Real-World Dosing Patterns of Ruxolitinib in Patients With Polycythemia Vera Who Are Resistant to or Intolerant of Hydroxyurea.

INTRODUCTION: Approximately one-quarter of patients with polycythemia vera become resistant to and/or intolerant of hydroxyurea. This analysis characterizes reasons patients were switched from hydroxyurea to ruxolitinib and describes ruxolitinib dosing patterns and outcomes in real-world clinical practice. PATIENTS AND METHODS: This medical chart review of United States community hematology/oncology practices in the Cardinal Health Oncology Provider Extended Network included patients with polycythemia vera who were ≥18 years old, received hydroxyurea for ≥3 months, started ruxolitinib between January 1, 2015 and December 31, 2016, and had ≥2 visits during the subsequent 6 months. Clinical data were collected at predefined intervals from diagnosis to last provider visit. RESULTS: Providers identified 249 patients for inclusion. jcauses of hydroxyurea discontinuation were resistance (78%; frequently for hematocrit ≥45% [79%]) and intolerance (28%; frequently for nausea/vomiting [50%]). Initial ruxolitinib dosing was 10 mg twice daily (recommended dose) in 131 patients (53%). Among these patients, median treatment duration was 29.2 months, 35 (27%) had dose modification (increase, n = 24; decrease, n = 11) and 4 had interruptions within 6 months. The most common reason for dose increase was continued need for phlebotomy (46%); 6 patients had dose reductions owing to reduced platelets. Hematocrit control at initiation and during the first 6 months of ruxolitinib treatment was 15% and 63%, respectively. CONCLUSION: Most patients initiated ruxolitinib upon hydroxyurea resistance. Approximately half initiated ruxolitinib at the recommended dose, 27% of whom experienced dosing modifications within the first 6 months. After switching to ruxolitinib, most patients achieved hematocrit control and continued treatment for extended time frames.

Neurological Complications of COVID-19: Underlying Mechanisms and Management.

COVID-19 is a severe respiratory disease caused by the newly identified human coronavirus (HCoV) Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). The virus was discovered in December 2019, and in March 2020, the disease was declared a global pandemic by the World Health Organization (WHO) due to a high number of cases. Although SARS-CoV-2 primarily affects the respiratory system, several studies have reported neurological complications in COVID-19 patients. Headache, dizziness, loss of taste and smell, encephalitis, encephalopathy, and cerebrovascular diseases are the most common neurological complications that are associated with COVID-19. In addition, seizures, neuromuscular junctions' disorders, and Guillain-Barré syndrome were reported as complications of COVID-19, as well as neurodegenerative and demyelinating disorders. However, the management of these conditions remains a challenge. In this review, we discuss the prevalence, pathogenesis, and mechanisms of these neurological sequelae that are secondary to SARS-CoV-2 infection. We aim to update neurologists and healthcare workers on the possible neurological complications associated with COVID-19 and the management of these disease conditions.

Comparative Effectiveness of Palliative Chemotherapy in Metastatic Breast Cancer: A Real-World Evidence Analysis.

BACKGROUND: In the absence of randomized controlled trials, real-world evidence may aid practitioners in optimizing the selection of therapy for patients with cancer. The study's aim was to determine real-word use, as well as compare effectiveness, of single-agent and combination chemotherapy as palliative treatment for female patients with metastatic breast cancer (mBC). MATERIALS AND METHODS: Using administrative claims data from the Symphony Health's Integrated Oncology Dataverse, female patients with mBC treated with at least one chemotherapy-only treatment (COT) between January 1, 2013, and December 31, 2017 were selected. The frequency of use of single-agent versus combination chemotherapy overall and by line of therapy (LOT) was calculated whereas effectiveness was measured using time to next treatment (TNT). RESULTS: A total of 12,381 patients with mBC were identified, and 3,777 (31%) received at least one line of COT. Of the 5,586 observed LOTs among the 3,777 patients, 66.5% were single-agent and 33.5% combination chemotherapy. Combination chemotherapy was most frequently used in first-line (45%) and least frequently in fifth-line (16%). Across all LOTs, median TNT was significantly longer for single-agent versus combination chemotherapy (5.3 months vs. 4.1 months, p < .0001). Comparison of median TNT by LOT showed significance in third-line and greater but not in first-line or second-line. Among single agents, the median TNT for patients receiving capecitabine was longest in comparison to all other single agents. CONCLUSIONS: The frequency of combination COT use, particularly in first-line, warrants further research given published guideline recommendations. The observed TNT difference favoring single-agent treatment in later lines supports guideline recommendations. Variance between single-agent preference and observed TNT was noteworthy. IMPLICATIONS FOR PRACTICE: Although published data from evidence- and consensus-based guidelines recommend single-agent over combination chemotherapy, the extensive list of agents available for use and a gap in the comparative effectiveness research of these agents have resulted in significant variances in patterns of care. The aim of this study was to assess real-world treatment patterns and their effectiveness during palliative therapy of metastatic breast cancer. The objective was to understand when and how chemotherapy-only treatment is used in metastatic breast cancer and whether comparative effectiveness analysis supports the observed patterns of care.

Reports of the demise of chemotherapy have been greatly exaggerated.

Does the rapid integration of both targeted and immuno-oncology drugs into treatment guidelines across solid tumors and hematologic malignancies herald the beginning of the end of chemotherapy as a foundational element in systemic cancer treatment? We respond to similar assertions posited after the 2018 American Society of Clinical Oncology Annual Meeting with an analysis of past, current, and future treatment of breast cancer-a tumor central to the evolution of modern cancer treatment principles. Our conclusions assert that reports of the demise of chemotherapy are greatly exaggerated and, as chemotherapy is likely to remain foundational for years to come, research is warranted to improve its patient-centricity.

Temporal pattern of left ventricular structural and functional remodeling following reversal of volume overload heart failure.

Current surgical management of volume overload-induced heart failure (HF) leads to variable recovery of left ventricular (LV) function despite a return of LV geometry. The mechanisms that prevent restoration of function are unknown but may be related to the timing of intervention and the degree of LV contractile impairment. This study determined whether reduction of aortocaval fistula (ACF)-induced LV volume overload during the compensatory stage of HF results in beneficial LV structural remodeling and restoration of pump function. Rats were subjected to ACF for 4 wk; a subset then received a load-reversal procedure by closing the shunt using a custom-made stent graft approach. Echocardiography or in vivo pressure-volume analysis was used to assess LV morphology and function in sham rats; rats subjected to 4-, 8-, or 15-wk ACF; and rats subjected to 4-wk ACF followed by 4- or 11-wk reversal. Structural and functional changes were correlated to LV collagen content, extracellular matrix (ECM) proteins, and hypertrophic markers. ACF-induced volume overload led to progressive LV chamber dilation and contractile dysfunction. Rats subjected to short-term reversal (4-wk ACF + 4-wk reversal) exhibited improved chamber dimensions (LV diastolic dimension) and LV compliance that were associated with ECM remodeling and normalization of atrial and brain natriuretic peptides. Load-independent parameters indicated LV systolic (preload recruitable stroke work, Ees) and diastolic dysfunction (tau, arterial elastance). These changes were associated with an altered α/ß-myosin heavy chain ratio. However, these changes were normalized to sham levels in long-term reversal rats (4-wk ACF + 11-wk reversal). Acute hemodynamic changes following ACF reversal improve LV geometry, but LV dysfunction persists. Gradual restoration of function was related to normalization of eccentric hypertrophy, LV wall stress, and ECM remodeling. These results suggest that mild to moderate LV systolic dysfunction may be an important indicator of the ability of the myocardium to remodel following the reversal of hemodynamic overload.

Mesenteric resistance arteries in type 2 diabetic db/db mice undergo outward remodeling.

OBJECTIVE: Resistance vessel remodeling is controlled by myriad of hemodynamic and neurohormonal factors. This study characterized structural and molecular remodeling in mesenteric resistance arteries (MRAs) in diabetic (db/db) and control (Db/db) mice. METHODS: Structural properties were assessed in isolated MRAs from 12 and 16 wk-old db/db and Db/db mice by pressure myography. Matrix regulatory proteins were measured by Western blot analysis. Mean arterial pressure and superior mesenteric blood flow were measured in 12 wk-old mice by telemetry and a Doppler flow nanoprobe, respectively. RESULTS: Blood pressure was similar between groups. Lumen diameter and medial cross-sectional area were significantly increased in 16 wk-old db/db MRA compared to control, indicating outward hypertrophic remodeling. Moreover, wall stress and cross-sectional compliance were significantly larger in diabetic arteries. These remodeling indices were associated with increased expression of matrix regulatory proteins matrix metalloproteinase (MMP)-9, MMP-12, tissue inhibitors of matrix metalloproteinase (TIMP)-1, TIMP-2, and plasminogen activator inhibitor-1 (PAI-1) in db/db arteries. Finally, superior mesenteric artery blood flow was increased by 46% in 12 wk-old db/db mice, a finding that preceded mesenteric resistance artery remodeling. CONCLUSIONS: These data suggest that flow-induced hemodynamic changes may supersede the local neurohormonal and metabolic milieu to culminate in hypertrophic outward remodeling of type 2 DM mesenteric resistance arteries.

Coronary arterioles in type 2 diabetic (db/db) mice undergo a distinct pattern of remodeling associated with decreased vessel stiffness.

Little is known about the impact of type 2 diabetes mellitus (DM) on coronary arteriole remodeling. The aim of this study was to determine the mechanisms that underlie coronary arteriole structural remodeling in type 2 diabetic (db/db) mice. Passive structural properties of septal coronary arterioles isolated from 12- to 16-week-old diabetic db/db and control mice were assessed by pressure myography. Coronary arterioles from 12-week-old db/db mice were structurally similar to age-matched controls. By 16 weeks of age, coronary wall thickness was increased in db/db arterioles (p < 0.01), while luminal diameter was reduced (control: 118 ± 5 µm; db/db: 102 ± 4 µm, p < 0.05), augmenting the wall-to-lumen ratio by 58% (control: 5.9 ± 0.6; db/db: 9.5 ± 0.4, p < 0.001). Inward hypertrophic remodeling was accompanied by a 56% decrease in incremental elastic modulus (p < 0.05, indicating decreased vessel coronary wall stiffness) and a ~30% reduction in coronary flow reserve (CFR) in diabetic mice. Interestingly, aortic pulse wave velocity and femoral artery incremental elastic modulus were increased (p < 0.05) in db/db mice, indicating macrovascular stiffness. Molecular tissue analysis revealed increased elastin-to-collagen ratio in diabetic coronaries when compared to control and a decrease in the same ratio in the diabetic aortas. These data show that coronary arterioles isolated from type 2 diabetic mice undergo inward hypertrophic remodeling associated with decreased stiffness and increased elastin-to-collagen ratio which results in a decreased CFR. This study suggests that coronary microvessels undergo a different pattern of remodeling from macrovessels in type 2 DM.

Environmentally persistent free radicals decrease cardiac function before and after ischemia/reperfusion injury in vivo.

Exposure to airborne particles is associated with increased cardiovascular morbidity and mortality. During the combustion of chlorine-containing hazardous materials and fuels, chlorinated hydrocarbons chemisorb to the surface of transition metal-oxide-containing particles, reduce the metal, and form an organic free radical. These radical-particle systems can survive in the environment for days and are called environmentally persistent free radicals (EPFRs). This study determined whether EPFRs could decrease left ventricular function before and after ischemia and reperfusion (I/R) in vivo. Male Brown-Norway rats were dosed (8 mg/kg, intratracheal) 24 h prior to testing with particles containing the EPFR of 1, 2-dichlorobenzene (DCB230). DCB230 treatment decreased systolic and diastolic function. DCB230 also produced pulmonary and cardiac inflammation. After ischemia, systolic, but not diastolic function was significantly decreased in DCB230-treated rats. Ventricular function was not affected by I/R in control rats. There was greater oxidative stress in the heart and increased 8-isoprostane (biomarker of oxidative stress) in the plasma of treated vs. control rats after I/R. These data demonstrate for the first time that DCB230 can produce inflammation and significantly decrease cardiac function at baseline and after I/R in vivo. Furthermore, these data suggest that EPFRs may be a risk factor for cardiac toxicity in healthy individuals and individuals with ischemic heart disease. Potential mechanisms involving cytokines/chemokines and/or oxidative stress are discussed.

Oxidative stress contributes to methamphetamine-induced left ventricular dysfunction.

AIMS: Our aim was to test the hypothesis that the repeated, binge administration of methamphetamine would produce oxidative stress in the myocardium leading to structural remodeling and impaired left ventricular function. METHODS AND RESULTS: Echocardiography and Millar pressure-volume catheters were used to monitor left ventricular structure and function in rats subjected to four methamphetamine binges (3 mg/kg, iv for 4 days, separated by a 10-day drug-free period). Hearts from treated and control rats were used for histological or proteomic analysis. When compared with saline treatment, four methamphetamine binges produced eccentric left ventricular hypertrophy. The drug also significantly impaired systolic function (decreased fractional shortening, ejection fraction, and adjusted maximal power) and produced significant diastolic dysfunction (increased -dP/dt and tau). Dihydroethedium staining showed that methamphetamine significantly increased (285%) the levels of reactive oxygen species in the left ventricle. Treatment with methamphetamine also resulted in the tyrosine nitration of myofilament (desmin, myosin light chain) and mitochondrial (ATP synthase, NADH dehydrogenase, cytochrome c oxidase, prohibitin) proteins. Treatment with the superoxide dismutase mimetic, tempol in the drinking water prevented methamphetamine-induced left ventricular dilation and systolic dysfunction; however, tempol (2.5 mM) did not prevent the diastolic dysfunction. Tempol significantly reduced, but did not eliminate dihydroethedium staining in the left ventricle, nor did it prevent the tyrosine nitration of mitochondrial and contractile proteins. CONCLUSION: This study shows that oxidative stress plays a significant role in mediating methamphetamine-induced eccentric left ventricular dilation and systolic dysfunction.

Effects of PARP-1 deficiency on airway inflammatory cell recruitment in response to LPS or TNF: differential effects on CXCR2 ligands and Duffy Antigen Receptor for Chemokines.

We reported that PARP-1 exhibits differential roles in expression of inflammatory factors. Here, we show that PARP-1 deletion was associated with a significant reduction in inflammatory cell recruitment to mouse airways upon intratracheal administration of LPS. However, PARP-1 deletion exerted little effect in response to TNF exposure. LPS induced massive neutrophilia and moderate recruitment of macrophages, and TNF induced recruitment of primarily macrophages with smaller numbers of neutrophils in the lungs. Following either exposure, macrophage recruitment was blocked severely in PARP-1(-/-) mice, and this was associated with a marked reduction in MCP-1 and MIP-1alpha. This association was corroborated partly by macrophage recruitment in response to intratracheal administration of MCP-1 in PARP-1(-/-) mice. Surprisingly, although neutrophil recruitment was reduced significantly in LPS-treated PARP-1(-/-) mice, neutrophil numbers increased in TNF-treated mice, suggesting that PARP-1 deletion may promote a macrophagic-to-neutrophilic shift in the inflammatory response upon TNF exposure. Neutrophil-specific chemokines mKC and MIP-2 were reduced significantly in lungs of LPS-treated but only partially reduced in TNF-treated PARP-1(-/-) mice. Furthermore, the MIP-2 antagonist abrogated the shift to a neutrophilic response in TNF-exposed PARP-1(-/-) mice. Although CXCR2 expression increased in response to either stimulus in PARP-1(+/+) mice, the DARC increased only in lungs of TNF-treated PARP-1(+/+) mice; both receptors were reduced to basal levels in treated PARP-1(-/-) mice. Our results show that the balance of pro-neutrophilic or pro-macrophagic stimulatory factors and the differential influence of PARP-1 on these factors are critical determinants for the nature of the airway inflammatory response.

Ecstasy produces left ventricular dysfunction and oxidative stress in rats.

AIMS: Our aim was to determine whether the repeated, binge administration of 3,4-methylenedioxymethamphetamine (ecstasy; MDMA) produces structural and/or functional changes in the myocardium that are associated with oxidative stress. METHODS AND RESULTS: Echocardiography and pressure-volume conductance catheters were used to assess left ventricular (LV) structure and function in rats subjected to four ecstasy binges (9 mg/kg i.v. for 4 days, separated by a 10 day drug-free period). Hearts from treated and control rats were used for either biochemical and proteomic analysis or the isolation of adult LV myocytes. After the fourth binge, treated hearts showed eccentric LV dilation and diastolic dysfunction. Systolic function was not altered in vivo; however, the magnitude of the contractile responses to electrical stimulation was significantly smaller in myocytes from rats treated in vivo with ecstasy compared with myocytes from control rats. The magnitude of the peak increase in intracellular calcium (measured by Fura-2) was also significantly smaller in myocytes from ecstasy-treated vs. control rats. The relaxation kinetics of the intracellular calcium transients were significantly longer in myocytes from ecstasy-treated rats. Ecstasy significantly increased nitrotyrosine content in the left ventricle. Proteomic analysis revealed increased nitration of contractile proteins (troponin-T, tropomyosin alpha-1 chain, myosin light polypeptide, and myosin regulatory light chain), mitochondrial proteins (Ub-cytochrome-c reductase and ATP synthase), and sarcoplasmic reticulum calcium ATPase. CONCLUSION: The repeated binge administration of ecstasy produces eccentric LV dilation and dysfunction that is accompanied by oxidative stress. These functional responses may result from the redox modification of proteins involved in excitation-contraction coupling and/or mitochondrial energy production. Together, these results indicate that ecstasy has the potential to produce serious cardiac toxicity and ventricular dysfunction.

Activator of G protein signaling 3 null mice: I. Unexpected alterations in metabolic and cardiovascular function.

Activator of G protein signaling (AGS)-3 plays functional roles in cell division, synaptic plasticity, addictive behavior, and neuronal development. As part of a broad effort to define the extent of functional diversity of AGS3-regulated-events in vivo, we generated AGS3 null mice. Surprisingly, AGS3 null adult mice exhibited unexpected alterations in cardiovascular and metabolic functions without any obvious changes in motor skills, basic behavioral traits, and brain morphology. AGS3 null mice exhibited a lean phenotype, reduced fat mass, and increased nocturnal energy expenditure. AGS3 null mice also exhibited altered blood pressure control mechanisms. These studies expand the functional repertoire for AGS3 and other G protein regulatory proteins providing unexpected mechanisms by which G protein systems may be targeted to influence obesity and cardiovascular function.

Low positive end-expiratory pressure does not exacerbate nebulized-acid lung injury in dogs.

It is not clear if low end-expiratory pressures contribute to ventilator-induced lung injury in large animals. We sought to determine whether ventilation with a low level of positive end-expiratory pressure (PEEP) worsens preexisting permeability lung injury in dogs. Lung injury was initiated in 20 mongrel dogs by ventilating with nebulized 3N hydrochloric acid until a lower inflection point (LIP) appeared on the respiratory system pressure-volume loop. One group of 10 dogs was then ventilated for 4 hours with PEEP set below the LIP (low PEEP), whereas the remaining group of dogs was ventilated for the same time period with similar tidal volumes but with PEEP set above the LIP (high PEEP). We found histologic evidence of reduced alveolar volumes in the low-PEEP animals. However, there were no differences in neutrophil infiltration, lung lobe weights, pulmonary capillary hemorrhage or congestion, or arterial endothelin-1 concentration between the 2 protocol groups. In conclusion, we were unable to demonstrate that ventilation with PEEP set below the LIP exacerbates hydrochloric acid-induced lung injury in dogs.

Electronic tongue for pharmaceutical analytics: quantification of tastes and masking effects.

The organoleptic aspects of pharmaceutical formulations affect their acceptability to the patient and hence can have an important effect on concordance with treatment. Objective evaluation of these aspects, particularly the taste of the formulation and the drug substance it contains, is difficult. Whilst volunteer taste panels can be used to good effect their utility is limited, particularly during very early stage development when the toxicological profile of the active pharmaceutical ingredient (API) is yet to be established in detail. A potentiometric "electronic tongue" has been applied to analyse a variety of 41 individual substances and mixtures of particular interest for pharmaceutical research and development. The electronic tongue (ET) was capable of discriminating between substances with different taste modalities and could also distinguish different substances eliciting the same basic taste; the ET is promising in terms of quantifying the content of each substance and has an ability to detect nuances of the basic taste (e.g. lingering or short-lived). After calibration the electronic tongue was successfully applied to predicting bitterness strength of binary mixtures with a sweetener in terms of "apparent" or "perceived" quinine content. In order to render a formulation palatable it is often necessary to mask the (usually bitter) taste of the API by the addition of masking agents such as sweeteners and flavours. The ET proved capable of distinguishing between formulations with different levels of sweetener and/or flavour in a manner that was consistent with their masking efficiency as perceived by a small human taste panel. A suitably calibrated ET could have the benefit of providing the pharmaceutical formulator with reliable data concerning the taste of the product quickly and with a reduced need to ask volunteers to taste active pharmaceutical samples. Early development activities could be facilitated when human tasting is usually not possible in the absence of the required toxicological data.

Changes in cardiovascular responsiveness and cardiotoxicity elicited during binge administration of Ecstasy.

The recreational use of 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy) is often characterized by a repeated pattern of frequent drug administrations (binge) followed by a period of abstinence. Radiotelemetry was used to characterize the cardiovascular responses elicited during three MDMA binges (3 or 9 mg/kg b.i.d. for 4 days), each of which was separated by a 10-day MDMA-free period. The heart rate and mean arterial pressure (MAP) responses elicited by 3-mg/kg doses of MDMA were consistent within and between the three binges. In the first binge the 9-mg/kg doses of MDMA increased MAP and produced a biphasic (decrease/increase) heart rate response. The bradycardia elicited by MDMA in the first binge (-75 bpm) was enhanced in the second and third binges (-186 and -287 bpm, respectively). Significant hypotension accompanied the increased bradycardic responses. Atropine abolished the hypotension and significantly attenuated the bradycardic responses. The MAP and heart rate responses elicited by sodium nitroprusside, acetylcholine, phenylephrine, and serotonin (5-HT) were evaluated before each binge and 10 days after the last binge. The hypotension, but not the tachycardia elicited by sodium nitroprusside was attenuated by the repeated administration of MDMA. The responses to phenylephrine, acetylcholine, and 5-HT were unaltered after MDMA. The hearts of treated rats contained foci of inflammatory infiltrates (lymphocytes and macrophages), some of which contained necrotic cells and/or disrupted cytoarchitecture. MDMA produced cardiac arrhythmias in some rats. These results indicate that the binge administration of MDMA can significantly alter cardiovascular and cardiovascular reflex function and produce cardiac toxicity.

Pulmonary capillary pressure during acute lung injury in dogs.

OBJECTIVES: To measure pulmonary capillary pressure and pulmonary artery occlusion pressures both during control conditions and during acute lung injury and to evaluate the effects of inotropic therapy and volume loading on these measurements after lung injury. DESIGN: Prospective, randomized, controlled laboratory trial. SETTING: University research laboratory. SUBJECTS: Eighteen heartworm-free mongrel dogs. INTERVENTIONS: Dogs were anesthetized (sodium pentobarbital, 30 mg/kg intravenously), intubated, and mechanically ventilated. A femoral artery and vein and the right external jugular vein were cannulated. After a median sternotomy, two pulmonary artery catheters were inserted via the jugular vein into the left and right lower lobar pulmonary arteries. Oleic acid (0.03 mL/kg) was administered to all dogs via the left pulmonary artery catheter, whereas the right lower lobe served as control. A baseline group of dogs received no further interventions, whereas two additional groups were given dobutamine (30-60 microg x kg(-1) x min(-1)intravenously) or saline boluses (1-2 L) before measurements were obtained after oleic acid lung injury. MEASUREMENTS AND MAIN RESULTS: Capillary pressure was estimated in both lower lung lobes by using the pulmonary artery occlusion method. Pulmonary capillary and pulmonary artery occlusion pressures were measured before and 2 hrs after oleic acid administration. Left lower lobar capillary pressure increased in all three groups, as did the difference between capillary pressure and pulmonary artery occlusion pressure. Capillary pressure in the control right lower lobe increased significantly only in the saline-loaded dogs, whereas the difference between the right-sided capillary and occlusion pressures increased only in the dogs given dobutamine. CONCLUSIONS: Oleic acid lung injury increases pulmonary capillary pressure independent of pulmonary artery occlusion pressure. The gradient between the two pressures was not significantly affected by volume loading or dobutamine infusion.