Compliance-Adjusted Estimates of Aspirin Effects Among Older Persons in the ASPREE Randomized Trial.

The Aspirin in Reducing Events in the Elderly (ASPREE) Trial recruited 19,114 participants across Australia and the United States during 2010-2014. Participants were randomized to receive either 100 mg of aspirin daily or matching placebo, with disability-free survival as the primary outcome. During a median 4.7 years of follow-up, 37% of participants in the aspirin group permanently ceased taking their study medication and 10% commenced open-label aspirin use. In the placebo group, 35% and 11% ceased using study medication and commenced open-label aspirin use, respectively. In order to estimate compliance-adjusted effects of aspirin, we applied rank-preserving structural failure time models. The results for disability-free survival and most secondary endpoints were similar in intention-to-treat and compliance-adjusted analyses. For major hemorrhage, cancer mortality, and all-cause mortality, compliance-adjusted effects of aspirin indicated greater risks than were seen in intention-to-treat analyses. These findings were robust in a range of sensitivity analyses. In accordance with the original trial analyses, compliance-adjusted results showed an absence of benefit with aspirin for primary prevention in older people, along with an elevated risk of clinically significant bleeding.

The Association between Metabolic Syndrome, Frailty and Disability-Free Survival in Healthy Community-dwelling Older Adults.

OBJECTIVES: To examine the association between metabolic syndrome (MetS) and frailty, and determine whether co-existent MetS and frailty affect disability-free survival (DFS), assessed through a composite of death, dementia or physical disability. DESIGN: Longitudinal study. SETTING AND PARTICIPANTS: Community-dwelling older adults from Australia and the United States (n=18,264) from "ASPirin in Reducing Events in the Elderly" (ASPREE) study. MEASUREMENTS: MetS was defined according to American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines (2018). A modified Fried phenotype and a deficit accumulation Frailty Index (FI) were used to assess frailty. Association between MetS and frailty was examined using multinomial logistic regression. Cox regression was used to analyze the association between MetS, frailty and DFS over a median follow-up of 4.7 years. RESULTS: Among 18,264 participants, 49.9% met the criteria for MetS at baseline. Participants with Mets were more likely to be pre-frail [Relative Risk Ratio (RRR): 1.22; 95%Confidence Interval (CI): 1.14, 1.30)] or frail (RRR: 1.66; 95%CI: 1.32, 2.08) than those without MetS. MetS alone did not shorten DFS while pre-frailty or frailty alone did [Hazard Ratio (HR): 1.68; 95%CI: 1.45, 1.94; HR: 2.65; 95%CI:1.92, 3.66, respectively]. Co-existent MetS with pre-frailty/frailty did not change the risk of shortened DFS. CONCLUSIONS: MetS was associated with pre-frailty or frailty in community-dwelling older individuals. Pre-frailty or frailty increased the risk of reduced DFS but presence of MetS did not change this risk. Assessment of frailty may be more important than MetS in predicting survival free of dementia or physical disability.

The relationship between long-term blood pressure variability and cortical thickness in older adults.

High blood pressure variability (BPV) is a risk factor for cognitive decline and dementia, but its association with cortical thickness is not well understood. Here we use a topographical approach, to assess links between long-term BPV and cortical thickness in 478 (54% men at baseline) community dwelling older adults (70-88 years) from the ASPirin in Reducing Events in the Elderly NEURO sub-study. BPV was measured as average real variability, based on annual visits across three years. Higher diastolic BPV was significantly associated with reduced cortical thickness in multiple areas, including temporal (banks of the superior temporal sulcus), parietal (supramarginal gyrus, post-central gyrus), and posterior frontal areas (pre-central gyrus, caudal middle frontal gyrus), while controlling for mean BP. Higher diastolic BPV was associated with faster progression of cortical thinning across the three years. Diastolic BPV is an important predictor of cortical thickness, and trajectory of cortical thickness, independent of mean blood pressure. This finding suggests an important biological link in the relationship between BPV and cognitive decline in older age.

The Association between Frailty and All-Cause Mortality in Community-Dwelling Older Individuals: An Umbrella Review.

Frailty is associated with multiple adverse health outcomes, including mortality. Several methods have been used to characterize frailty, each based on different frailty scales. These include scales based on phenotype, multidomain, and deficit accumulations. Several systematic reviews have examined the association between frailty and mortality; however, it is unclear whether these different frailty scales similarly predict mortality. This umbrella review aims to examine the association between frailty assessed by different frailty scales and all-cause mortality among community-dwelling older adults. A protocol was registered at PROSPERO, and it was conducted following the PRISMA statement. MEDLINE, Embase, PubMed, Cochrane Database of Systematic Reviews, Joanna Briggs Institute (JBI) EBP database, and Web of Science database was searched. Methodological quality was assessed using the JBI critical appraisal checklist and online AMSTAR-2 critical appraisal checklist. For eligible studies, essential information was extracted and synthesized qualitatively. Five systematic reviews were included, with a total of 434,115 participants. Three systematic reviews focused on single frailty scales; one evaluated Fried's physical frailty phenotype and its modifications; another focused on the deficit accumulation frailty index. The third evaluated the FRAIL (Fatigue, Resistance, Ambulation, Illness, and Loss of weight) scale. The two other systematic reviews determined the association between frailty and mortality using different frailty scales. All of the systematic reviews found that frailty was significantly associated with all-cause mortality. This umbrella review demonstrates that frailty is a significant predictor of all-cause mortality, irrespective of the specific frailty scale.

Do antibiotics affect the quality of life of patients with upper respiratory tract illnesses? It might depend on one's luck.

OBJECTIVE: Upper respiratory tract illnesses (URTI) are known to cause measurable decline in health-related quality of life (HRQL). We studied whether antibiotics impacted patients' HRQL after obtaining medical care for URTI. METHODS: Adults seeking care for URTI at a family medicine office were eligible for this study. Decisions to prescribe antibiotics were left to their physicians. Subjects completed the Quality of Well-Being questionnaire on enrolment and on days 3, 7, 14 and 28. Analysis of HRQL was undertaken using repeated measures ANOVA and ANCOVA. RESULTS: Seventy-three patients (mean age 35.8 years) were studied. Thirty-six of the subjects (50.7%) received prescriptions for antibiotics from their physicians at the index visit. By day 28, 78.4% of the subjects in the antibiotic group and 77.8% of the other group reported cure (p = 0.95). Receiving a prescription for an antibiotic at the initial visit did not influence subsequent HRQL reported by subjects (p = 0.98). However, when subjects receiving antibiotics were subgrouped by whether they reported an antibiotic adverse event we found significant differences in final HRQL. Subjects receiving antibiotics but not experiencing adverse events reported higher HRQL by day 28 than did subjects receiving an antibiotic but also reporting adverse events and subjects not receiving any antibiotics (p = 0.02). CONCLUSION: Providing patients experiencing URTIs with prescriptions for antibiotics does not, on average, positively impact HRQL over the following 28 days. However, the subgroup of patients who receive antibiotics and do not experience an adverse event may come out ahead.

Growth medium effect on the antifungal activity of LY 303366.

The impact of growth medium selection on antifungal susceptibility testing has been well documented. Previously we described the antifungal characteristics of LY 303366 via time-kill curve methods using RPMI 1640 buffered with 0.165 M morpholinepropane-sulfonic acid as growth medium. The purpose of the current study was to compare the previously reported kill curve results with results obtained using antibiotic medium number three (AM #3) as growth medium. Antifungal activity was assessed via susceptibility testing and time-kill studies in both media. Two isolates each of Candida albicans, C. glabrata, and C. tropicalis were studied. MICs for the six isolates were found to be 10 to 100 times lower in AM #3. Time-kill studies were conducted with multiples of the MIC ranging from 0.125 x MIC to 16 x MIC. LY 303366 exhibited fungicidal (> or = 3 log10 reduction in CFU) activity against all isolates in AM #3; however, fungicidal activity was noted only for three of the six isolates when tested in RPMI. Furthermore, the rate of fungicidal activity was more rapid when AM #3 was utilized. Not only were the rate and extent of activity influenced by choice of media, but the relationships between LY 303366 concentrations and activity were also found to be media dependent. The findings from this study serve to highlight further the importance of media selection for in vitro evaluation of antifungal activity. In vivo studies need to be conducted with LY 303366 to determine which media provides the best correlation between in vitro and in vivo findings.

In vitro pharmacodynamic properties of MK-0991 determined by time-kill methods.

MK-0991 has demonstrated activity against a variety of fungal pathogens. We evaluated the MIC endpoint for MK-0991 by reading the endpoint using three methods and comparing these results with minimum fungicidal concentrations and electron micrographs. The concentration that resulted in 80% inhibition of fungal growth compared with control, similar to the endpoint for the azole antifungal agents, provided the most consistent results. Additionally, we investigated the time-kill properties of this agent against two isolates each of Candida albicans, Candida glabrata and Candida tropicalis at concentrations ranging from 0.125 x MIC to 16 x MIC. Kill curves were performed using RPMI buffered with morpholine propanesulfonic acid as growth media. Samples were obtained at predetermined time points over 24 h and plated for colony counting. Fungicidal activity was observed with one isolate of C. albicans, two isolates of C. glabrata, and one isolate of C. tropicalis. MK-0991 displayed concentration-dependent activity, which was fungicidal or fungistatic depending on the isolate tested.

Antifungal dynamics of LY 303366, an investigational echinocandin B analog, against Candida ssp.

Two isolates each of Candida albicans, Candida tropicalis, and Candida glabrata were selected for time-kill curve testing against LY 303366 at concentrations ranging from 0.125 x MIC to 16 x MIC. RPMI 1640 buffered morpholinepropanesulfonic acid (MOPS) was utilized as growth medium. Samples were obtained at predetermined time points over 24 hours and streaked for colony count determination. Against C. albicans (one strain) and C. glabrata isolates, LY 303366 exhibited fungicidal (> or = three log10 reduction in CFU) activity. In contrast, fungistatic activity was observed with LY 303366 against C. albicans (one strain) and C. tropicalis isolates at all of the multiples of the MIC tested. With the exception of one C. glabrata strain, the rate and extent of activity against test isolates was not enhanced with concentrations exceeding the MIC. Our data indicate that maximal antifungal activity with LY 303366 may be achieved by optimizing the time of fungal exposure to the drug. Additionally, these data suggest that use of the current interpretive endpoint for MICs in RPMI may underestimate the antifungal activity of LY 303366. Thus, the MIC endpoint may need to be re-evaluated, or perhaps an alternative media, such as antibiotic medium #3, should be utilized for determination of LY 303366 MICs.

Mibefradil, a pharmacologically distinct calcium antagonist.

Mibefradil is the prototype of a new class of calcium antagonists that selectively block T-type voltage-gated plasma membrane calcium channels in vascular smooth muscle. The drug is structurally and pharmacologically different from traditional calcium antagonists. It does not have negative inotropism at therapeutic concentrations, and is not associated with reflex activation of neurohormonal and sympathetic systems. In clinical studies of hypertension, mibefradil 50 and 100 mg/day reduced trough sitting diastolic and systolic blood pressures in a dose-related manner. Dosages exceeding 100 mg/day generally did not result in significantly greater efficacy, but were associated with a higher frequency of adverse events. No first-dose hypotensive phenomenon was observed. Mibefradil has antiischemic properties resulting from dilation of coronary and peripheral vascular smooth muscle, and a slight reduction in heart rate. In clinical studies of chronic stable angina pectoris, dose-related increases in exercise duration, time to onset of angina, and time to 1-mm ST-segment depression during exercise tolerance tests occurred. Mibefradil reduced the number and duration of ischemic events recorded by 48-hour ambulatory electrocardiograph (ECG) monitoring, as well as number of anginal episodes and nitroglycerin consumption. Favorable hemodynamic and clinical profiles are reported, including high trough:peak ratios (> 80%), high oral bioavailability, and long elimination half-life (17-25 hrs) permitting once/day dosing. Dizziness, headache, leg edema, and lightheadedness are frequently reported, but overall the agent is well tolerated. First-degree atrioventricular block and sinus bradycardia are the most frequent ECG changes caused by the drug. In vitro studies indicate mibefradil inhibits cytochrome P450 1A2, 2D6, and 3A4, resulting in elevated plasma concentrations of drugs metabolized by those isoenzymes. Therefore, it is contraindicated in patients receiving terfenadine, astemizole, cisapride, lovastatin, or simvastatin.

Effectively treating common infections in residents of long-term care facilities.

Clinicians involved in caring for institutionalized elderly frequently must treat common infections endemic to the setting. Numerous factors specific to these patients make accurate diagnosis and management more difficult than in healthy ambulatory adults. Three infections are commonly encountered in residents of long-term care facilities: bacterial pneumonia, urinary tract infections, and skin and soft tissue infections. More antimicrobial agents are available now than ever before; therefore, judicious administration of drugs and familiarity with current treatment recommendations are imperative.

Use of point-of-service health status assessments by community pharmacists to identify and resolve drug-related problems in patients with musculoskeletal disorders.

STUDY OBJECTIVE: To determine whether community pharmacists can use point-of-service health status assessments to identify and resolve drug-related problems (DRPs) in ambulatory patients with selected musculoskeletal (MSK) disorders. DESIGN: Twelve-month, prospective, multicenter demonstration project. SETTING: Twelve independent community pharmacies in eastern Iowa. PATIENTS: Ambulatory patients with self-reported diagnosis of osteoarthritis, rheumatoid arthritis, or low back pain. MEASUREMENTS: During quarterly pharmacy visits for 1 year, patients used touch-screen computers to report their health status. Patients answered questions on the Short Form-36 (SF-36) general health survey, as well as questions assessing limitations associated with their MSK condition. Pharmacists used this data in interviewing patients to assess for DRPs. MAIN RESULTS: The study enrolled 461 patients, of whom 388 returned for the 12-month visit. During this 1-year period, community pharmacists identified 926 cumulative DRPs. Patients with no DRPs had significantly higher physical component summary scores on the SF-36 (p<0.05) than patients with more than one DRP at baseline (36.2 vs 31.6), 6 months (39.2 vs 33.3), and 12 months (40.1 vs 35.4). At 12 months, actions performed by pharmacists led to resolution or improvement of 70.7% of DRPs. CONCLUSION: Drug-related problems are numerous in community-dwelling patients with MSK disorders and correspond to decreased physical health status. Community pharmacists can use patient-reported measures of health status to identify DRPs and initiate processes to resolve them.

Assessment of patients' perceptions and beliefs regarding herbal therapies.

We evaluated the demographics and beliefs regarding safety and efficacy of herbal therapy among individuals in Iowa and assessed the willingness to discuss the use of these products with health care providers. We distributed 1300 surveys to two random samples: patients attending eight clinics, and residents of the state (mailing). Data were categorized according to herb use and compared between users and nonusers. The response rate was 61% (794 people), with 41.6% of respondents reporting herb use. They were predominately white women and were likely to have had education beyond high school (p<0.05). Their use of prescription drugs was high (p<0.05). Although users rated safety and efficacy of herbs higher than nonusers (p<0.05), both groups believed that health care providers should be aware of use and would provide this information.

Tolcapone: a novel approach to Parkinson's disease.

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of tolcapone are reviewed. Tolcapone is the first drug brought to market from the new class of selective and reversible inhibitors of catechol-O-methyltransferase. Tolcapone is indicated for use in the treatment of Parkinson's disease as an adjunct to levodopa-carbidopa therapy in patients who are experiencing fluctuations in symptoms and who are not responding to or are not appropriate candidates for other adjunctive therapies. The absolute bioavailability of tolcapone after an oral dose is about 65%. Clinical trials have demonstrated that tolcapone 50-200 mg three times daily reduces "off" time in patients refractory to levodopa-carbidopa, Unified Parkinson's Disease Rating Scale scores, and the dosage of levodopa-carbidopa required for symptom suppression. The most frequent adverse effects of tolcapone are dyskinesia, nausea, sleep disorders, dystonia, orthostatic hypotension, diarrhea, dizziness, and hallucinations; also, there is a potential for elevation of liver transaminase concentrations in the blood. To date, three deaths from fulminant hepatic failure in association with tolcapone have been reported. Extensive liver function testing is required of all patients before and during therapy. The recommended starting dosage is 100 mg orally three times daily as an adjunct to levodopacarbidopa therapy; a concurrent reduction in the levodopa dosage of about 30% is suggested. Patient response should be monitored carefully during the first three weeks of therapy; treatment should be discontinued in patients failing to respond during this initial use. Tolcapone is of benefit in fluctuating Parkinson's disease, but benefits must be carefully weighed against risks in individual patients.

Levofloxacin and trovafloxacin: the next generation of fluoroquinolones?

The pharmacology, spectrum of activity, pharmacokinetics, clinical efficacy, and adverse effects of levofloxacin, recently approved by FDA, and trovafloxacin, currently undergoing clinical trials, are reviewed. Compared with quinolones in current use, levofloxacin is more potent against gram-negative bacteria and exhibits better antipseudomonal activity as well as greater oral bioavailability. Trovafloxacin is more potent than existing quinolones against gram-positive bacteria. Both agents exert their antibacterial effects by inhibiting bacterial DNA synthesis. Compared with other quinolones, levofloxacin and trovafloxacin both demonstrate superior activity against the Bacteroides fragilis group, Chlamydia spp., Mycoplasma pneumoniae, and Mycobacterium spp. The half-life (t1/2) of levofloxacin is nearly eight hours. Levofloxacin can therefore be administered once daily for mild to moderate infections and twice daily for more serious infections. The recommended daily dose is 500 mg. Trovafloxacin has a t1/2 of 12 hours, which allows for single daily doses, and is extensively metabolized. Levofloxacin has demonstrated clinical efficacy in the treatment of community-acquired respiratory-tract infections, genitourinary infections, skin and skin-structure infections, acute bacterial sinusitis, and infections of the head and neck. Trovafloxacin may have a role in treating skin and skin-structure or soft-tissue infections respiratory-tract infections, sexually transmitted diseases, and meningitis. Both agents are well tolerated, with central-nervous-system and gastrointestinal adverse effects reported most frequently. Concomitant administration of antacids or compounds containing meal cations decreases absorption of these quinolones. Levofloxacin and trovafloxacin have favorable antimicrobial and pharmacokinetic profiles, offering the advantages of once-daily doses as well as superior potency and spectrum of activity compared with currently available quinolones.

Indication-specific 6-h systolic blood pressure thresholds can approximate 24-h determination of blood pressure control.

Ambulatory blood pressure monitoring (ABPM) is an accurate method for evaluating hypertension, yet its use in clinical practice may be limited by availability, cost and patient inconvenience. The objective of this study was to investigate the ability of a 6-h ABPM window to predict blood pressure control, judging by that of the full 24-h ABPM session across several clinical indications in a cohort of 486 patients referred for ABPM. Sensitivities and specificities of the 6-h systolic blood pressure mean to accurately classify patients as hypertensive were determined using a fixed reference point of 130 mm Hg for the 24-h mean. For four common indications, in which ABPM was ordered, prediction tables were constructed varying the thresholds for the 6-h mean to find the optimal value that best predicted the 24-h hypertensive status as determined from the full 24-h interval. Using a threshold of 137 mm Hg for the indications of borderline hypertension, evaluation of current antihypertensive regimen and suspected white-coat hypertension, sensitivity and specificity ranged from 0.83-0.88 to 0.80-0.88, respectively, for the ability of 6-h ABPM to correctly categorize hypertensive status. Using 133 mm Hg as the threshold for treatment resistance resulted in a sensitivity and specificity of 0.93 and 0.83, respectively. We conclude that a shortened ABPM session of 6 h can be used to accurately classify blood pressure as controlled or not, based on the results of a 24-h session. The optimal 6-h threshold for comparison depends upon indication for referral.

Acyclovir- and ganciclovir-induced neurotoxicity.

With increasing use of acyclovir and ganciclovir, primarily due to the increased number of AIDS and transplant patients, further cases of neurologic toxicity will undoubtedly be encountered. Discontinuation or dosage reduction of acyclovir and ganciclovir is necessary to manage neurologic toxicity that is directly attributed to either agent. Renal dysfunction is a known risk factor for acyclovir neurotoxicity, and case reports indicate that renal dysfunction may also be a risk factor for ganciclovir neurotoxicity. Since ganciclovir is structurally related to acyclovir, clinicians should monitor for signs and symptoms of neurotoxicity as they would with acyclovir until the risk factors are more clearly defined. Dosage reduction for both agents and increased monitoring should occur when renal dysfunction is present, to minimize the risk of neurotoxicity and other serious adverse effects. Tables 1 and 2 summarize the recommended dosages of acyclovir and ganciclovir, respectively, in the presence of renal dysfunction. However, as a few case reports describe, neurotoxicity from these agents has also occurred in patients with normal renal function. Therefore, clinicians should always remain vigilant in monitoring for signs of neurotoxicity when acyclovir or ganciclovir is administered, and have a high index of suspicion for these agents if neurotoxicity is encountered during therapy.

Methylxanthine use in anaphylaxis: what does the evidence tell us?

OBJECTIVE: To review the literature examining the use of methylxanthines in the treatment of anaphylaxis. DATA SOURCES: A MEDLINE search (January 1966-December 1998) was performed using the terms aminophylline, theophylline, and anaphylaxis. STUDY SELECTION AND DATA EXTRACTION: Articles discussing methylxanthine use in anaphylaxis were independently examined by each author. Additional information was obtained through the references of these articles. Articles not written in English were excluded. DATA SYNTHESIS: No human studies were identified. Limited published data were found in animal models of anaphylaxis. CONCLUSIONS: Safer agents with proven efficacy exist for the treatment of bronchoconstriction in anaphylaxis. Until data are available in humans, methylxanthines should not be recommended in the treatment of anaphylactic reactions.