources were derived from bibliographies of articles, product labeling, manufacturer's website, and news releases. ClinicalTrials.gov was searched for additional studies. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the data sources were reviewed and evaluated. Case reports/series and phase 1 through 3 clinical trials were included. DATA SYNTHESIS: SCD is an inherited disorder associated with significant morbidity and early mortality. Three medications approved for SCD reduce SCD-associated complications but do not selectively ameliorate the underlying disease. Voxelotor is a novel agent that targets the pathophysiology of SCD. A phase 3 trial reported an increase in mean Hb level from baseline for voxelotor compared with placebo (1.1 vs -0.1 g/dL; P < 0.001). Voxelotor is generally well tolerated, with common adverse effects including headache, diarrhea, nausea, and arthralgia. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Voxelotor may be considered for patients with SCD who have continued anemia and hemolysis despite being on maximum tolerated dose of hydroxyurea or in those who are hydroxyurea intolerant. Voxelotor is costly; therefore, both cost and benefit should be weighed before prescribing. CONCLUSION: Voxelotor appears to be safe and effective as monotherapy or in combination with hydroxyurea for patients with SCD who are 12 years of age and older.

Overcoming anti-PEG antibody mediated accelerated blood clearance of PEGylated liposomes by pre-infusion with high molecular weight free PEG.

Antibodies that specifically bind polyethylene glycol (PEG), i.e. anti-PEG antibodies (APA), are associated with reduced efficacy and increased risk of serious adverse events for several PEGylated therapeutics. Here, we explored the concept of using free PEG molecules to saturate circulating APA. Surprisingly, we found that 40 kDa free PEG effectively restored the prolonged circulation of PEGylated liposomes in the presence of high titers of pre-existing APA for at least 48 h in mice. In contrast, lower molecular weight free PEG (≤10 kDa) failed to restore circulation beyond a few hours. These in vivo results were consistent with estimates from a minimal physiologically based pharmacokinetic model. Importantly, the infusion of free PEG appeared to be safe in mice previously sensitized by injection of PEGylated liposomes, and free PEG did not elicit excess APA production even in mice with pre-existing adaptive immunity against PEG. Our results support further investigation of high molecular weight free PEG as a potential method to control and overcome high titers of APA, restoring the prolonged circulation of PEGylated liposomes and possibly other PEGylated therapeutics.

Senior PharmAssist: Less Hospital Use with Enrollment in an Innovative Community-Based Program.

OBJECTIVES: To evaluate changes in acute health services use of Senior PharmAssist participants. DESIGN: Retrospective analysis. SETTING: Community-based, nonprofit program in Durham County, North Carolina. PARTICIPANTS: Adults aged 60 and older with income of 200% of the federal poverty level or less who enrolled in the Senior PharmAssist program (N = 191) between August 1, 2011, and March 15, 2017. INTERVENTION: Medication therapy management (MTM), customized community referrals, Medicare insurance counseling, and medication copayment assistance provided by Senior PharmAssist. MEASUREMENTS: Primary outcomes were self-reported emergency department (ED) visits and hospital admissions in the previous year, assessed at baseline and every 6 months for up to 2 years. RESULTS: Mean number of ED visits declined over time (0.83 visits per year at baseline to 0.53 visits per year at 24 months, P = .002), as did the percentage of participants reporting an ED visit in the past year (49% at baseline to 31% at 24 months, P = .003). Mean hospital admissions also decreased (0.56 admissions per year at baseline to 0.4 admissions per year at 24 months, P = .02). There was no significant change in percentage of participants reporting a hospital admission in the past year (33% at baseline to 25% at 24 months, P = .23). CONCLUSION: Older adults who enrolled in a community-based program that helps them manage medications, connect with community resources, and overcome barriers to medication access experienced reductions in acute health services use. J Am Geriatr Soc 66:2394-2400, 2018.

Pharmacokinetic and screening studies of the interaction between mononuclear phagocyte system and nanoparticle formulations and colloid forming drugs.

Studies have shown that nanoparticles (NPs) are cleared through the mononuclear phagocyte system (MPS). Pharmacokinetic studies of Doxil, DaunoXome, micellar doxorubicin (SP1049C) and small molecule (SM) doxorubicin were performed in SCID mice, Sprague-Dawley rats, and beagle dogs. An ex vivo MPS profiling platform was used to evaluate the interaction between the same agents, as well as colloid-forming and non-colloid forming SM drugs. In all species, the systemic clearance was highest for SP1049C and lowest for Doxil. With the exception of dog blood, the MPS screening results of mouse and rat blood showed that the greatest reduction in phagocytosis occurred after the ex vivo addition of SM-doxorubicin>SP1049C>DaunoXome>Doxil. The MPS profiling platform in rats, but not dogs, could differentiate between colloid forming and non-colloid forming drugs. The results of the MPS profiling platform were generally consistent with in vivo clearance rates of NP and SM anticancer drugs in mice and rats. This study suggests the MPS profiling platform is an effective method to screen and differentiate the important characteristics of NPs and colloid-forming drugs that affect their in vivo clearance. Implications of these findings on preclinical prediction of human clearance are discussed.

Profiling the relationship between tumor-associated macrophages and pharmacokinetics of liposomal agents in preclinical murine models.

The mononuclear phagocyte system (MPS) has previously been shown to significantly affect the clearance, tumor delivery, and efficacy of nanoparticles (NPs). This study profiled MPS cell infiltration in murine preclinical tumor models and evaluated how these differences may affect tumor disposition of PEGylated liposomal doxorubicin (PLD) in models sensitive and resistant to PLD. Significant differences in MPS presence existed between tumor types (e.g. ovarian versus endometrial), cell lines within the same tumor type, and location of tumor implantation (i.e. flank versus orthotopic xenografts). Further, the differences in MPS presence of SKOV-3 ovarian and HEC1A endometrial orthotopic cancer models may account for the 2.6-fold greater PLD tumor exposure in SKOV-3, despite similar plasma, liver and spleen exposures. These findings suggest that profiling the presence of MPS cells within and between tumor types is important in tumor model selection and in tumor types and patients likely to respond to NP treatment.