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1.
Biomedicines ; 11(1)2022 Dec 27.
Article in English | MEDLINE | ID: mdl-36672573

ABSTRACT

Lung cancer maintains a relatively small survival rate (~19%) over a 5-year period and up to 80-85% of all lung cancer diagnoses are Non-Small Cell Lung Cancer (NSCLC). To determine whether metformin reduces non-small cell lung cancer (NSCLC) LL/2 cell growth, cells were grown in vitro and treated with metformin for 48 h. qPCR was used to assess genes related to cell cycle regulation and pro-apoptotic markers, namely Cyclin D, CDK4, p27, p21, and HES1. Treatment with 10 mM metformin significantly reduced HES1 expression (p = 0.011). Furthermore, 10 mM metformin treatment significantly decreased REDD1 (p = 0.0082) and increased p-mTOR Ser2448 (p = 0.003) protein expression. Control cells showed significant reductions in phosphorylated p53 protein expression (p = 0.0367), whereas metformin treated cells exhibited reduced total p53 protein expression (p = 0.0078). There were no significant reductions in AMPK, PKB/AKT, or STAT3. In addition, NSCLC cells were treated for 48 h. with 10 mM metformin, 4 µM gamma-secretase inhibitor (GSI), or the combination of metformin (10 mM) and GSI (4 µM) to determine the contribution of respective signaling pathways. Metformin treatment significantly reduced total nucleus expression of the proliferation maker Ki-67 with an above 65% reduction in Ki-67 expression between control and metformin-treated cells (p = 0.0021). GSI (4 µM) treatment significantly reduced Ki-67 expression by ~20% over 48 h (p = 0.0028). Combination treatment (10 mM metformin and 4 µM GSI) significantly reduced Ki-67 expression by more than 50% over 48 h (p = 0.0245). As such, direct administration of metformin (10 mM for 48 h) proved to be an effective pharmaceutical agent in reducing the proliferation of cultured non-small cell cancer cells. These intriguing in vitro results, therefore, support the further study of metformin in appropriate in vivo models as an anti-oncogenic agent and/or an adjunctive therapy.

2.
Kidney360 ; 3(12): 2019-2026, 2022 12 29.
Article in English | MEDLINE | ID: mdl-36591361

ABSTRACT

Background: Hyperkalemia is a common electrolyte abnormality in patients with CKD, which is associated with worse outcomes and limits use of renin-angiotensin-aldosterone system inhibitors (RAASi). This post hoc subgroup analysis of three clinical trials evaluated the efficacy and safety of the sodium-free, potassium-binding polymer, patiromer, for the treatment of hyperkalemia in adults with nondialysis CKD. Methods: Data from the 4-week treatment periods of AMETHYST-DN, OPAL-HK, and TOURMALINE studies were combined. Patients had baseline diagnosis of CKD, hyperkalemia (serum potassium >5.0 mEq/L), and received patiromer 8.4-33.6 g/day. Patients were stratified by baseline eGFR into two subgroups: severe/end-stage CKD (stage 3b-5; eGFR <45 ml/min per 1.73 m2) and mild/moderate CKD (stage 1-3a; eGFR ≥45 ml/min per 1.73 m2). Efficacy was assessed by the change in serum potassium (mean±SE) from baseline to week 4. Safety assessments included incidence and severity of adverse events (AEs). Results: Efficacy analyses (n=626; 62% male, mean age 66 years) included 417 (67%) patients with severe/end-stage CKD and 209 (33%) with mild/moderate CKD. Most patients were receiving RAASi therapy at baseline (severe/end-stage CKD 92%; mild/moderate CKD 98%). The mean±SE change in serum potassium (baseline to week 4) was -0.84±0.03 in the severe/end-stage CKD subgroup, and -0.60±0.04 mEq/L in the mild/moderate CKD subgroup. AEs were reported for 40% and 27% patients in the severe/end-stage and mild/moderate CKD subgroups, respectively, with 16% and 12% reporting AEs considered related to patiromer. The most frequent AEs were mild-to-moderate constipation (8% and 3%) and diarrhea (4% and 2%). AEs leading to patiromer discontinuation occurred in 6% and 2% of patients with severe/end-stage CKD, and mild/moderate CKD, respectively. Conclusions: Patiromer was effective for treatment of hyperkalemia and well tolerated in patients across stages of CKD, most of whom were receiving guideline-recommended RAASi therapy.


Subject(s)
Hyperkalemia , Renal Insufficiency, Chronic , Adult , Humans , Male , Aged , Female , Hyperkalemia/drug therapy , Hyperkalemia/etiology , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Randomized Controlled Trials as Topic , Potassium/therapeutic use , Polymers/adverse effects , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/drug therapy
3.
Article in English | MEDLINE | ID: mdl-34886282

ABSTRACT

The evolutionarily conserved signaling pathway Notch is unequivocally essential for embryogenesis. Notch's contribution to the muscle repair process in adult tissue is complex and obscure but necessary. Notch integrates with other signals in a functional antagonist manner to direct myoblast activity and ultimately complete muscle repair. There is profound recent evidence describing plausible mechanisms of Notch in muscle repair. However, the story is not definitive as evidence is slowly emerging that negates Notch's importance in myoblast proliferation. The purpose of this review article is to examine the prominent evidence and associated mechanisms of Notch's contribution to the myogenic repair phases. In addition, we discuss the emerging roles of Notch in diseases associated with muscle atrophy. Understanding the mechanisms of Notch's orchestration is useful for developing therapeutic targets for disease.


Subject(s)
Receptors, Notch , Signal Transduction , Embryonic Development , Muscles , Myoblasts
4.
Biomedicines ; 9(11)2021 Nov 14.
Article in English | MEDLINE | ID: mdl-34829914

ABSTRACT

Non-small-cell lung cancer (NSCLC) makes up 80-85% of lung cancer diagnoses. Lung cancer patients undergo surgical procedures, chemotherapy, and/or radiation. Chemotherapy and radiation can induce deleterious systemic side effects, particularly within skeletal muscle. To determine whether metformin reduces NSCLC tumor burden while maintaining skeletal muscle health, C57BL/6J mice were injected with Lewis lung cancer (LL/2), containing a bioluminescent reporter for in vivo tracking, into the left lung. Control and metformin (250 mg/kg) groups received treatments twice weekly. Skeletal muscle was analyzed for changes in genes and proteins related to inflammation, muscle mass, and metabolism. The LL/2 model effectively mimics lung cancer growth and tumor burden. The in vivo data indicate that metformin as administered was not associated with significant improvement in tumor burden in this immunocompetent NSCLC model. Additionally, metformin was not associated with significant changes in key tumor cell division and inflammation markers, or improved skeletal muscle health. Metformin treatment, while exhibiting anti-neoplastic characteristics in many cancers, appears not to be an appropriate monotherapy for NSCLC tumor growth in vivo. Future studies should pursue co-treatment modalities, with metformin as a potentially supportive drug rather than a monotherapy to mitigate cancer progression.

6.
Cells ; 10(7)2021 07 15.
Article in English | MEDLINE | ID: mdl-34359954

ABSTRACT

It has been demonstrated that inhibiting Notch signaling through γ-secretase inhibitor (GSI) treatment increases myogenesis, AKT/mTOR signaling, and muscle protein synthesis (MPS) in C2C12 myotubes. The purpose of this study was to determine if GSI-mediated effects on myogenesis and MPS are dependent on AKT/mTOR signaling. C2C12 cells were assessed for indices of myotube formation, anabolic signaling, and MPS following GSI treatment in combination with rapamycin and API-1, inhibitors of mTOR and AKT, respectively. GSI treatment increased several indices of myotube fusion and MPS in C2C12 myotubes. GSI-mediated effects on myotube formation and fusion were completely negated by treatment with rapamycin and API-1. Meanwhile, GSI treatment was able to rescue MPS in C2C12 myotubes exposed to rapamycin or rapamycin combined with API-1. Examination of protein expression revealed that GSI treatment was able to rescue pGSK3ß Ser9 despite AKT inhibition by API-1. These findings demonstrate that GSI treatment is able to rescue MPS independent of AKT/mTOR signaling, possibly via GSK3ß modulation.


Subject(s)
Amyloid Precursor Protein Secretases/drug effects , Muscle Fibers, Skeletal/drug effects , Protein Biosynthesis/drug effects , Protein Synthesis Inhibitors/pharmacology , Amyloid Precursor Protein Secretases/metabolism , Animals , Cell Differentiation/drug effects , Mice , Muscle Fibers, Skeletal/metabolism , Muscle Proteins/metabolism , Muscle, Skeletal/metabolism , Myoblasts/drug effects , Myoblasts/metabolism , Protein Synthesis Inhibitors/metabolism , Signal Transduction/drug effects
7.
Kidney Med ; 3(3): 360-367.e1, 2021.
Article in English | MEDLINE | ID: mdl-34136782

ABSTRACT

RATIONALE & OBJECTIVE: Older people are more likely to have reduced kidney function and multiple comorbid conditions predisposing them to hyperkalemia. This post hoc subgroup analysis aimed to evaluate the effectiveness of patiromer, a sodium-free nonabsorbed polymer, in lowering serum potassium levels in older patients receiving a renin-angiotensin-aldosterone system inhibitor with chronic kidney disease (CKD), type 2 diabetes mellitus (T2DM), and hypertension. STUDY DESIGN: Post hoc subgroup analysis of the randomized open-label AMETHYST-DN clinical trial. SETTING & PARTICIPANTS: Multicenter clinical trial. Individuals 75 years and older with CKD, T2DM, hypertension, and hyperkalemia at baseline (N = 60; mean age, 77 years; 30 men [50%]; mean estimated glomerular filtration rate, 41.6 ± 14.3 mL/min/1.73 m2). INTERVENTION: Patients with hyperkalemia were randomly assigned to receive patiromer at doses ranging from 4.2 to 16.8 g twice daily. OUTCOMES: We evaluated changesin serum potassium levels from baseline to week 4 and time points through 52 weeks. Long-term safety and tolerability were assessed through the end of 52 weeks and included frequency of adverse events, clinical laboratory measurements, and vital signs. RESULTS: Of 306 AMETHYST-DN participants, 60 were 75 years or older. All 60 patients had CKD and T2DM; 37% had heart failure. At screening, patients had an estimated glomerular filtration rate of 42 mL/min/1.73 m2, median urinary albumin-creatinine ratio of 127 mg/g, and baseline mean serum potassium level of 5.19 mEq/L. Mean serum potassium level was reduced at each time point from the first postbaseline visit (day 3) through week 52. LIMITATIONS: This small subgroup analysis was not prespecified and therefore randomization was lost; thus, it should be considered hypothesis generating. CONCLUSIONS: Among older patients with hyperkalemia and diabetic kidney disease, treatment with patiromer resulted in significant reductions in serum potassium levels after 4 weeks and lasted through 52 weeks. Patiromer was effective in lowering serum potassium levels and was well tolerated in older patients. FUNDING: Vifor Pharma, Inc. TRIAL REGISTRATION: NCT01371747.

9.
Article in English | MEDLINE | ID: mdl-33418916

ABSTRACT

Skeletal muscle mass and strength are lost with aging. Phytoecdysteroids, in particular 20-hydroxyecdysone (20E), increase protein synthesis in C2C12 skeletal muscle cells and muscle strength in young rats. The objective of this study was to determine whether an extract from Ajuga turkestanica (ATE), enriched in phytoecdysteroids, and 20E affect skeletal muscle mass and fiber size, fiber type, activation of the PI3K-Akt signaling pathway, and the mRNA levels of MAFbx, MuRF-1, and myostatin in sedentary aging mice. Aging male C57BL/6 mice (20 months old) received ATE, 20E, or vehicle (CT) once per day for 28 days or a single acute dose. Treatment did not alter body, muscle, or organ mass; fiber cross-sectional area; or fiber type in the triceps brachii or plantaris muscles. Likewise, protein synthesis signaling markers (i.e., phosphorylation of AktSer473 and p70S6kThr389) measured after either 28 days or acutely were unchanged. Neither ATE nor 20E treatment for 28 days affected the mRNA levels of MAFbx, MuRF-1, and myostatin. In conclusion, these data indicate that phytoecdysteroid treatment does not alter muscle mass or fiber type, nor does it activate protein synthesis signaling in the skeletal muscle of sedentary aging mice.


Subject(s)
Anabolic Agents , Aging , Animals , Male , Mice , Mice, Inbred C57BL , Muscle, Skeletal , Phosphatidylinositol 3-Kinases , Rats
10.
Kidney360 ; 2(3): 425-434, 2021 03 25.
Article in English | MEDLINE | ID: mdl-35369022

ABSTRACT

Background: Mineralocorticoid receptor antagonists reduce mortality in patients with heart failure with reduced ejection fraction and have become a standard of care in those with resistant hypertension (rHTN). Yet, their use is limited among patients with CKD, primarily due to hyperkalemia. Methods: AMBER was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study that reported that the use of the potassium-binding drug patiromer allowed a more persistent use of spironolactone in patients with CKD and rHTN. In this report, we compare the safety and efficacy of patiromer in advanced CKD as a prespecified analysis. Results: Of the 295 patients randomized, 66 fell into the eGFR 25 to <30 subgroup. In this subgroup, persistent use of spironolactone was seen in 19 of 34 (56%) in the placebo group and 27 of 32 (84%) in the patiromer group (absolute difference 29%; P<0.02). In the eGFR 30-45 subgroup, persistent use of spironolactone was seen in 79 of 114 (69%) in the placebo group and 99 of 115 (86%) in the patiromer group (absolute difference 17%; P=0.003). There was no significant interaction between eGFR subgroups (P=0.46). Systolic BP reduction with spironolactone in the eGFR 25 to <30 subgroup was 6-7 mm Hg; in the eGFR 30-45 subgroup, it was 12-13 mm Hg. There was no significant interaction between eGFR subgroups on BP reduction (P=0.79). Similar proportions of patients reported adverse events (59% in the eGFR 25 to <30 subgroup; 53% in the eGFR 30-45 subgroup). Conclusions: Patiromer facilitates the use of spironolactone among patients with rHTN, and its efficacy and safety are comparable in those with eGFR 25 to <30 and 30-45 ml/min per 1.73 m2. Clinical Trial registry name and registration number: Clinicaltrials.gov, NCT03071263.


Subject(s)
Hypertension , Renal Insufficiency, Chronic , Humans , Hypertension/drug therapy , Polymers/adverse effects , Renal Insufficiency, Chronic/complications , Spironolactone/adverse effects
11.
Biology (Basel) ; 9(6)2020 Jun 02.
Article in English | MEDLINE | ID: mdl-32498424

ABSTRACT

The role of Notch signaling is widely studied in skeletal muscle regeneration but little is known about its influences on muscle protein synthesis (MPS). The purpose of this study was to investigate whether Notch signaling is involved in the regulation of MPS. C2C12 cells were treated with a γ-secretase inhibitor (GSI), to determine the effect of reduced Notch signaling on MPS and anabolic signaling markers. GSI treatment increased myotube hypertrophy by increasing myonuclear accretion (nuclei/myotube: p = 0.01) and myonuclear domain (myotube area per fusing nuclei: p < 0.001) in differentiating C2C12 cells. GSI treatment also elevated myotube hypertrophy in differentiated C2C12s (area/myotube; p = 0.01). In concert, GSI treatment augmented pmTOR Ser2448 (p = 0.01) and protein synthesis (using SUnSET method) in myotubes (p < 0.001). Examining protein expression upstream of mTOR revealed reductions in PTEN (p = 0.04), with subsequent elevations in pAKT Thr308 (p < 0.001) and pAKT Ser473 (p = 0.05). These findings reveal that GSI treatment elevates myotube hypertrophy through both augmentation of fusion and MPS. This study sheds light on the potential multifaceted roles of Notch within skeletal muscle. Furthermore, we have demonstrated that Notch may modulate the PTEN/AKT/mTOR pathway.

12.
Eur J Heart Fail ; 22(8): 1462-1471, 2020 08.
Article in English | MEDLINE | ID: mdl-32452085

ABSTRACT

AIMS: The AMBER trial demonstrated that concomitant use of patiromer enabled the more persistent use of spironolactone by reducing the risk of hyperkalaemia in patients with resistant hypertension and advanced chronic kidney disease. We report herein the pre-specified subgroup analysis in patients with heart failure (HF). METHODS AND RESULTS: Participants were randomly assigned (1:1) to receive either placebo or patiromer (8.4 g once daily), in addition to open-label spironolactone (starting at 25 mg once daily) and their baseline blood pressure medications. Dose titrations were permitted after 1 week for patiromer/placebo and after 3 weeks for spironolactone. The primary endpoint was the between-group difference at week 12 in the proportion of patients on spironolactone. Efficacy endpoints and safety were assessed in all randomized patients (intention to treat). A total of 295 patients were enrolled, of whom 132 (45%) had HF. In the HF subgroup, 68.1% of patients receiving placebo remained on spironolactone at week 12, compared with 84.1% of patients receiving patiromer (P = 0.0504). The reason for discontinuation from spironolactone use was hyperkalaemia in the majority of both groups. There was no significant interaction between the subgroups with HF and without HF (P = 0.8085) for the primary endpoint. CONCLUSIONS: Consistent with the overall AMBER trial results, this pre-specified subgroup analysis in patients with HF, resistant hypertension and advanced chronic kidney disease demonstrated that patiromer enabled more persistent use of spironolactone by reducing the risk of hyperkalaemia.


Subject(s)
Heart Failure , Hypertension , Renal Insufficiency, Chronic , Aged , Amber , Female , Heart Failure/complications , Heart Failure/drug therapy , Heart Failure/epidemiology , Humans , Hyperkalemia/epidemiology , Hypertension/drug therapy , Hypertension/epidemiology , Male , Mineralocorticoid Receptor Antagonists/therapeutic use , Polymers , Potassium , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/epidemiology , Spironolactone , Treatment Outcome
13.
Article in English | MEDLINE | ID: mdl-31118599

ABSTRACT

Objective: We investigated the impact of preexisting COPD and its subtypes, chronic bronchitis and emphysema, on overall survival among Medicare enrollees diagnosed with non-small-cell lung cancer (NSCLC). Methods: Using SEER-Medicare data, we included patients ≥66 years of age diagnosed with NSCLC at any disease stage between 2006 and 2010 and continuously enrolled in Medicare Parts A and B in the 12 months prior to diagnosis. Preexisting COPD in patients with NSCLC were identified using ICD-9 codes. Kaplan-Meier method and log-rank tests were used to examine overall survival by COPD status and COPD subtype. Multivariable Cox proportional hazards models were fit to assess the risk of death after cancer diagnosis. Results: We identified 66,963 lung cancer patients. Of these, 22,497 (33.60%) had documented COPD before NSCLC diagnosis. For each stage of NSCLC, median survival was shorter in the COPD compared to the non-COPD group (Stage I: 692 days vs 1,130 days, P<0.0001; Stage II: 473 days vs 627 days, P<0.0001; Stage III: 224 days vs 229 days; P<0.0001; Stage IV: 106 days vs 112 days, P<0.0001). For COPD subtype, median survival for patients with preexisting chronic bronchitis was shorter compared to emphysema across all stages of NSCLC (Stage I: 672 days vs 811 days, P<0.0001; Stage II 582 days vs 445 days, P<0.0001; Stage III: 255 days vs 229 days, P<0.0001; Stage IV: 105 days vs 112 days, P<0.0001). In Cox proportional hazard model, COPD patients exhibited 11% increase in risk of death than non-COPD patients (HR: 1.11, 95%CI: 1.09-1.13). Conclusion: NSCLC patients with preexisting COPD had shorter survival with marked differences in early stages of lung cancer. Chronic bronchitis demonstrated a greater association with time to death than emphysema.


Subject(s)
Bronchitis, Chronic/epidemiology , Insurance Benefits , Lung Neoplasms/epidemiology , Medicare , Pulmonary Disease, Chronic Obstructive/epidemiology , Pulmonary Emphysema/epidemiology , Aged , Aged, 80 and over , Bronchitis, Chronic/diagnosis , Bronchitis, Chronic/mortality , Bronchitis, Chronic/therapy , Databases, Factual , Female , Humans , Lung Neoplasms/diagnosis , Lung Neoplasms/mortality , Lung Neoplasms/therapy , Male , Neoplasm Staging , Prognosis , Pulmonary Disease, Chronic Obstructive/diagnosis , Pulmonary Disease, Chronic Obstructive/mortality , Pulmonary Disease, Chronic Obstructive/therapy , Pulmonary Emphysema/diagnosis , Pulmonary Emphysema/mortality , Pulmonary Emphysema/therapy , Retrospective Studies , Risk Assessment , Risk Factors , SEER Program , Time Factors , United States/epidemiology
14.
Anal Biochem ; 568: 41-50, 2019 03 01.
Article in English | MEDLINE | ID: mdl-30605634

ABSTRACT

Apelin, the endogenous ligand for the APJ receptor, has generated interest due to its beneficial effects on the cardiovascular system. Synthesized as a 77 amino acid preproprotein, apelin is post-translationally cleaved to a series of shorter peptides. Though (Pyr)1apelin-13 represents the major circulating form in plasma, it is highly susceptible to proteolytic degradation and has an extremely short half-life, making it challenging to quantify. Literature reports of apelin levels in rodents have historically been determined with commercial ELISA kits which suffer from a lack of selectivity, recognizing a range of active and inactive isoforms of apelin peptide. (Pyr)1apelin-13 has demonstrated beneficial hemodynamic effects in humans, and we wished to evaluate if similar effects could be measured in pre-clinical models. Despite development of a highly selective LC/MS/MS method, in rodent studies where (Pyr)1apelin-13 was administered exogenously the peptide was not detectable until a detailed stabilization protocol was implemented during blood collection. Further, the inherent high clearance of (Pyr)1apelin-13 required an extended release delivery system to enable chronic dosing. The ability to deliver sustained doses and stabilize (Pyr)1apelin-13 in plasma allowed us to demonstrate for the first time the link between systemic concentration of apelin and its pharmacological effects in animal models.


Subject(s)
Intercellular Signaling Peptides and Proteins/pharmacokinetics , Peptides/analysis , Animals , Chromatography, Liquid , Dogs , Enzyme-Linked Immunosorbent Assay , Hemodynamics , Humans , Intercellular Signaling Peptides and Proteins/blood , Intercellular Signaling Peptides and Proteins/metabolism , Male , Mice , Peptides/metabolism , Rats , Rats, Sprague-Dawley , Tandem Mass Spectrometry
15.
Am J Nephrol ; 48(3): 172-180, 2018.
Article in English | MEDLINE | ID: mdl-30176673

ABSTRACT

BACKGROUND: While chronic kidney disease (CKD) is common in resistant hypertension (RHTN), prior studies -evaluating mineralocorticoid receptor antagonists excluded patients with reduced kidney function due to risk of hyperkalemia. AMBER (ClinicalTrials.gov identifier NCT03071263) will evaluate if the potassium-binding polymer patiromer used concomitantly with spironolactone in patients with RHTN and CKD prevents hyperkalemia and allows more persistent spironolactone use for hypertension management. METHODS: Randomized, double-blind, placebo-controlled parallel group 12-week study of patiromer and spironolactone versus placebo and spironolactone in patients with uncontrolled RHTN and CKD. RHTN is defined as unattended systolic automated office blood pressure (AOBP) of -135-160 mm Hg during screening despite taking ≥3 antihypertensives, including a diuretic, and an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker -(unless not tolerated or contraindicated). The CKD inclusion criterion is an estimated glomerular filtration rate (eGFR) of 25 to ≤45 mL/min/1.73 m2. Screening serum potassium must be 4.3-5.1 mEq/L. The primary efficacy endpoint is the between-group difference (spironolactone plus patiromer versus spironolactone plus placebo) in the proportion of patients remaining on spironolactone at Week 12. RESULTS: Baseline characteristics have been analyzed as of March 2018 for 146 (of a targeted 290) patients. Mean (SD) baseline age is 69.3 (10.9) years; 52.1% are male, 99.3% White, and 47.3% have diabetes. Mean (SD) baseline serum potassium is 4.68 (0.25) mEq/L, systolic AOBP is 144.3 (6.8) mm Hg, eGFR is 35.7 (7.7) mL/min/1.73 m2. CONCLUSION: AMBER will define the ability of patiromer to facilitate the use of spironolactone, an effective antihypertensive therapy for patients with RHTN and CKD.


Subject(s)
Chelating Agents/administration & dosage , Hyperkalemia/prevention & control , Hypertension/drug therapy , Mineralocorticoid Receptor Antagonists/administration & dosage , Polymers/administration & dosage , Renal Insufficiency, Chronic/complications , Spironolactone/administration & dosage , Aged , Clinical Trials as Topic , Double-Blind Method , Drug Resistance , Drug Therapy, Combination , Female , Humans , Hyperkalemia/chemically induced , Hypertension/blood , Hypertension/etiology , Male , Middle Aged , Mineralocorticoid Receptor Antagonists/adverse effects , Multicenter Studies as Topic , Potassium/blood , Randomized Controlled Trials as Topic , Renal Insufficiency, Chronic/blood , Research Design , Spironolactone/adverse effects , Treatment Outcome
16.
J Med Econ ; 21(9): 861-868, 2018 Sep.
Article in English | MEDLINE | ID: mdl-29857784

ABSTRACT

AIM: To estimate the healthcare utilization and costs in elderly lung cancer patients with and without pre-existing chronic obstructive pulmonary disease (COPD). METHODS: Using Surveillance, Epidemiology and End Results (SEER)-Medicare data, this study identified patients with lung cancer between 2006-2010, at least 66 years of age, and continuously enrolled in Medicare Parts A and B in the 12 months prior to cancer diagnosis. The diagnosis of pre-existing COPD in lung cancer patients was identified using ICD-9 codes. Healthcare utilization and costs were categorized as inpatient hospitalizations, skilled nursing facility (SNF) use, physician office visits, ER visits, and outpatient encounters for every stage of lung cancer. The adjusted analysis was performed using a generalized linear model for healthcare costs and a negative binomial model for healthcare utilization. RESULTS: Inpatient admissions in the COPD group increased for each stage of non-small cell lung cancer (NSCLC) compared to the non-COPD group per 100 person-months (Stage I: 14.67 vs 9.49 stays, p < .0001; Stage II: 14.13 vs 10.78 stays, p < .0001; Stage III: 28.31 vs 18.91 stays, p < .0001; Stage IV: 49.5 vs 31.24 stays, p < .0001). A similar trend was observed for outpatient visits, with an increase in utilization among the COPD group (Stage I: 1136.04 vs 796 visits, p < .0001; Stage II: 1325.12 vs 983.26 visits, p < .0001; Stage III: 2025.47 vs 1656.64 visits, p < .0001; Stage IV: 2825.73 vs 2422.26 visits, p < .0001). Total direct costs per person-month in patients with pre-existing COPD were significantly higher than the non-COPD group across all services ($54,799.16 vs $41,862.91). Outpatient visits represented the largest cost category across all services in both groups, with higher costs among the COPD group ($41,203 vs $31,140.08). CONCLUSION: Healthcare utilization and costs among lung cancer patients with pre-existing COPD was ∼2-3-times higher than the non-COPD group.


Subject(s)
Carcinoma, Non-Small-Cell Lung/epidemiology , Health Services/statistics & numerical data , Lung Neoplasms/epidemiology , Medicare/statistics & numerical data , Pulmonary Disease, Chronic Obstructive/epidemiology , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/economics , Carcinoma, Non-Small-Cell Lung/pathology , Comorbidity , Female , Health Expenditures/statistics & numerical data , Health Resources/economics , Health Resources/statistics & numerical data , Health Services/economics , Humans , Lung Neoplasms/economics , Lung Neoplasms/pathology , Male , Medicare/economics , Middle Aged , Models, Econometric , Neoplasm Staging , Racial Groups , Retrospective Studies , SEER Program , United States
17.
Am J Physiol Regul Integr Comp Physiol ; 314(3): R468-R477, 2018 03 01.
Article in English | MEDLINE | ID: mdl-29187383

ABSTRACT

Protein kinase C-θ (PKC-θ) is a lipid-sensitive molecule associated with lipid-induced insulin resistance in skeletal muscle. Rodent models have not cohesively supported that PKC-θ impairs insulin responsiveness in skeletal muscle. The purpose of this study was to generate mice that lack PKC-θ in skeletal muscle and determine how lipid accumulation and insulin responsiveness are affected in that tissue. Mice lacking PKC-θ in skeletal muscle (SkMPKCθKO) and controls (SkMPKCθWT) were placed on a regular diet (RD) or high-fat diet (HFD) for 15 wk, followed by determination of food intake, fasting glucose levels, lipid accumulation, and insulin responsiveness. There were no differences between SkMPKCθWT and SkMPKCθKO mice on a RD. SkMPKCθKO mice on a HFD gained less weight from 10 through 15 wk of dietary intervention ( P < 0.05). This was likely due to less caloric consumption ( P = 0.0183) and fewer calories from fat ( P < 0.001) compared with SkMPKCθWT mice on a HFD. Intramyocellular lipid accumulation ( P < 0.0001), fatty acid binding protein 4, and TNF-α mRNA levels ( P < 0.05) were markedly reduced in SkMPKCθKO compared with SkMPKCθWT mice on a HFD. As a result, fasting hyperglycemia was mitigated and insulin responsiveness, as indicated by Akt phosphorylation, was maintained in SkMPKCθKO on a HFD. Liver lipid accumulation was not affected by genotype, suggesting the deletion of PKC-θ from skeletal muscle has a tissue-specific effect. PKC-θ is a regulator of lipid-induced insulin resistance in skeletal muscle. However, the effects of this mutation may be tissue specific. Further work is warranted to comprehensively evaluated whole body metabolic responses in this model.


Subject(s)
Insulin Resistance , Insulin/metabolism , Lipid Metabolism , Muscle, Skeletal/enzymology , Protein Kinase C-theta/deficiency , Animals , Blood Glucose/metabolism , Diet, High-Fat , Fatty Acid-Binding Proteins/genetics , Fatty Acid-Binding Proteins/metabolism , Genotype , Male , Mice, Inbred C57BL , Mice, Knockout , Phenotype , Phosphorylation , Protein Kinase C-theta/genetics , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , Weight Gain
18.
Am J Med ; 131(5): 555-564.e3, 2018 05.
Article in English | MEDLINE | ID: mdl-29180023

ABSTRACT

BACKGROUND: Older people are predisposed to hyperkalemia because of impaired renal function, comorbid conditions, and polypharmacy. Renin-angiotensin-aldosterone system inhibitors (RAASi), which are recommended to treat chronic kidney disease and heart failure augment the risk. Patiromer, a nonabsorbed potassium binder, was shown in the phase 3 OPAL-HK study to decrease serum potassium in patients with chronic kidney disease taking RAASi. We studied the efficacy and safety of patiromer in a prespecified subgroup of patients aged ≥65 years from OPAL-HK. METHODS: Chronic kidney disease patients with mild or moderate-to-severe hyperkalemia received patiromer, initially 8.4 g/d or 16.8 g/d, respectively, for 4 weeks (treatment phase, part A). Eligible patients entered an 8-week randomized withdrawal phase (part B) and continued patiromer or switched to placebo. RESULTS: Mean ± standard error change in serum potassium from baseline to week 4 of part A (primary endpoint) in patients aged ≥65 years was -1.01 ± 0.05 mEq/L (P < .001); 97% achieved serum potassium 3.8-<5.1 mEq/L. The serum potassium increase during the first 4 weeks of part B was greater in patients taking placebo than in those taking patiromer (P < .001). Fewer patients taking patiromer (30%) than placebo (92%) developed recurrent hyperkalemia (serum potassium ≥5.1 mEq/L). Mild-to-moderate constipation occurred in 15% (part A) and 7% (part B) of patients aged ≥65 years. Serum potassium <3.5 mEq/L and serum magnesium <1.4 mg/dL were infrequent (4% each in patients aged ≥65 years in part A). CONCLUSIONS: Patiromer reduced recurrent hyperkalemia and was well tolerated in older chronic kidney disease patients taking RAASi.


Subject(s)
Hyperkalemia/drug therapy , Polymers/therapeutic use , Renal Insufficiency, Chronic/drug therapy , Aged , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Female , Heart Failure/complications , Humans , Male , Mineralocorticoid Receptor Antagonists/therapeutic use , Potassium/blood , Renal Insufficiency, Chronic/blood , Renal Insufficiency, Chronic/complications , Renin/antagonists & inhibitors
19.
J Hypertens ; 35 Suppl 1: S57-S63, 2017 05.
Article in English | MEDLINE | ID: mdl-28129247

ABSTRACT

OBJECTIVE: Recurrent hyperkalemia frequently limits use of renin-angiotensin-aldosterone system inhibitors (RAASi) in chronic kidney disease (CKD) patients with hypertension, diabetes, and/or heart failure. Patiromer is a sodium-free, nonabsorbed potassium (K)-binding polymer approved by the US Food and Drug Administration for the treatment of hyperkalemia. This post-hoc analysis of OPAL-HK examined the effectiveness and safety of patiromer in reducing serum K in hyperkalemic CKD patients on RAASi, with hypertension, receiving diuretic therapy versus those not on diuretics. METHODS: Depending on the degree of hyperkalemia at baseline, CKD patients with serum K from 5.1 to less than 6.5 mmol/l on RAASi (n = 243) were assigned to a patiromer of total dose 8.4 or 16.8 g, divided twice daily. Changes in serum K, and tolerability and safety were assessed over 4 weeks in patients on and not on diuretics. RESULTS: At baseline, 132 patients used diuretics and 111 were not on diuretics, mean age was 64.3 and 64.0 years, respectively, and 63 and 51% were men. Similar reductions in serum K were seen over 4 weeks in both subgroups. At week 4, serum K fell by -0.95 ±â€Š0.04 mmol/l with any diuretic and -1.04 ±â€Š0.05 mmol/l with no diuretic. Patiromer was well tolerated, with mild-to-moderate constipation reported as the most common adverse event (7.6 and 14.4% of patients on any diuretic or no diuretic, respectively). Hypokalemia (s-K <3.5 mEq/l) was reported in 2.3% of patients on any diuretic and in 3.7% not on diuretics. CONCLUSION: The serum K-lowering efficacy and safety profile of patiromer in hyperkalemia patients with CKD was not compromised by diuretic therapy.


Subject(s)
Chelating Agents/therapeutic use , Diuretics/therapeutic use , Hyperkalemia/drug therapy , Hypertension/drug therapy , Polymers/therapeutic use , Aged , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Chelating Agents/adverse effects , Constipation/chemically induced , Female , Humans , Hyperkalemia/blood , Hyperkalemia/etiology , Hypertension/complications , Hypokalemia/chemically induced , Male , Middle Aged , Polymers/adverse effects , Potassium/blood , Renal Insufficiency, Chronic/blood , Renal Insufficiency, Chronic/complications
20.
BMC Public Health ; 17(1): 965, 2017 12 19.
Article in English | MEDLINE | ID: mdl-29320996

ABSTRACT

BACKGROUND: North Carolina Nutrition and Physical Activity Self-Assessment for Child Care (NAP SACC) resources improve child body mass index (BMI) when the resources are introduced by nurses to child care providers, and offered with workshops and incentives. In San Francisco, public health and child care agencies partnered to adapt NAP SACC resources into an annual "Healthy Apple" quality improvement program (HAP). METHODS: This cluster randomized controlled trial pilot-tested integration of the HAP with bi-annual public health screenings by nurses. All child care centers that participated in Child Care Health Program (CCHP) screenings in San Francisco in 2011-2012 were offered routine services plus HAP in 2012-2013 (CCHP + HAP, n = 19) or routine services with delayed HAP in 2014-2015 (CCHP + HAP Delayed, n = 24). Intention-to-treat analyses (robust SE or mixed models) used 4 years of screening data from 12 to 17 CCHP + HAP and 17 to 20 CCHP + HAP Delayed centers, regarding 791 to 945 children ages 2 to 5y, annually. Year-specific, child level models tested if children in CCHP + HAP centers had greater relative odds of exposure to 3 index best practices and smaller Autumn-to-Spring changes in BMI percentile and z-score than children in CCHP + HAP Delayed centers, controlling for age, sex, and Autumn status. Multi-year, child care center level models tested if HAP support modified year-to-year changes (2013-2014 and 2014-2015 vs 2011-2012) in child care center annual mean Autumn-to-Spring BMI changes. RESULTS: In 2011-2012, the CCHP + HAP and CCHP + HAP Delayed centers had similar index practices (<15% of children were exposed to a physical activity curriculum, staff joining in active play, and drinking water pitchers) and annual BMI changes. In 2013-2014: 60% of children in CCHP + HAP centers were exposed to the 3 index practices vs 19% in CCHP + HAP Delayed centers; Mean (SE) child BMI percentile (-2.6 (0.9), p = 0.003) and z-score (-0.08 (0.03), p = 0.007) decreased more in CCHP + HAP vs CCHP + HAP Delayed centers. In 2014-2015, after all centers were offered HAP, the index practices and BMI changes were improved for all centers vs 2011-2012. CONCLUSIONS: Integration of the HAP with existing public health nursing services was associated with significantly more children exposed to best practices and improvement in child BMI change. The results warrant continued integration of HAP into local public health infrastructure. TRIAL REGISTRATION: ISRCTN18857356 (24/04/2015) Retrospectively registered.


Subject(s)
Child Day Care Centers , Diet, Healthy , Mass Screening/nursing , Pediatric Obesity/prevention & control , Public Health Nursing , Child, Preschool , Cluster Analysis , Exercise/psychology , Female , Humans , Male , Malus , Nutritional Status , Pilot Projects , Program Evaluation , San Francisco
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