Browsing by Subject "therapeutic use"
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Item Challenging the catechism of therapeutics for chronic neuropathic pain: targeting CaV2.2 interactions with CRMP2 peptides(Elsevier, 2013-12-17) Feldman, Polina; Khanna, Rajesh; Department of Pharmacology and Toxicology, IU School of MedicineChronic neuropathic pain management is a worldwide concern. Pharmaceutical companies globally have historically targeted ion channels as the therapeutic catechism with many blockbuster successes. Remarkably, no new pain therapeutic has been approved by European or American regulatory agencies over the last decade. This article will provide an overview of an alternative approach to ion channel drug discovery: targeting regulators of ion channels, specifically focusing on voltage-gated calcium channels. We will highlight the discovery of an anti-nociceptive peptide derived from a novel calcium channel interacting partner – the collapsin response mediator protein 2 (CRMP2). In vivo administration of this peptide reduces pain behavior in a number of models of neuropathic pain without affecting sympathetic-associated cardiovascular activity, memory retrieval, sensorimotor function, or depression. A CRMP2-derived peptide analgesic, with restricted access to the CNS, represents a completely novel approach to the treatment of severe pain with an improved safety profile. As peptides now represent one of the fastest growing classes of new drugs, it is expected that peptide targeting of protein interactions within the calcium channel complex may be a paradigm shift in ion channel drug discovery.Item Characterization of hepatic enzyme activity in older adults with dementia: potential impact on personalizing pharmacotherapy(Dove Medical Press, 2015) Campbell, Noll L.; Skaar, Todd C.; Perkins, Anthony J.; Gao, Sujuan; Li, Lang; Khan, Babar A.; Boustani, Malaz A.; Department of Medicine, IU School of MedicineOBJECTIVE: To determine the frequency of pharmacogenomic variants and concurrent medications that may alter the efficacy and tolerability of acetylcholinesterase inhibitors (AChEIs). MATERIALS AND METHODS: A multisite cross-sectional study was carried out across four memory care practices in the greater Indianapolis area. Participants were adults aged 65 years and older with a diagnosis of probable or possible Alzheimer's disease (AD) (n=105). Blood samples and self-reported medication data were collected. Since two of the three AChEIs are metabolized by cytochrome P450 (CYP)-2D6, we determined the frequency of functional genetic variants in the CYP2D6 gene and calculated their predicted CYP2D6-activity scores. Concurrent medication data were collected from self-reported medication surveys, and their predicted effect on the pharmacokinetics of AChEIs was determined based on their known effects on CYP2D6 and CYP3A4/5 enzyme activities. RESULTS: Among the 105 subjects enrolled, 72% were female and 36% were African American. Subjects had a mean age of 79.6 years. The population used a mean of eight medications per day (prescription and nonprescription). The CYP2D6 activity score frequencies were 0 (3.8%), 0.5 (4.8%), 1.0 (36.2%), 1.5-2.0 (51.4%), and >2.0 (3.8%). Nineteen subjects (18.1%) used a medication considered a strong or moderate inhibitor of CYP2D6, and eight subjects (7.6%) used a medication considered a strong or moderate inhibitor of CYP3A4/5. In total, 28.6% of the study population was predicted to have reduced activity of the CYP2D6 or CYP3A4/5 enzymes due to either genetic variants or concomitant medications. CONCLUSION: Both pharmacogenetic variants and concurrent drug therapies that are predicted to alter the pharmacokinetics of AChEIs should be evaluated in older adults with AD. Pharmacogenetic and drug-interaction data may help personalize AD therapy and increase adherence by improving tolerability.Item Combination therapies prevent the neuropathic, proinflammatory characteristics of bone marrow in streptozotocin-induced diabetic rats(American Diabetes Association, 2015-02) Dominguez, James M.; Yorek, Mark A.; Grant, Maria B.; Department of Ophthalmology, IU School of MedicineWe previously showed that peripheral neuropathy of the bone marrow was associated with loss of circadian rhythmicity of stem/progenitor cell release into the circulation. Bone marrow neuropathy results in dramatic changes in hematopoiesis that lead to microvascular complications, inflammation, and reduced endothelial repair. This series of events represents early pathogenesis before development of diabetic retinopathy. In this study we characterized early alterations within the bone marrow of streptozotocin (STZ)-induced diabetic rats following treatments that prevent experimental peripheral neuropathy. We asked whether bone marrow neuropathy and the associated bone marrow pathology were reversed with treatments that prevent peripheral neuropathy. Three strategies were tested: inhibition of neutral endopeptidase, inhibition of aldose reductase plus lipoic acid supplementation, and insulin therapy with antioxidants. All strategies prevented loss of nerve conduction velocity resulting from STZ-induced diabetes and corrected the STZ-induced diabetes-associated increase of immunoreactivity of neuropeptide Y, tyrosine hydroxylase, and somatostatin. The treatments also reduced concentrations of interleukin-1β, granulocyte colony-stimulating factor, and matrix metalloproteinase 2 in STZ-induced diabetic bone marrow supernatant and decreased the expression of NADPH oxidase 2, nitric oxide synthase 2, and nuclear factor-κB1 mRNA in bone marrow progenitor cells. These therapies represent novel approaches to attenuate the diabetic phenotype within the bone marrow and may constitute an important therapeutic strategy for diabetic microvascular complications.Item Comprehensive evaluation of caregiver-reported antiretroviral therapy adherence for HIV-infected children(Springer-Verlag, 2015-04) Vreeman, Rachel C.; Nyandiko, Winstone M.; Liu, Hai; Tu, Wanzhu; Scanlon, Michael L.; Slaven, James E.; Ayaya, Samuel O.; Inui, Thomas S.; Department of Pediatrics, IU School of MedicineFor HIV-infected children, adherence to antiretroviral therapy (ART) is often assessed by caregiver report but there are few data on their validity. We conducted prospective evaluations with 191 children ages 0-14 years and their caregivers over 6 months in western Kenya to identify questionnaire items that best predicted adherence to ART. Medication Event Monitoring Systems(®) (MEMS, MWV/AARDEX Ltd., Switzerland) electronic dose monitors were used as external criterion for adherence. We employed a novel variable selection tool using the LASSO technique with logistic regression to identify items best correlated with dichotomized MEMS adherence (≥90 or <90 % doses taken). Nine of 48 adherence items were identified as the best predictors of adherence, including missed or late doses in the past 7 days, problems giving the child medicines, and caregiver-level factors like not being present at medication taking. These items could be included in adherence assessment tools for pediatric patients.Item Cost-effectiveness of first-line antiretroviral therapy for HIV-infected African children less than 3 years of age(Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2015-06-19) Ciaranello, Andrea L.; Doherty, Kathleen; Penazzato, Martina; Lindsey, Jane C.; Harrison, Linda; Kelly, Kathleen; Walensky, Rochelle P.; Essajee, Shaffiq; Losina, Elena; Muhe, Lulu; Wools-Kaloustian, Kara; Ayaya, Samuel; Weinstein, Milton C.; Palumbo, Paul; Freedberg, Kenneth A.; Department of Medicine, IU School of MedicineBACKGROUND: The International Maternal, Pediatric, and Adolescent Clinical Trials P1060 trial demonstrated superior outcomes for HIV-infected children less than 3 years old initiating antiretroviral therapy (ART) with lopinavir/ritonavir compared to nevirapine, but lopinavir/ritonavir is four-fold costlier. DESIGN/METHODS: We used the Cost-Effectiveness of Preventing AIDS Complications (CEPAC)-Pediatric model, with published and P1060 data, to project outcomes under three strategies: no ART; first-line nevirapine (with second-line lopinavir/ritonavir); and first-line lopinavir/ritonavir (second-line nevirapine). The base-case examined South African children initiating ART at age 12 months; sensitivity analyses varied all key model parameters. Outcomes included life expectancy, lifetime costs, and incremental cost-effectiveness ratios [ICERs; dollars/year of life saved ($/YLS)]. We considered interventions with ICERs less than 1× per-capita gross domestic product (South Africa: $7500)/YLS as 'very cost-effective,' interventions with ICERs below 3× gross domestic product/YLS as 'cost-effective,' and interventions leading to longer life expectancy and lower lifetime costs as 'cost-saving'. RESULTS: Projected life expectancy was 2.8 years with no ART. Both ART regimens markedly improved life expectancy and were very cost-effective, compared to no ART. First-line lopinavir/ritonavir led to longer life expectancy (28.8 years) and lower lifetime costs ($41 350/person, from lower second-line costs) than first-line nevirapine (27.6 years, $44 030). First-line lopinavir/ritonavir remained cost-saving or very cost-effective compared to first-line nevirapine unless: liquid lopinavir/ritonavir led to two-fold higher virologic failure rates or 15-fold greater costs than in the base-case, or second-line ART following first-line lopinavir/ritonavir was very ineffective. CONCLUSIONS: On the basis of P1060 data, first-line lopinavir/ritonavir leads to longer life expectancy and is cost-saving or very cost-effective compared to first-line nevirapine. This supports WHO guidelines, but increasing access to pediatric ART is critical regardless of the regimen used.Item DNA repair targeted therapy: The past or future of cancer treatment?(Elsevier, 2016-04) Gavande, Navnath S.; VanderVere-Carozza, Pamela S.; Hinshaw, Hilary D.; Jalal, Shadia I.; Sears, Catherine R.; Pawelczak, Katherine S.; Turchi, John J.; Department of Medicine, School of MedicineThe repair of DNA damage is a complex process that relies on particular pathways to remedy specific types of damage to DNA. The range of insults to DNA includes small, modest changes in structure including mismatched bases and simple methylation events to oxidized bases, intra- and interstrand DNA crosslinks, DNA double strand breaks and protein-DNA adducts. Pathways required for the repair of these lesions include mismatch repair, base excision repair, nucleotide excision repair, and the homology directed repair/Fanconi anemia pathway. Each of these pathways contributes to genetic stability, and mutations in genes encoding proteins involved in these pathways have been demonstrated to promote genetic instability and cancer. In fact, it has been suggested that all cancers display defects in DNA repair. It has also been demonstrated that the ability of cancer cells to repair therapeutically induced DNA damage impacts therapeutic efficacy. This has led to targeting DNA repair pathways and proteins to develop anti-cancer agents that will increase sensitivity to traditional chemotherapeutics. While initial studies languished and were plagued by a lack of specificity and a defined mechanism of action, more recent approaches to exploit synthetic lethal interaction and develop high affinity chemical inhibitors have proven considerably more effective. In this review we will highlight recent advances and discuss previous failures in targeting DNA repair to pave the way for future DNA repair targeted agents and their use in cancer therapy.Item Educational interventions to increase HPV vaccination acceptance: A systematic review(Elsevier, 2014-04-07) Fu, Linda Y.; Bonhomme, Lize-Anne; Cooper, Spring Chenoa; Joseph, Jill G.; Zimet, Gregory D.; Department of Pediatrics, IU School of MedicineBackground The Human papillomavirus (HPV) vaccine has been available for protection against HPV-associated cervical cancer and genital warts since 2006. Nonetheless, uptake has varied among countries and populations within countries. Studies have found that individuals’ knowledge and attitudes toward the vaccine are associated with immunization uptake. The purpose of the current review is to summarize and evaluate the evidence for educational interventions to increase HPV vaccination acceptance. Methods We searched the databases of PubMed and Web of Science for English-language articles describing educational interventions designed to improve HPV vaccination uptake, intention or attitude. Results We identified 33 studies of HPV vaccination educational interventions: 7 tested the effectiveness of interventions with parents, 8 with adolescents or young adults, and 18 compared the effectiveness of different message frames in an educational intervention among adolescents, young adults or their parents. Most studies involved populations with higher educational attainment and most interventions required participants to be literate. The minority of studies used the outcome of HPV vaccine uptake. Well-designed studies adequately powered to detect change in vaccine uptake were rare and generally did not demonstrate effectiveness of the tested intervention. Conclusions There is not strong evidence to recommend any specific educational intervention for wide-spread implementation. Future studies are required to determine the effectiveness of culturally-competent interventions reaching diverse populations.Item Effect of collaborative care for depression on risk of cardiovascular events: data from the IMPACT randomized controlled trial(Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2014-01) Stewart, Jesse C.; Perkins, Anthony J.; Callahan, Christopher M.; Department of Psychology, School of ScienceOBJECTIVE: Although depression is a risk and prognostic factor for cardiovascular disease (CVD), depression trials involving cardiac patients have not observed the anticipated cardiovascular benefits. To test our hypothesis that depression treatment delivered before clinical CVD onset reduces risk of CVD events, we conducted an 8-year follow-up study of the Indiana sites of the Improving Mood-Promoting Access to Collaborative Treatment (IMPACT) randomized controlled trial. METHODS: Participants were 235 primary care patients 60 years or older with major depression or dysthymia who were randomized to a 12-month collaborative care program involving antidepressants and psychotherapy (85 without and 35 with baseline CVD) or usual care (83 without and 32 with baseline CVD). Hard CVD events (fatal/nonfatal) were identified using electronic medical record and Medicare/Medicaid data. RESULTS: A total of 119 patients (51%) had a hard CVD event. As hypothesized, the treatment × baseline CVD interaction was significant (p = .021). IMPACT patients without baseline CVD had a 48% lower risk of an event than did usual care patients (28% versus 47%, hazard ratio = 0.52, 95% confidence interval = 0.31-0.86). The number needed to treat to prevent one event for 5 years was 6.1. The likelihood of an event did not differ between IMPACT and usual care patients with baseline CVD (86% versus 81%, hazard ratio = 1.19, 95% confidence interval, 0.70-2.03). CONCLUSIONS: Collaborative depression care delivered before CVD onset halved the excess risk of hard CVD events among older, depressed patients. Our findings raise the possibility that the IMPACT intervention could be used as a CVD primary prevention strategy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01561105.Item Effect of lisinopril and atenolol on aortic stiffness in patients on hemodialysis(American Society of Nephrology (ASN), 2015-04-07) Georgianos, Panagiotis I.; Agarwal, Rajiv; Department of Medicine, IU School of MedicineBACKGROUND AND OBJECTIVES: Whether improvements in arterial compliance with BP lowering are because of BP reduction alone or if pleiotropic effects of antihypertensive agents contribute remains unclear. It was hypothesized that, among patients on hemodialysis, compared with a β-blocker (atenolol), a lisinopril-based therapy will better reduce arterial stiffness. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Among 200 participants of the Hypertension in Hemodialysis Patients Treated with Atenolol or Lisinopril Trial, 179 patients with valid assessment of aortic pulse wave velocity at baseline (89 patients randomly assigned to open-label lisinopril and 90 patients randomly assigned to atenolol three times a week after dialysis) were included in the secondary analysis. Among them, 109 patients had a valid pulse wave velocity measurement at 6 months. Monthly measured home BP was targeted to <140/90 mmHg by addition of antihypertensive drugs and dry weight adjustment. The difference between drugs in percentage change of aortic pulse wave velocity from baseline to 6 months was analyzed. RESULTS: Contrary to the hypothesis, atenolol-based treatment induced greater reduction in aortic pulse wave velocity relative to lisinopril (between drug difference, 14.8%; 95% confidence interval, 1.5% to 28.5%; P=0.03). Reduction in 44-hour ambulatory systolic and diastolic BP was no different between groups (median [25th, 75th percentile]; atenolol: -21.5 [-37.7, -7.6] versus lisinopril: -15.8 [-28.8, -1.5] mmHg; P=0.27 for systolic BP; -14.1 [-22.6, -5.3] versus -10.9 [-18.4, -0.9] mmHg, respectively; P=0.30 for diastolic BP). Between-drug difference in change of aortic pulse wave velocity persisted after adjustments for age, sex, race, other cardiovascular risk factors, and baseline ambulatory systolic BP but disappeared after adjustment for change in ambulatory systolic BP (11.8%; 95% confidence interval, -2.3% to 25.9%; P=0.10). CONCLUSIONS: Among patients on dialysis, atenolol was superior in improving arterial stiffness. However, differences between atenolol and lisinopril in improving aortic stiffness among patients on hemodialysis may be explained by BP-lowering effects of drugs.Item The Effects of Cinacalcet in Older and Younger Patients on Hemodialysis: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial(American Society of Nephrology, 2015-05-07) Parfrey, Patrick S.; Drüeke, Tilman B.; Block, Geoffrey A.; Correa-Rotter, Ricardo; Floege, Jürgen; Herzog, Charles A.; London, Gerard M.; Mahaffey, Kenneth W.; Moe, Sharon M.; Wheeler, David C.; Kubo, Yumi; Dehmel, Bastian; Goodman, William G.; Chertow, Glenn M.; Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial Investigators; Department of Medicine, IU School of MedicineBACKGROUND AND OBJECTIVES: The calcimimetic cinacalcet reduced the risk of death or cardiovascular (CV) events in older, but not younger, patients with moderate to severe secondary hyperparathyroidism (HPT) who were receiving hemodialysis. To determine whether the lower risk in younger patients might be due to lower baseline CV risk and more frequent use of cointerventions that reduce parathyroid hormone (kidney transplantation, parathyroidectomy, and commercial cinacalcet use), this study examined the effects of cinacalcet in older (≥65 years, n=1005) and younger (<65 years, n=2878) patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) was a global, multicenter, randomized placebo-controlled trial in 3883 prevalent patients on hemodialysis, whose outcomes included death, major CV events, and development of severe unremitting HPT. The age subgroup analysis was prespecified. RESULTS: Older patients had higher baseline prevalence of diabetes mellitus and CV comorbidity. Annualized rates of kidney transplantation and parathyroidectomy were >3-fold higher in younger relative to older patients and were more frequent in patients randomized to placebo. In older patients, the adjusted relative hazard (95% confidence interval) for the primary composite (CV) end point (cinacalcet versus placebo) was 0.70 (0.60 to 0.81); in younger patients, the relative hazard was 0.97 (0.86 to 1.09). Corresponding adjusted relative hazards for mortality were 0.68 (0.51 to 0.81) and 0.99 (0.86 to 1.13). Reduction in the risk of severe unremitting HPT was similar in both groups. CONCLUSIONS: In the EVOLVE trial, cinacalcet decreased the risk of death and of major CV events in older, but not younger, patients with moderate to severe HPT who were receiving hemodialysis. Effect modification by age may be partly explained by differences in underlying CV risk and differential application of cointerventions that reduce parathyroid hormone.