Harry uman Veterans Administration Medical Center

Columbia, MO, United States

Harry uman Veterans Administration Medical Center

Columbia, MO, United States
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Salas J.,Saint Louis University | Salas J.,Harry uman Veterans Administration Medical Center | Scherrer J.F.,Saint Louis University | Scherrer J.F.,Harry uman Veterans Administration Medical Center | And 10 more authors.
Pain | Year: 2017

Recent studies suggest that longer durations of opioid use, independent of maximum morphine equivalent dose (MED) achieved, is associated with increased risk of new-onset depression (NOD). Conversely, other studies, not accounting for duration, found that higher MED increased probability of depressive symptoms. To determine whether rate of MED increase is associated with NOD, a retrospective cohort analysis of Veterans Health Administration data (2000-2012) was conducted. Eligible patients were new, chronic (>90 days) opioid users, aged 18 to 80, and without depression diagnoses for 2 years before start of follow-up (n = 7051). Mixed regression models of MED across follow-up defined 4 rate of dose change categories: Stable, decrease, slow increase, and rapid increase. Cox proportional hazard models assessed the relationship of rate of dose change and NOD, controlling for pain, duration of use, maximum MED, and other confounders using inverse probability of treatment-weighted propensity scores. Incidence rate for NOD was 14.1/1000PY (person-years) in stable rate, 13.0/1000PY in decreasing, 19.3/1000PY in slow increasing, and 27.5/1000PY in rapid increasing dose. Compared with stable rate, risk of NOD increased incrementally for slow (hazard ratio = 1.22; 95% confidence interval: 1.05-1.42) and rapid (hazard ratio = 1.58; 95% confidence interval: 1.30-1.93) rate of dose increase. Faster rates of MED escalation contribute to NOD, independent of maximum dose, pain, and total opioid duration. Dose escalation may be a proxy for loss of control or undetected abuse known to be associated with depression. Clinicians should avoid rapid dose increase when possible and discuss risk of depression with patients if dose increase is warranted for pain. © 2016 International Association for the Study of Pain.

Scherrer J.F.,Saint Louis University | Scherrer J.F.,Harry uman Veterans Administration Medical Center | Salas J.,Saint Louis University | Salas J.,Harry uman Veterans Administration Medical Center | And 12 more authors.
Annals of Family Medicine | Year: 2016

PURPOSE Recent results suggests the risk of a new onset of depression increases with longer duration of opioid analgesic use. It is unclear whether new-onset depression related to opioid analgesic use is a function of the dose prescribed or the duration of use or both. METHODS Using a retrospective cohort design, we collected patient data from 2000 to 2012 from the Veterans Health Administration (VHA), and from 2003 to 2012 from both Baylor Scott & White Health (BSWH) and the Henry Ford Health System (HFHS). Patients (70,997 VHA patients, 13,777 BSWH patients, and 22,981 HFHS patients) were new opioid users, aged 18 to 80 years, without a diagnosis of depression at baseline. Opioid analgesic use duration was defined as 1 to 30, 31 to 90, and more than 90 days, and morphine equivalent dose (MED) was defined as 1 to 50 mg/d, 51 to 100 mg/d, and greater than 100 mg/d of analgesic. Pain and other potential confounders were controlled for by inverse probability of treatment–weighted propensity scores. RESULTS New-onset depression after opioid analgesic use occurred in 12% of the VHA sample, 9% of the BSWH sample, and 11% of the HFHS sample. Compared with 1- to 30-day users, new-onset depression increased in those with longer opioid analgesic use. Risk of new-onset depression with 31 to 90 days of opioid analgesic use ranged from hazard ratio [HR] = 1.18 (95% CI, 1.10-1.25) in VHA to HR = 1.33 (95% CI, 1.16-1.52) in HFHS; in opioid analgesic use of more than 90 days, it ranged from HR = 1.35 (95% CI, 1.26-1.44) in VHA to HR = 2.05 (95% CI, 1.75-2.40) in HFHS. Dose was not significantly associated with a new onset of depression. CONCLUSIONS Opioid-related new onset of depression is associated with longer duration of use but not dose. Patients and practitioners should be aware that opioid analgesic use of longer than 30 days imposes risk of new-onset depression. Opioid analgesic use, not just pain, should be considered a potential source when patients report depressed mood. © 2016, Annals of Family Medicine, Inc. All rights reserved.

Scherrer J.F.,Saint Louis University | Scherrer J.F.,Harry uman Veterans Administration Medical Center | Salas J.,Saint Louis University | Salas J.,Harry uman Veterans Administration Medical Center | And 9 more authors.
Pharmacoepidemiology and Drug Safety | Year: 2016

Purpose: Longer duration of prescription opioid use is associated with risk of major depression after controlling for daily morphine equivalent dose and pain. It is not known if risk of depression varies as a function of the type of opioid prescribed. Methods: A retrospective cohort design was used to model onset of new depression diagnosis among 11462 Veterans Health Administration (VA) patients who were prescribed only codeine, only hydrocodone or only oxycodone for >30days. Patients were free of prevalent opioid use and depression at baseline (2000-2001). Follow-up was 2002-2012. Propensity scores and weighting were used to balance covariates across opioid type. Cox-proportional hazard models were computed, using weighted data and additional adjustment for morphine equivalent dose (MED), duration of use, and pain after opioid initiation, to estimate the risk of new depression diagnosis among patients prescribed only codeine, only oxycodone vs. those prescribed only hydrocodone. Results: After controlling for confounding, we observed that patients prescribed codeine, compared to hydrocodone, were significantly more likely to have a new depression diagnosis (HR=1.27; 95%CI: 1.12-1.43). Oxycodone was significantly associated with onset of new depression diagnosis when exposure was modeled as total days exposed in post-hoc analysis, but not when exposure was duration of incident period of use. Conclusions: Although codeine is a less potent opioid, after controlling for MED, chronic use of this agent is associated with nearly a 30% greater risk of depression compared to hydrocodone. Additional research is needed to determine the mechanisms for this association. © 2016 John Wiley & Sons, Ltd.

Rodvelt K.R.,University of Missouri | Lever S.Z.,University of Missouri | Lever J.R.,University of Missouri | Lever J.R.,Harry uman Veterans Administration Medical Center | And 3 more authors.
Pharmacology Biochemistry and Behavior | Year: 2011

Cocaine exhibits preferential (~ 15-fold) affinity for σ 1 over σ 2 sigma receptors, and previous research has shown an interaction of σ 1 receptor-selective ligands and cocaine's behavioral effects. The present study investigated the effect of the putative sigma receptor agonist SA 4503 (1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl) piperazine dihydrochloride) on cocaine's locomotor stimulatory and discriminative stimulus properties. At doses without intrinsic activity, SA 4503 dose-dependently attenuated cocaine-induced hyperactivity in mice. This inhibition was overcome by increasing the cocaine dose. In rats trained to use cocaine as a discriminative stimulus in a drug discrimination task, doses of SA 4503 that did not substitute for the cocaine stimulus did not alter the cocaine substitution curve. However, SA 4503 potentiated the effect of methamphetamine to substitute for the cocaine stimulus. These data support a role for sigma receptors in the locomotor-activating properties of cocaine and, importantly, indicate a role for these receptors in the discriminative stimulus effects of methamphetamine. The data also suggest sigma receptors mediate the activity of different dopamine pathways responsible for the behavioral effects of psychostimulants. © 2010 Elsevier Inc.

Chanda N.,University of Missouri | Kan P.,University of Missouri | Watkinson L.D.,Harry uman Veterans Administration Medical Center | Shukla R.,University of Missouri | And 20 more authors.
Nanomedicine: Nanotechnology, Biology, and Medicine | Year: 2010

Biocompatibility studies and cancer therapeutic applications of nanoparticulate β-emitting gold-198 (198Au; βmax = 0.96 MeV; half-life of 2.7 days) are described. Gum arabic glycoprotein (GA)-functionalized gold nanoparticles (AuNPs) possess optimum sizes (12-18 nm core diameter and 85 nm hydrodynamic diameter) to target individual tumor cells and penetrate through tumor vasculature and pores. We report the results of detailed in vivo therapeutic investigations demonstrating the high tumor affinity of GA-198AuNPs in severely compromised immunodeficient (SCID) mice bearing human prostate tumor xenografts. Intratumoral administration of a single dose of β-emitting GA-198AuNPs (70 Gy) resulted in clinically significant tumor regression and effective control in the growth of prostate tumors over 30 days. Three weeks after administration of GA-198AuNPs, tumor volumes for the treated animals were 82% smaller as compared with tumor volume of control group. The treatment group showed only transitory weight loss in sharp contrast to the tumor-bearing control group, which underwent substantial weight loss. Pharmacokinetic studies have provided unequivocal evidence for the optimum retention of therapeutic payload of GA-198AuNPs within the tumor site throughout the treatment regimen with minimal or no leakage of radioactivity to various nontarget organs. The measurements of white and red blood cells, platelets, and lymphocytes within the treatment group resembled those of the normal SCID mice, thus providing further evidence on the therapeutic efficacy and concomitant in vivo tolerance and nontoxic features of GA-198AuNPs. From the Clinical Editor: In this study, the biocompatibility and cancer therapeutic applications of glycoprotein (GA) functionalized gold nanoparticles containing b-emitting Au-198 are described in SCID mice bearing human prostate tumor xenografts. The findings of significant therapeutic efficacy, good in vivo tolerance and non-toxic features make these particles ideal candidates for future human applications. © 2010.

Fan K.-H.,University of Missouri | Lever J.R.,University of Missouri | Lever J.R.,Harry uman Veterans Administration Medical Center | Lever S.Z.,University of Missouri
Bioorganic and Medicinal Chemistry | Year: 2011

5-Bromo-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-butyl)]-2, 3-dimethoxy-benzamide (1) is one of the most potent and selective σ2 receptor ligands reported to date. A series of new analogs, where the amine ring fused to the aromatic ring was varied in size (5-7) and the location of the nitrogen in this ring was modified, has been synthesized and assessed for their σ1/σ2 binding affinity and selectivity. The binding affinity of an open-chained variant of 1 was also evaluated. Only the five-membered ring congener of 1 displayed a higher σ1/σ2 selectivity, derived from a higher σ2 affinity and a lower σ1 affinity. Positioning the nitrogen adjacent to the aromatic ring in the five-membered and six-membered ring congeners dramatically decreased affinity for both subtypes. Thus, location of the nitrogen within a constrained ring is confirmed to be key to the exceptional σ2 receptor binding affinity and selectivity for this active series. © 2011 Elsevier B.V. All rights reserved.

Sage A.S.,University of Missouri | Oelrichs C.E.,University of Missouri | Davis D.C.,University of Missouri | Fan K.-H.,University of Missouri | And 5 more authors.
Pharmacology Biochemistry and Behavior | Year: 2013

The present study examined N-phenylpropyl-N'-substituted piperazine sigma receptor ligands on cocaineinduced changes in locomotor activity in mice. Previous reports indicate that N-phenylpropyl-N'-(4- methoxybenzyl)piperazine (Nahas-3h), N-phenylpropyl-N'-(4-methoxyphenethyl)piperazine (YZ-067), and N-phenylpropyl-N'-(3-methoxyphenethyl)piperazine (YZ-185) bind with high affinity (Ki values ≈ 1 nM) to σ1 sigma receptors. YZ-067 and YZ-185 are known to attenuate cocaine-induced convulsions, while Nahas-3h has not been tested in behavioral studies. Nahas-3h significantly attenuated cocaine-induced hyperactivity. YZ- 067 decreased the effect of cocaine in a dose-dependentmanner. Interestingly, YZ-185 inhibited cocaine's effect at higher doses, but enhanced cocaine's effect at a low dose. The YZ-185 inhibition of cocaine-induced hyperactivity was not surmounted by increasing the cocaine dose. Overall, this study is consistent with previous work showing the ability of certain sigma receptor ligands to affect cocaine-induced hyperactivity. Further, subtle alterations of ligand structure and the specific dosage levels employed influence the behavioral effects observed, with a 3-methoxy substituent apparently conferring the ability of a ligand to enhance cocaine's locomotor stimulatory effects. © 2013 Elsevier Inc. All rights reserved.

Rodvelt K.R.,University of Missouri | Oelrichs C.E.,University of Missouri | Blount L.R.,University of Missouri | Fan K.-H.,University of Missouri | And 4 more authors.
Drug and Alcohol Dependence | Year: 2011

Background: Methamphetamine's behavioral effects have been attributed to its interaction with monoamine transporters; however, methamphetamine also has affinity for sigma receptors. Method: The present study investigated the effect of the sigma receptor agonist SA 4503 and the sigma receptor antagonists BD-1047 and BD-1063 on methamphetamine-evoked [ 3H]dopamine release from preloaded rat striatal slices. The effect of SA 4503 on methamphetamine-induced hyperactivity and on the discriminative stimulus properties of methamphetamine also was determined. Results: SA 4503 attenuated methamphetamine-evoked [ 3H]dopamine release in a concentration-dependent manner. BD-1047 and BD-1063 did not affect release. SA 4503 dose-dependently potentiated and attenuated methamphetamine-induced hyperactivity. SA 4503 pretreatment augmented the stimulus properties of methamphetamine. Conclusions: Our findings indicate that SA 4503 both enhances and inhibits methamphetamine's effects and that sigma receptors are involved in the neurochemical, locomotor stimulatory and discriminative stimulus properties of methamphetamine. © 2011 Elsevier Ireland Ltd.

Ramanath V.,University of Missouri | Gupta D.,University of Missouri | Jain J.,University of Missouri | Chaudhary K.,Harry uman Veterans Administration Medical Center | And 2 more authors.
Reviews on Recent Clinical Trials | Year: 2012

Anemia is a very common complication of chronic kidney disease (CKD). Anemia confers significant risk of cardiovascular disease and contributes to decreased quality of life. Anemia in CKD patients can be multi-factorial, including but not invariably due to the underlying renal insufficiency. Identifying the type of anemia is important in this group of patients and can often be challenging. Diagnosing anemia of renal disease due to erythropoietin (EPO) deficiency is a diagnosis of exclusion. Erythropoiesis stimulating agents (ESA) are the mainstay for the treatment of anemia secondary to CKD. However, over the last four years the use of ESA in the treatment of anemia in CKD patients has undergone a severe interrogation as several trials have reported adverse outcomes with targeting higher hemoglobin (Hb) levels with these agents. Thereby, this review describes the pathophysiology of anemia in CKD patients, diagnosis and the current role of ESA's as it relates to anemia of CKD as well as safety and efficacy of ESA's. © 2012 Bentham Science Publishers.

Manrique C.,University of Missouri | DeMarco V.G.,University of Missouri | Aroor A.R.,University of Missouri | Mugerfeld I.,University of Missouri | And 5 more authors.
Endocrinology | Year: 2013

Cardiovascular disease (CVD), including heart failure, constitutes the main source of morbidity and mortality in men and women with diabetes. Although healthy young women are protected against CVD, postmenopausal and diabetic women lose this CVD protection. Obesity, insulin resistance, and diabetes promote heart failure in females, and diastolic dysfunction is the earliest manifestation of this heart failure. To examine the mechanisms promoting diastolic dysfunction in insulin-resistant females, this investigation evaluated the impact of 8 weeks of a high-fructose/high-fat Western diet (WD) on insulin sensitivity and cardiac structure and function in young C57BL6/J female versus male mice. Insulin sensitivity was determined by hyperinsulinemic-euglycemic clamps and two-dimensional echocardiograms were used to evaluate cardiac function. Both males and females developed systemic insulin resistance after 8 weeks of a WD. However, only the females developed diastolic dysfunction. The diastolic dysfunction promoted by the WD was accompanied by increases in collagen 1, a marker of stiffness, increased oxidative stress, reduced insulin metabolic signaling, and increased mitochondria and cardiac microvascular alterations as determined by electron microscopy. Aldosterone (a promoter of cardiac stiffness) levels were higher in females compared with males but were not affected by the WD in either gender. These data suggest a predisposition toward developing early diastolic heart failure in females exposed to a WD. These data are consistent with the notion that higher aldosterone levels, in concert with insulin resistance, may promote myocardial stiffness and diastolic dysfunction in response to overnutrition in females. Copyright © 2013 by The Endocrine Society.

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