Targeting hematologic malignancies by inhibiting E-selectin: A sweet spot for AML therapy?

E-selectin, a cytoadhesive glycoprotein, is expressed on venular endothelial cells and mediates leukocyte localization to inflamed endothelium, the first step in inflammatory cell extravasation into tissue. Constitutive marrow endothelial E-selectin expression also supports bone marrow hematopoiesis via NF-κB-mediated signaling. Correspondingly, E-selectin interaction with E-selectin ligand (sialyl Lewisx) on acute myeloid leukemia (AML) cells leads to chemotherapy resistance in vivo. Uproleselan (GMI-1271) is a carbohydrate analog of sialyl Lewisx that blocks E-selectin binding. A Phase 2 trial of MEC chemotherapy combined with uproleselan for relapsed/refractory AML showed a median overall survival of 8.8 months and low (2%) rates of severe oral mucositis. Clinical trials seek to confirm activity in AML and mitigation of neutrophil-mediated adverse events (mucositis and diarrhea) after intensive chemotherapy. In this review we summarize E-selectin biology and the rationale for uproleselan in combination with other therapies for hematologic malignancies. We also describe uproleselan pharmacology and ongoing clinical trials.

Application of the Frailty Framework among Vulnerable Populations to Hospitalization Outcomes of Individuals Experiencing Homelessness in Long Beach, California.

Background: Individuals experiencing homelessness have a high prevalence of infectious diseases that may result in hospitalization. However, low ability to navigate the healthcare system and lack of health insurance may mean that those who are experiencing homelessness may not receive the healthcare that they need. Objectives: This study uses risk factors at baseline to predict hospitalization at follow-up. This paper also presents the associations between reporting homelessness and selected infectious diseases. Research design: Longitudinal study of baseline and follow-up conducted August 2000 through July 2014. Subjects: 4916 Not experiencing homelessness mean age 37.9 years, 29% female, and 2692 experiencing homelessness age 42.1 years, 29% female received services from a research/service center in a low-income, high-crime area of Long Beach, CA. Measures: Risk Behavior Assessment, Risk Behavior Follow-up Assessment, laboratory testing for hepatitis A, hepatitis B, hepatitis C, syphilis, chlamydia, and gonorrhea. Results: Predictors of hospitalization at follow-up were ever use of crack cocaine, income from Social Security or disability, reporting homelessness, female, and those who identify as Black compared to White race/ethnicity. Conclusions: Income from the safety net of Social Security or disability appears to provide the participant with experience that transfers to being able to obtain healthcare. A higher proportion of those experiencing homelessness, compared to those not experiencing homelessness, appear to be hospitalized at follow-up. Women, those who identified as Black, and those who used crack at baseline are more likely to be hospitalized at follow-up whether or not they were experiencing homelessness. We recommend coordination with substance abuse treatment programs for discharge planning for homeless patients. Our findings support use of the Frailty Framework when working with individuals experiencing both homelessness and hospitalization.

Daily motivational text messages impact on college students' nutritional awareness and physical activity levels.

Objective: To examine the effect of receiving daily motivational text messages on the change in college students' nutritional choices and levels of physical activity. Participants: Two hundred and one university students participated in an eight-week experimental/control group study. Methods: All participants received a brochure that contained nutritional and physical-activity information. The survey consisted of three parts: demographic information, health and diet, and physical activity. All participants completed a self-administered survey at the beginning and the end of the eight-week study. The experimental group participants received a daily motivational-text message. Results: There were significant interactions between group and time on most of the health and diet items, but there were no significant interactions on the physical activity items. Conclusions: It is crucial to monitor and promote college students' nutrition and physical activity behaviors. The study findings will be vital in designing interventions that enhance college students' general health.

Rectal douching in a community sample of men and women.

Rectal douching (RD) may be a vector for sexually transmitted infection (STI) acquisition. The aim of this study was to describe the relationship between RD, and the prevalence of various STIs and sexual behaviors in a sample of women and men in Long Beach, California. Five hundred and forty-seven men (mean age 42.8 years) and 530 women (mean age 37 years) recruited from a community-based setting between April 2010 and August 2014 completed the Risk Behavior Assessment and a questionnaire eliciting information on use of lubricants and enemas for vaginal intercourse (VI) and anal intercourse (AI). Participants were screened for high-risk behaviors for human immunodeficiency virus infection including injection drug use. Bivariate analyses were conducted separately for women and men. Based on the empirical results, separate logistic regression models for women and men were constructed. Sensitivity analysis was conducted to assess model fit for reduced samples of only those men and women who reported AI. For men, RD was associated with a lower odds of being hepatitis C antibody positive, greater odds of being positive for hepatitis B virus surface antigen, syphilis, and using lubricants for receptive anal intercourse (RAI). RD in women was associated with higher odds of a positive test for syphilis, ever vaginally douching for VI, and using lubricants for RAI. Men and women who practice RD report positive syphilis test results and use of lubricants for RAI. RD should not be perceived as preventing STIs.

Gender differences in risk taking behaviors for Chlamydia trachomatis.

Chlamydia trachomatis (CT) is a global problem. We compared the risk taking behaviors for CT infection between men and women. Adults (2299 females, 5559 males) were administered the Risk Behavior Assessment. In women, CT was associated with candidiasis, in men with gonorrhea, genital warts, and syphilis. Risk factors for both genders were trading sex for money, use of marijuana for women, and use of Ecstasy and Viagra for men. Those with CT had higher risk perception for HIV infection and were more likely to obtain HIV testing. Patient teaching and concurrent testing for HIV and CT are imperative.

The Role of the Medicaid Expansion in the Use of Preventive Health Care Services in California Men.

Men's use of preventive care services may be constrained due to a number of factors including lack of health care insurance. California used the Medicaid expansion provisions of the Affordable Care Act (ACA) to enroll low-income men between the ages of 18 and 64 years in publicly funded health insurance. Most studies on the effect of the ACA on health care services have focused on racial/ethnic differences rather than gender. Data from the California Health Interview Survey for the 2015-2016 survey period were used to model the use of preventive health care services in the year prior to interview. Population weights were used in the analysis which was done using PROC SURVEY LOGISTIC in SAS software, version 9.4. The sample consisted of men between the ages of 18 and 64 years (N = 6,180). Of these 66% (n = 4,088) reporting receiving any preventive care services in the year prior to interview. The largest proportions of respondents fell into the youngest group aged 18-25 (17%) followed by the oldest group aged 60-64 (16.9%); 43% reported they were married, 57% had incomes at greater than 300% of the federal poverty level. There was no effect of race or ethnicity on receiving preventive care services. Having a chronic condition such as hypertension or diabetes was associated with a greater odds of receiving preventive care. Expanding Medicaid to include low-income men below the age of 65 is associated with increased use of preventive health care, especially among those with chronic conditions.

Survival Sex Trading in Los Angeles County, California, USA.

Most studies on survival sex, defined as sex trading for money, drugs, or other needs, have limited their focus to adolescents. The current study reports about the relationships between survival sex trading (SST) and high-risk behaviors in a sample of adults. Bivariate analysis shows that HIV-positive status, use of cocaine, ketamine, methamphetamine, heroin, having received drug treatment, and having received medical services are associated with SST. SST are more likely to not use condoms with partners other than their main partner, to have partners who inject drugs and are more likely to use drugs with sex. A logistic regression model included unwanted sexual touching, partner abuse, identifying as bisexual, African American, higher age, gender (women more likely), homelessness, a higher number of sexual partners, having anal sex, injection drug use, HIV seropositivity, crack use, and the likelihood of injecting drugs. The model was retested on independently collected Risk Behavior Assessment (RBA) data and showed significant relationships between survival sex and crack use, gender (women more likely), HIV positivity, identifying as bisexual, having anal sex, African American, and a higher number of sex partners. These findings make it imperative to integrate victimization counseling and HIV education into substance abuse treatment programs.

Arrest and Trait Aggression Correlates of Emergency Department Use.

This study examined the associations between arrest and incarceration, trait aggression, and emergency department (ED) use. Data were collected from 525 clients who visited the Center for Behavioral Research and Services in Long Beach, CA, using the following instruments: Risk Behavior Assessment, Risk Behavior Follow-Up Assessment, the Aggression Questionnaire (AQ), the Displaced AQ, and the parole and Legal Status section of the Addiction Severity Index. The bivariate analysis suggested that ED use was significantly associated with trait aggression and trait-displaced aggression among those with a history of incarceration. In the logistic regression, weapons offenses, manslaughter/homicide, being male, and being Black were significantly associated with ED use. Identification and management of aggressive trait personality are important in improving the management of postrelease care in transition to clinical networks and community-based health care settings.

Health implications of sex trading characteristics in Long Beach, California, USA.

This study examined the comparative health risk behaviors of women who (a) traded sex for money, (b) traded sex for drugs, (c) traded sex for both drugs and money, or (d) did not trade sex. Self-report data were collected from 2369 women who received services through HIV and sexually transmitted infection (STI) testing programs and a subset were tested for HIV, hepatitis B, hepatitis C, and syphilis. Results revealed those women who traded sex only for money used condoms, were tested for HIV, and received the HIV test results more often than the other women. Women who traded sex for both drugs and money reported a significantly higher prevalence of gonorrhea, hepatitis B, and syphilis; were more likely to test positive for hepatitis B, syphilis, and HIV; engaged more often in sex acts without condoms; and were incarcerated for significantly more days. Based on these findings, the targets with greatest potential for STI prevention interventions are female sex workers who trade sex for both drugs and money.

Comparisons of New HIV Rapid Test Kit Performance.

The development of rapid point-of-care tests for HIV infection has greatly reduced the problem of failure to return for test results. Test manufacturers are now developing test kits that can test for two or even three diseases at the same time, multiple-disease test kits. This study reports on the sensitivity and specificity of HIV tests when included on multi-disease test kits. 1029 participants were recruited from 2011 to 2014. HIV test kit sensitivities ranged from 91.1 to 100%, and the HIV test kit specificities from 99.5 to 100%. The two HIV kits which used oral fluid instead of blood performed well.

A latent class analysis of alcohol and drug use immediately before or during sex among women.

BACKGROUND: Alcohol and drug use by women is related to high-risk sexual practices and protective behaviors. OBJECTIVES: To determine sexual risk and protective behaviors using information about women's drug use immediately before or during sex. METHODS: Latent class analysis using PROC LCA in SAS software was used to determine classes of women using both past 30-day drug use and before or during sex. Participants were recruited from a community-based research site located in a low socio-economic area of Los Angeles County and completed the Risk Behavior Assessment, which elicits information on drug and sex risk behaviors. RESULTS: The Risk Behavior Assessment and HIV and sexually transmitted infections testing was obtained on 812 women. Five distinct groups were identified by PROC LCA: An Abstinent group comprised of 26% of participants; an Alcohol and Marijuana group (16%); an Amphetamine group (11%); a No Sex-with-Alcohol group (37%); and a Poly Drug group (11%). Multinomial logistic regression revealed that sexual behaviors and condom use were different across the five groups: The Alcohol and Marijuana group had a higher odds of vaginal intercourse, while the No Sex-with-Alcohol group was most likely to use condoms for vaginal intercourse. The Poly Drug group had the highest risk for anal intercourse while the Amphetamine and Poly Drug groups had high proportions of women with injection-drug using and men-who-have-sex-with-men sexual partners. CONCLUSION: Identifying women based on drug use immediately before or during sex can help providers understand prevention and risk-reduction practices and interventions for drug-using women.

Pharmacokinetic Properties of a Sufentanil Sublingual Tablet Intended to Treat Acute Pain.

BACKGROUND: Desirable product attributes for treatment of moderate-to-severe acute pain in many medically supervised settings are rapid onset and a route of administration not requiring intravenous access. The pharmacokinetic characteristics of sublingually administered tablets containing 15 or 30 µg of sufentanil are described. METHODS: Blood was sampled from healthy subjects (four studies, 122 subjects) and patients (seven studies, 944 patients). Studies in healthy subjects determined bioavailability, effect of inhibition of cytochrome P450 3A4, and the plasma concentration profile with single and hourly sublingual doses. Studies in patients evaluated effects of weight, age, sex, and organ impairment on apparent clearance. Noncompartmental and mixed-effect population methods were used. RESULTS: Bioavailability of a single sublingual tablet was 52%, decreasing to 35% with repeat dosing. Ketoconazole (CYP3A4 inhibitor) increased maximum plasma concentration 19% and increased the area under the curve 77%. After a single 30-µg dose, plasma concentrations reached the published sufentanil analgesic threshold (24 pg/ml) within 30 min, peaked at 1 h, and then decreased below therapeutic concentrations by ~3 h. With hourly administration, plasma concentrations plateaued by the fifth dose. Time for concentrations to decrease 50% from maximal values was similar after 1 dose (2.5 ± 0.85 h) and 12 doses (2.5 ± 0.72 h). Clearance increased with weight, decreased with age, and was not affected by renal or hepatic impairment. CONCLUSIONS: The time course of a single 30-µg dose was consistent with onset of analgesia and redosing frequency observed in clinical trials. Sublingual sufentanil tablets provide the opportunity to noninvasively and rapidly treat moderate-to-severe pain in a monitored setting.

Stressful point-of-care rapid testing for human immunodeficiency virus, hepatitis C virus, and syphilis.

Even with technological advances in point-of-care rapid testing for HIV, hepatitis, and syphilis, individuals may still find the experience of submitting to testing, and receiving results, to be stressful. Participants completed the rapid test experience questionnaires to assess stress both prior to and after the specimen collection. Participants completed the risk behavior assessment, the coping strategies indicator, and the Barratt impulsivity scale. Participants chose which rapid tests they wanted using a list administered via computer. Logistic regression analysis was used to model self-reported stress prior to testing and after testing. A total of 1097 individuals completed testing. Individuals who scored high on avoidance reported a stressful experience at pretest (OR = 1.15, CI = 1.04, 1.26) while higher educational attainment was associated with no stress at both time points. Injection drug users, avoidant, and impulsive individuals experience stress either before or after rapid testing. Education appears to be protective against stressful testing.

Pharmacokinetic and Pharmacodynamic Modeling of MOD-4023, a Long-Acting Human Growth Hormone, in Growth Hormone Deficiency Children.

BACKGROUND/AIMS: MOD-4023 is a long-acting human growth hormone (hGH) in clinical trials for the treatment of growth hormone deficiency (GHD). A key goal is maintenance of serum concentrations of insulin-like growth factor (IGF) 1 within normal range throughout GH dosing. The study aimed to develop a pharmacokinetic model for MOD-4023 and a pharmacodynamic model for the effect of MOD-4023 on IGF-1 to allow estimation of peak and mean IGF-1 and to identify the optimal IGF-1 sampling day. METHODS: MOD-4023 (0.25, 0.48, or 0.66 mg/kg) was administered weekly for 12 months to 41 GH-naive GHD children (age 3-11 years). The control group (n = 11, age 4-9 years) received daily recombinant human growth hormone (r-hGH; 34 µg/kg). Sparse samples (4/subject) were obtained to determine serum concentrations of MOD-4023 or r-hGH and IGF-1. RESULTS: A 2-compartment pharmacokinetic model with first-order absorption fit MOD-4023 data well; a 1-compartment model was appropriate for r-hGH. For both, weight-normalized systemic parameters were preferred over allometric scaling. For MOD-4023, an indirect model fit IGF-1 SDS data well; baseline IGF-1 increased over time. At steady state, samples obtained 4 days following dose administration predicted mean IGF-1 SDS during the dosing interval well. CONCLUSION: The IGF-1 profile is consistent with the weekly dosing interval. Sampling 4 days following dose administration allows estimation of mean IGF-1 SDS during the dosing interval in GHD patients.

Attention Deficit Hyperactivity Disorder, Aggression, and Illicit Stimulant Use: Is This Self-Medication?

This study compares adults with and without attention deficit hyperactivity disorder (ADHD) on measures of direct and displaced aggression and illicit drug use. Three hundred ninety-six adults were administered the Wender Utah Rating Scale, the Risk Behavior Assessment, the Aggression Questionnaire (AQ), and the Displaced Aggression Questionnaire (DAQ). Those with ADHD were higher on all scales of the AQ and DAQ, were younger at first use of amphetamines, and were more likely to have ever used crack and amphetamines. A Structural Equation Model found a significant interaction in that for those with medium and high levels of verbal aggression, ADHD predicts crack and amphetamine. Follow-up logistic regression models suggest that blacks self-medicate with crack and whites and Hispanics self-medicate with amphetamine when they have ADHD and verbal aggression.

Failure to get into substance abuse treatment.

Among substance abusers in the US, the discrepancy in the number who access substance abuse treatment and the number who need treatment is sizable. This results in a major public health problem of access to treatment. The purpose of this study was to examine characteristics of Persons Who Use Drugs (PWUDs) that either hinder or facilitate access to treatment. 2646 participants were administered the Risk Behavior Assessment (RBA) and the Barratt Impulsiveness Scale. The RBA included the dependent variable which was responses to the question "During the last year, have you ever tried, but been unable, to get into a drug treatment or detox program?" In multivariate analysis, factors associated with being unable to access treatment included: Previously been in drug treatment (OR=4.51), number of days taken amphetamines in the last 30days (OR=1.18), traded sex for drugs (OR=1.53), homeless (OR=1.73), Nonplanning subscale of the Barratt Impulsiveness Scale (OR=1.19), age at interview (OR=0.91), and sexual orientation, with bisexual men and women significantly more likely than heterosexuals to have tried but been unable to get into treatment. The answers to the question on "why were you unable to get into treatment" included: No room, waiting list; not enough money, did not qualify, got appointment but no follow through, still using drugs, and went to jail before program start. As expected, findings suggest that limiting organizational and financial obstacles to treatment may go a long way in increasing drug abuse treatment accessibility to individuals in need. Additionally, our study points to the importance of developing approaches for increasing personal planning skills/reducing Nonplanning impulsivity among PWUDs when they are in treatment as a key strategy to ensure access to additional substance abuse treatment in the future.

A Randomized Trial Comparing the Pharmacokinetics, Safety, and Tolerability of DFN-02, an Intranasal Sumatriptan Spray Containing a Permeation Enhancer, With Intranasal and Subcutaneous Sumatriptan in Healthy Adults.

OBJECTIVE/BACKGROUND: Intranasal sumatriptan (Imitrex® ) may be an alternative for patients who refuse injections and cannot tolerate oral agents, but due to low bioavailability and slow absorption, the clinical utility of the currently marketed formulation is limited, highlighting an unmet need for an effective non-oral migraine medication with a rapid onset of action. To overcome the slow absorption profile associated with intranasal administration, we evaluated the impact of 1-O-n-Dodecyl-ß-D-Maltopyranoside (DDM, Intravail A-3™), a permeation enhancer, on sumatriptan's pharmacokinetic profile by comparing the pharmacokinetic characteristics of two commercial sumatriptan products, 4 mg subcutaneous and 6 mg subcutaneous in healthy adults, with DFN-02 - a novel intranasal agent comprised of sumatriptan 10 mg plus 0.20% DDM. We also determined the pharmacokinetic characteristics of DDM and evaluated its safety and tolerability. METHODS: We conducted two studies: a randomized, three-way crossover study comparing monodose and multidose devices for delivery of single doses of DFN-02 with commercially available intranasal sumatriptan 20 mg in 18 healthy, fasted adults, and an open-label, randomized, single-dose, three-way crossover bioavailability study comparing DFN-02 with 4 mg and 6 mg subcutaneous sumatriptan in 78 healthy, fasted adults. In the study comparing DFN-02 with IN sumatriptan, subjects received a single dose of DFN-02 (sumatriptan 10 mg plus DDM 0.20%) via monodose and multidose delivery systems with at least 5 days between treatments. In the comparison with SC sumatriptan, subjects received a single dose of each treatment with at least 3 days between treatments. In both studies, blood was sampled for pharmacokinetic evaluation of sumatriptan and DDM through 24 hours post-dose; safety and tolerability were monitored throughout. RESULTS: In the comparison with commercially available intranasal sumatriptan 20 mg, DFN-02 had a more rapid absorption profile; tmax was 15 minutes for DFN-02 monodose, 10.2 minutes for DFN-02 multidose, and 2.0 hours for commercially available intranasal sumatriptan 20 mg. Compared with 4 and 6 mg subcutaneous sumatriptan, DFN-02's median tmax (10 minutes) was significantly earlier (15 minutes; P < .0001). Mean sumatriptan exposure metrics were similar for DFN-02 and 4 mg sumatriptan: AUC0-2 : 35.12 and 44.82 ng*hour/mL, respectively; AUC0-∞ : 60.70 and 69.21 ng*hour/mL, respectively; Cmax : 51.79 and 49.07 ng/mL, respectively. With 6 mg subcutaneous sumatriptan, these exposure metrics were about 50% larger (AUC0-2 : 67.17 ng*hour/mL; AUC0-∞ : 103.78 ng*hour/mL; Cmax : 72.75 ng/mL). Inter-subject variability of AUC0-2 , AUC0-∞ , and Cmax was 42-58% for DFN-02, 15-22% for 4 mg subcutaneous sumatriptan, and 15-25% for 6 mg subcutaneous sumatriptan. DDM exposure was low (mean Cmax : 1.63 ng/mL), tmax was 30 minutes, and it was undetectable by 4 hours. There were no serious adverse events, discontinuations due to adverse events, or remarkable findings for vital signs, physical examinations (including nasal and injection site examinations), or clinical laboratory assessments. The overall incidence of adverse events was comparable across treatments, and all treatment-related events were mild in severity. Adverse events occurring in ≥10% of subjects were dysgeusia (19%), headache (18%), nausea (15%), paresthesia (15%), and dizziness (12%). CONCLUSIONS: In healthy subjects, DFN-02, an intranasal spray containing 10 mg sumatriptan plus DDM, had a more rapid absorption profile than commercially available intranasal sumatriptan 20 mg, and systemic exposure from a single-dose administration of DFN-02 was similar to 4 mg SC sumatriptan and two-thirds that of 6 mg SC sumatriptan. With DFN-02, plasma sumatriptan peaked 5 minutes earlier than with both subcutaneous formulations. Systemic exposure to sumatriptan was similar with DFN-02 and 4 mg subcutaneous sumatriptan; both yielded lower systemic exposure than 6 mg subcutaneous sumatriptan. Systemic exposure to DFN-02's excipient DDM was short-lived. DFN-02's safety and tolerability appear to be comparable to subcutaneous sumatriptan. Addition of a permeation enhancer improved the absorption profile compared with commercially available intranasal sumatriptan 20 mg.