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1.  Antimicrobial Properties of MX-2401, an Expanded-Spectrum Lipopeptide Active in the Presence of Lung Surfactant▿ 
MX-2401 is an expanded-spectrum lipopeptide antibiotic selective for Gram-positive bacteria that is a semisynthetic analog of the naturally occurring lipopeptide amphomycin. It was active against Enterococcus spp., including vancomycin-sensitive Enterococcus (VSE), vanA-, vanB-, and vanC-positive vancomycin-resistant Enterococcus (VRE), linezolid- and quinupristin-dalfopristin-resistant isolates (MIC90 of 4 μg/ml), methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) (MIC90 of 2 μg/ml), coagulase-negative staphylococci, including methicillin-sensitive Staphylococcus epidermidis (MSSE) and methicillin-resistant S. epidermidis (MRSE) (MIC90 of 2 μg/ml), and Streptococcus spp. including viridans group streptococci, and penicillin-resistant, penicillin-sensitive, penicillin-intermediate and macrolide-resistant isolates of Streptococcus pneumoniae (MIC90 of 2 μg/ml). MX-2401 demonstrated a dose-dependent postantibiotic effect varying from 1.5 to 2.4 h. Furthermore, MX-2401 was rapidly bactericidal at 4 times the MIC against S. aureus and Enterococcus faecalis, with more than 99.9% reduction in viable bacterial attained at 4 and 24 h, respectively. The MICs of MX-2401 against MRSA, MSSA, VSE, and VRE strains serially exposed for 15 passages to sub- to supra-MICs of MX-2401 remained within three dilutions of the original MIC. In contrast to that of the lipopeptide daptomycin, the antibacterial activity of MX-2401 was not affected in vitro by the presence of lung surfactant, and MX-2401 was active in vivo in the bronchial-alveolar pneumonia mouse model, in which daptomycin failed to show any activity. Moreover, the activity of MX-2401 was not as strongly dependent on the Ca2+ concentration as is the activity of daptomycin. In conclusion, MX-2401 is a promising new-generation lipopeptide for the treatment of serious infections with Gram-positive bacteria, including hospital-acquired pneumonia.
PMCID: PMC3147646  PMID: 21576435
2.  Antibacterial Activity of 2-(2′,4′-Dibromophenoxy)-4,6-dibromophenol from Dysidea granulosa 
Marine Drugs  2009;7(3):464-471.
2-(2′,4′-Dibromophenoxy)-4,6-dibromophenol isolated from the marine sponge Dysidea granulosa (Bergquist) collected off the coast of Lakshadweep islands, Indian Ocean, exhibited potent and broad spectrum in-vitro antibacterial activity, especially against methicillin resistant Staphylococcus aureus (MRSA), methicillin sensitive Staphylococcus aureus (MSSA), vancomycin resistant Enterococci (VRE), vancomycin sensitive Enterococci (VSE) and Bacillus spp. Minimal inhibitory concentration (MIC) was evaluated against 57 clinical and standard strains of Gram positive and Gram negative bacteria. The observed MIC range was 0.117–2.5 μg/mL against all the Gram positive bacteria and 0.5–2 μg/mL against Gram negative bacteria. The in-vitro antibacterial activity observed was better than that of the standard antibiotic linezolid, a marketed anti-MRSA drug. The results establish 2-(2′,4′-dibromophenoxy)-4,6-dibromophenol, as a potential lead molecule for anti-MRSA and anti-VRE drug development.
PMCID: PMC2763112  PMID: 19841726
Dysidea granulosa; 2-(2′,4′-dibromophenoxy)-4,6-dibromophenol; antibacterial activity; methicillin resistant Staphylococcus aureus; vancomycin resistant enterococci
3.  Cost-effectiveness of rosuvastatin in comparison with generic atorvastatin and simvastatin in a Swedish population at high risk of cardiovascular events 
To assess the long-term cost-effectiveness of rosuvastatin therapy compared with generic simvastatin and generic atorvastatin in reducing the incidence of cardiovascular events and mortality in a Swedish population with Framingham risk ≥20%.
A probabilistic Monte Carlo simulation model based on data from JUPITER (the Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) was used to estimate the long-term cost-effectiveness of rosuvastatin 20 mg daily versus simvastatin or atorvastatin 40 mg for the prevention of cardiovascular death and morbidity. The three- stage model included cardiovascular event prevention simulating the 4 years of JUPITER, initial prevention beyond the trial, and subsequent cardiovascular event prevention. A Swedish health care payer perspective (direct costs only) was modeled for a lifetime horizon, with 2008/2009 as the costing period. Univariate and probabilistic sensitivity analyses were performed.
The incremental cost per quality-adjusted life-year (QALY) gained with rosuvastatin 20 mg over simvastatin or atorvastatin 40 mg ranged from SEK88,113 (rosuvastatin 20 mg versus simvastatin 40 mg; Framingham risk ≥30%; net avoidance of 34 events/1000 patients) to SEK497,542 (versus atorvastatin 40 mg: Framingham risk ≥20%; net avoidance of 11 events/1000 patients) over a lifetime horizon. Probabilistic sensitivity analyses indicated that at a willingness-to-pay threshold of SEK500,000/QALY, rosuvastatin 20 mg would be cost-effective for approximately 75%–85% of simulations relative to atorvastatin or simvastatin 40 mg. Sensitivity analyses indicated the findings to be robust.
Rosuvastatin 20 mg is cost-effective over a lifetime horizon compared with generic simvastatin or atorvastatin 40 mg in patients at high cardiovascular risk in Sweden.
PMCID: PMC3278203  PMID: 22347800
cardiovascular disease; cost-benefit analysis; cost-effectiveness; rosuvastatin; simvastatin; atorvastatin; generic; high risk
4.  Colonization with antibiotic-susceptible strains protects against methicillin-resistant Staphylococcus aureus but not vancomycin-resistant enterococci acquisition: a nested case-control study 
Critical Care  2011;15(5):R210.
Harboring sensitive strains may prevent acquisition of resistant pathogens by competing for colonization of ecological niches. Competition may be relevant to decolonization strategies that eliminate sensitive strains and may predispose to acquiring resistant strains in high-endemic settings. We evaluated the impact of colonization with methicillin-sensitive Staphylococcus aureus (MSSA) and vancomycin-sensitive enterococci (VSE) on acquisition of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), respectively, when controlling for other risk factors.
We conducted a nested case-control study of patients admitted to eight ICUs performing admission and weekly bilateral nares and rectal screening for MRSA and VRE, respectively. Analyses were identical for both pathogens. For MRSA, patients were identified who had a negative nares screen and no prior history of MRSA. We evaluated predictors of MRSA acquisition, defined as a subsequent MRSA-positive clinical or screening culture, compared to those with a subsequent MRSA-negative nares screen within the same hospitalization. Medical records were reviewed for the presence of MSSA on the initial MRSA-negative nares screen, demographic and comorbidity information, medical devices, procedures, antibiotic utilization, and daily exposure to MRSA-positive patients in the same ward. Generalized linear mixed models were used to assess predictors of acquisition.
In multivariate models, MSSA carriage protected against subsequent MRSA acquisition (OR = 0.52, CI: 0.29, 0.95), even when controlling for other risk factors. MRSA predictors included intubation (OR = 4.65, CI: 1.77, 12.26), fluoroquinolone exposure (OR = 1.91, CI: 1.20, 3.04), and increased time from ICU admission to initial negative swab (OR = 15.59, CI: 8.40, 28.94). In contrast, VSE carriage did not protect against VRE acquisition (OR = 1.37, CI: 0.54, 3.48), whereas hemodialysis (OR = 2.60, CI: 1.19, 5.70), low albumin (OR = 2.07, CI: 1.12, 3.83), fluoroquinolones (OR = 1.90, CI: 1.14, 3.17), third-generation cephalosporins (OR = 1.89, CI: 1.15, 3.10), and increased time from ICU admission to initial negative swab (OR = 15.13, CI: 7.86, 29.14) were predictive.
MSSA carriage reduced the odds of MRSA acquisition by 50% in ICUs. In contrast, VSE colonization was not protective against VRE acquisition. Studies are needed to evaluate whether decolonization of MSSA ICU carriers increases the risk of acquiring MRSA when discharging patients to high-endemic MRSA healthcare settings. This may be particularly important for populations in whom MRSA infection may be more frequent and severe than MSSA infections, such as ICU patients.
PMCID: PMC3334754  PMID: 21914221
5.  Adherence to Drug Label Recommendations for Avoiding Drug Interactions Causing Statin-Induced Myopathy–A Nationwide Register Study 
PLoS ONE  2013;8(8):e69545.
To investigate the extent to which clinicians avoid well-established drug-drug interactions that cause statin-induced myopathy. We hypothesised that clinicians would avoid combining erythromycin or verapamil/diltiazem respectively with atorvastatin or simvastatin. In patients with statin-fibrate combination therapy, we hypothesised that gemfibrozil was avoided to the preference of bezafibrate or fenofibrate. When combined with verapamil/diltiazem or fibrates, we hypothesized that the dispensed doses of atorvastatin/simvastatin would be decreased.
Cross-sectional analysis of nationwide dispensing data. Odds ratios of interacting erythromycin, verapamil/diltiazem versus respective prevalence of comparator drugs doxycycline, amlodipine/felodipine in patients co-dispensed interacting statins simvastatin/atorvastatin versus patients unexposed (pravastatin/fluvastatin/rosuvastatin) was calculated. For fibrates, OR of gemfibrozil versus fenofibrate/bezafibrate in patients co-dispensed any statin was assessed.
OR of interacting erythromycin versus comparator doxycycline did not differ between patients on interacting and comparator statins either in patients dispensed high or low statin doses (adjusted OR 0.87; 95% CI 0.60–1.25 and 0.92; 95% CI 0.69–1.23). Interacting statins were less common among patients dispensed verapamil/diltiazem as compared to patients on amlodipine/felodipine (OR high dose 0.62; CI 0.56–0.68 and low dose 0.63; CI 0.58–0.68). Patients on any statin were to a lesser extent dispensed gemfibrozil compared to patients not dispensed a statin (OR high dose 0.65; CI 0.55–0.76 and low dose 0.70; CI 0.63–0.78). Mean DDD (SD) for any statin was substantially higher in patients co-dispensed gemfibrozil 178 (149) compared to patients on statin monotherapy 127 (93), (p<0.001).
Prescribers may to some extent avoid co-prescription of statins with calcium blockers and fibrates with an increased risk of myopathy. We found no evidence for avoiding co-prescriptions of statins and antibiotics with an increased risk of statin-induced adverse drug reactions. Co-prescription of statins and gemfibrozil is paradoxically associated with a marked increased statin dose, further aggravating the risk for severe myopathy.
PMCID: PMC3735530  PMID: 23940522
6.  Comparison of efficacy, safety, and cost-effectiveness of various statins in dyslipidemic diabetic patients 
Indian Journal of Pharmacology  2014;46(1):88-93.
Background and Aim:
To determine efficacy safety and the cost effectiveness, of the four most commonly prescribed statins (rosuvastatin, atorvastatin, pravastatin, and simvastatin) in the treatment of dyslipidemia among diabetic patients.
Materials and Methods:
This is a cohort, observational, population-based study conducted at diabetic clinics of the Hamad Medical Hospital and Primary Health Care Centers (PHCC) over a period from January 2007 to September 2012. The study included 1,542 consecutive diabetes patients above 18 years of age diagnosed with dyslipidemia and prescribed any of the indicated statins. Laboratory investigations were taken from the Electronic Medical Records Database (EMR-viewer). The sociodemographic, height, weight, and physical activities were collected from Patient's Medical Records. Information about statin was extracted from the pharmacy drug database. The effective reductions in total cholesterol using rosuvastatin with atorvastatin, simvastatin, and pravastatin in achieving cholesterol goals and improving plasma lipids in dyslipidemic diabetic patients were measured. Serum lipid levels measured a 1 week before the treatment and at the end 2nd year.
Rosuvastatin (10 mg) was the most effective in reducing low-density lipoprotein cholesterol (LDL-C; 28.59%), followed by simvastatin 20 mg (16.7%), atorvastatin 20 mg (15.9%), and pravastatin 20 mg (11.59.3%). All statins were safe with respect to muscular and hepatic functions. Atorvastatin was the safest statin as it resulted in the least number of patients with microalbuminuria (10.92%) as compared to other statins. Treatment with rosuvastatin 10 mg was more effective in allowing patients to reach European and Adult Treatment Plan (ATP) III LDL-C goals as compared to other statins (P < 0.0001) and produced greater reductions in LDL-C, total cholesterol, and non-HDL-C, produced similar or greater reductions in triglycerides (TGs) and increased in HDL-C.
Rosuvastatin 10 mg was the most effective statin in reducing serum lipids and total cholesterol in dyslipidemic diabetic patients.
PMCID: PMC3912814  PMID: 24550591
Atorvastatin; cost effective; dyslipidemic diabetic patients; efficacy; pravastatin; rosuvastatin; safety of statin use in dyslipidemic diabetic patients; safety; simvastatin
7.  A Review of Time Courses and Predictors of Lipid Changes with Fenofibric Acid-Statin Combination 
Cardiovascular Drugs and Therapy  2012;26(3):245-255.
Fibrates activate peroxisome proliferator activated receptor α and exert beneficial effects on triglycerides, high-density lipoprotein cholesterol, and low density lipoprotein subspecies. Fenofibric acid (FA) has been studied in a large number of patients with mixed dyslipidemia, combined with a low- or moderate-dose statin. The combination of FA with simvastatin, atorvastatin and rosuvastatin resulted in greater improvement of the overall lipid profile compared with the corresponding statin dose. The long-term efficacy of FA combined with low- or moderate- dose statin has been demonstrated in a wide range of patients, including patients with type 2 diabetes mellitus, metabolic syndrome, or elderly subjects. The FA and statin combination seems to be a reasonable option to further reduce cardiovascular risk in high-risk populations, although trials examining cardiovascular disease events are missing.
PMCID: PMC3368211  PMID: 22592524
Fenofibric acid; Fibrate; Statin; Simvastatin; Atorvastatin; Rosuvastatin; Triglycerides; High-density lipoprotein cholesterol
8.  Statins Activate Human PPARα Promoter and Increase PPARα mRNA Expression and Activation in HepG2 Cells 
PPAR Research  2008;2008:316306.
Statins increase peroxisome proliferator-activated receptor α (PPARα) mRNA expression, but the mechanism of this increased PPARα production remains elusive. To examine the regulation of PPARα production, we examined the effect of 7 statins (atorvastatin, cerivastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin) on human PPARα promoter activity, mRNA expression, nuclear protein levels, and transcriptional activity. The main results are as follows. (1) Majority of statins enhanced PPARα promoter activity in a dose-dependent manner in HepG2 cells transfected with the human PPARα promoter. This enhancement may be mediated by statin-induced HNF-4α. (2) PPARα mRNA expression was increased by statin treatment. (3) The PPARα levels in nuclear fractions were increased by statin treatment. (4) Simvastatin, pravastatin, and cerivastatin markedly enhanced transcriptional activity in 293T cells cotransfected with acyl-coenzyme A oxidase promoter and PPARα/RXRα expression vectors. In summary, these data demonstrate that PPARα production and activation are upregulated through the PPARα promoter activity by statin treatment.
PMCID: PMC2610383  PMID: 19125197
9.  Statin use and the risk of Clostridium difficile in academic medical centres 
Gut  2012;61(11):1538-1542.
To estimate the possible relationship between statin use and the risk of healthcare facility onset Clostridium difficile.
Patients over 18 years of age admitted to hospitals contributing data to the University HealthSystem Consortium between 2002 and 2009 were eligible. Patients with the ICD-9-CM code 008.45 who received a minimum 3-day course of either metronidazole or oral vancomycin on/after day 5 of admission were considered incident cases of C difficile infection. 31 472 incident cases of C difficile infection were identified and matched to five controls, on hospital, year/quarter of admission date, and age ±10 years (N=78 096). Patients who were administered one drug in the statin class (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin or simvastatin) before the index date were considered to be exposed. Conditional logistic regression modelling provided adjusted odds ratios and 95% CI.
Compared with non-users, users of any drug within the statin class were 0.78 times less likely to develop C difficile infection in the hospital (95% CI 0.75 to 0.81) adjusting for potential confounders. Differences in estimates for specific statins were minimal. Niacin, fibrates and selective cholesterol absorption inhibitors showed no association with the risk of C difficile infection.
Our data were consistent with a growing body of literature demonstrating a reduced risk of infections with statin use. Statins' pleiotropic properties may provide protection against C difficile infection.
PMCID: PMC3405173  PMID: 22442166
10.  Long-term use of rosuvastatin: a critical risk benefit appraisal and comparison with other antihyperlipidemics 
Rosuvastatin represents the latest inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase introduced in clinical practice for the treatment of hypercholesterolemia. In comparative trials, across dose ranges this statin reduced low-density lipoprotein (LDL) cholesterol and total cholesterol significantly more than atorvastatin, simvastatin, and pravastatin, and triglycerides significantly more than simvastatin and pravastatin. In healthy subjects with normal LDL cholesterol and elevated C-reactive protein, rosuvastatin treatment significantly decreased the incidence of cardiovascular events. Its chemical and pharmacokinetic properties (with a low lipophilicity and poor capacity to inhibit cytochrome P450 enzymes) suggest a very limited penetration in extrahepatic tissues with a lower risk of muscle toxicity and unlike metabolically mediated drug–drug interactions. This article reviews the most recent data on the pharmacologic and clinical properties of rosuvastatin, in order to enable the correct use of this statin for the treatment of hypercholesterolemia.
PMCID: PMC3108688  PMID: 21701608
statin; HMG-CoA reductase; LDL cholesterol; pharmacokinetics; safety
11.  Role of Antibiofilm-Antimicrobial Agents in Control of Device-Related Infections 
To assess the effects of N-acetylcysteine (NAC) on organism viability in planktonic and biofilm phases, biofilm thickness, and extracellular polysaccharide content.
We performed time-kill curves and broth macrodilution assays of bacterial and fungal clinical isolates with varying concentrations of NAC. We also created in-vitro bacterial biofilms, incubated them with NAC or control, and then stained with propidium iodide and FITC-labelled concanavalin A. We measured biofilm thickness, number of non-viable cells, and fluorescent intensity as a marker of extracellular matrix via a confocal laser scanning microscope. All experiments were conducted in triplicate. Tested organisms included methicillin-sensitive and - resistant Staphylococcus aureus (MSSA, MRSA), S. epidermidis, vancomycin-resistant Enterococcus faecalis (VRE), Pseudomonas aeruginosa, Enterobacter cloacae, Klebsiella pneumoniae, Candida albicans and C. krusei.
NAC 80 mg/ml was uniformly bactericidal (>99.9% reduction) against all tested bacteria with no recoverable organisms after 30 minutes of incubation, but was fungistatic against candida species. Minimum inhibitory and bactericidal concentrations of NAC ranged from 5–10 mg/ml. Biofilm thickness was significantly decreased in NAC-treated biofilms for all organisms except VRE. The number of non-viable cells in NAC-treated Gram-positive biofilms was increased (p<0.05 for MRSA and VRE). NAC-treated Gram-negative biofilms had scant cellularity and lacked complex 3-dimensional structures that were characteristic of controls. Fluorescent intensity was similar in the experimental and control arms.
NAC is bactericidal against clinically relevant and drug-resistant bacteria and also leads to biofilm disruption. NAC has the potential for use as a novel agent for prevention or treatment of biofilm-related infections.
PMCID: PMC3251652  PMID: 22094553
N-acetylcysteine; biofilm; time-kill curves
12.  Pharmacodynamics of Telavancin Studied in an In Vitro Pharmacokinetic Model of Infection▿  
The antibacterial effects of telavancin, vancomycin, and teicoplanin against six Staphylococcus aureus strains (1 methicillin-susceptible S. aureus [MSSA] strain, 4 methicillin-resistant S. aureus [MRSA] strains, and 1 vancomycin-intermediate S. aureus [VISA] strain) and three Enterococcus sp. strains (1 Enterococcus faecalis strain, 1 Enterococcus faecium strain, and 1 vancomycin-resistant E. faecium [VREF] strain) were compared using an in vitro pharmacokinetic model of infection. Analyzing the data from all five vancomycin-susceptible S. aureus (VSSA) strains or all 4 MRSA strains showed that telavancin was superior in its antibacterial effect as measured by the area under the bacterial kill curve at 24 h (AUBKC24) and 48 h (AUBKC48) in comparison to vancomycin or teicoplanin (P < 0.05). Telavancin was also superior to vancomycin and teicoplanin in terms of its greater early killing effect (P < 0.05). Against the three Enterococcus spp. tested, telavancin was superior to vancomycin in terms of its AUBKC24, AUBKC48, and greater early bactericidal effect (P < 0.05). Dose-ranging studies were performed to provide free-drug area under the concentration-time curve over 24 h in the steady state divided by the MIC (fAUC/MIC) exposures from 0 to 1,617 (7 to 14 exposures per strain) for 5 VSSA, 4 VISA, and the 3 Enterococcus strains. The fAUC/MIC values for a 24-h bacteriostatic effect and a 1-log-unit drop in the viable count were 43.1 ± 38.4 and 50.0 ± 39.0 for VSSA, 3.2 ± 1.3 and 4.3 ± 1.3 for VISA, and 15.1 ± 8.8 and 40.1 ± 29.4 for the Enterococcus spp., respectively. The reason for the paradoxically low fAUC/MIC values for VISA strains is unknown. There was emergence of resistance to telavancin in the dose-ranging studies, as indicated by subpopulations able to grow on plates containing 2× MIC telavancin concentrations compared to the preexposure population analysis profiles. Changes in population analysis profiles were less likely with enterococci than with S. aureus, and the greatest risk of changed profiles occurred for both species at fAUC/MIC ratios of 1 to 10. Maintaining a fAUC/MIC ratio of >50 reduced the risk of subpopulations able to grow on antibiotic-containing media emerging. These data help explain the clinical effectiveness of telavancin against MRSA and indicate that telavancin may have clinically useful activity against Enterococcus spp., and perhaps also VISA, at human doses of 10 mg/kg of body weight/day. In addition, they support a clinical breakpoint of sensitive at ≤1 mg/liter for both S. aureus and Enterococcus spp.
PMCID: PMC3028790  PMID: 21078943
13.  In Vitro Antibacterial Efficacy of 21 Indian Timber-Yielding Plants Against Multidrug-Resistant Bacteria Causing Urinary Tract Infection 
To screen methanolic leaf extracts of 21 timber-yielding plants for antibacterial activity against nine species of uropathogenic bacteria isolated from clinical samples of a hospital (Enterococcus faecalis, Staphylococcus aureus, Acinetobacter baumannii, Citrobacter freundii, Enterobacter aerogenes, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa).
Bacterial strains were subjected to antibiotic sensitivity tests by the Kirby–Bauer's disc diffusion method. The antibacterial potentiality of leaf extracts was monitored by the agar-well diffusion method with multidrug-resistant (MDR) strains of nine uropathogens.
Two Gram-positive isolates, E. faecalis and S. aureus, were resistant to 14 of the 18 antibiotics used. Gram-negative isolates A. baumannii, C. freundii, E. aerogenes, E. coli, K. pneumoniae, P. mirabilis, and P. aeruginosa were resistant to 10, 12, 9, 11, 11, 10, and 11 antibiotics, respectively, of the 14 antibiotics used. Methanolic leaf extracts of Anogeissus acuminata had the maximum zone of inhibition size—29 mm against S. aureus and 28 mm against E. faecalis and P. aeruginosa. Cassia tora had 29 mm as the zone of inhibition size for E. faecalis, E. aerogenes, and P. aeruginosa. Based on the minimum inhibitory concentration and minimum bactericidal concentration values, the most effective 10 plants against uropathogens could be arranged in decreasing order as follows: C. tora > A. acuminata > Schleichera oleosa > Pterocarpus santalinus > Eugenia jambolana > Bridelia retusa > Mimusops elengi > Stereospermum kunthianum > Tectona grandis > Anthocephalus cadamba. The following eight plants had moderate control capacity: Artocarpus heterophyllus, Azadirachta indica, Dalbergia latifolia, Eucalyptus citriodora, Gmelina arborea, Pongamia pinnata, Pterocarpus marsupium, and Shorea robusta. E. coli, followed by A. baumannii, C. freundii, E. aerogenes, P. mirabilis, and P. aeruginosa were controlled by higher amounts/levels of leaf extracts. Phytochemicals of all plants were qualitatively estimated.
A majority of timber-yielding plants studied had in vitro control capacity against MDR uropathogenic bacteria.
PMCID: PMC3922103  PMID: 24524024
antibiograms; Gram-negative bacteria; Gram-positive bacteria; multidrug resistance; timber-yielding plants; uropathogens
14.  In Vitro Activities of Daptomycin, Vancomycin, Linezolid, and Quinupristin-Dalfopristin against Staphylococci and Enterococci, Including Vancomycin- Intermediate and -Resistant Strains 
The in vitro activity of daptomycin was compared with those of vancomycin, linezolid, and quinupristin-dalfopristin against a variety (n = 203) of gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and S. epidermidis (MRSA and MRSE, respectively), vancomycin-resistant enterococci (VRE), and vancomycin-intermediate S. aureus (VISA). Overall, daptomycin was more active against all organisms tested, except Enterococcus faecium and VISA, against which its activity was similar to that of quinupristin-dalfopristin. In time-kill studies with MRSA, MRSE, VRE, and VISA, daptomycin demonstrated greater bactericidal activity than all other drugs tested, killing ≥3 log CFU/ml by 8 h. Daptomycin may be a potential alternative drug therapy for multidrug-resistant gram-positive organisms and warrants further investigation.
PMCID: PMC89814  PMID: 10722513
15.  Effects of Statins on High-Density Lipoproteins: A Potential Contribution to Cardiovascular Benefit 
Cardiovascular Drugs and Therapy  2008;22(4):321-338.
The objective was to systematically review clinical trial data on the effects of statins on high-density lipoproteins (HDL) and to examine the possibility that this provides cardiovascular benefits in addition to those derived from reductions in low-density lipoproteins (LDL).
The PubMed database was searched for publications describing clinical trials of atorvastatin, pravastatin, rosuvastatin, and simvastatin. On the basis of predefined criteria, 103 were selected for review.
Compared with placebo, statins raise HDL, measured as HDL-cholesterol (HDL-C) and apolipoprotein A-I (apo A-I); these elevations are maintained in the long-term. In hypercholesterolemia, HDL-C is raised by approximately 4% to 10%. The percentage changes are greater in patients with low baseline levels, including those with the common combination of high triglycerides (TG) and low HDL-C. These effects do not appear to be dose-related although there is evidence that, with the exception of atorvastatin, the changes in HDL-C are proportional to reductions in apo B-containing lipoproteins. The most likely explanation is a reduced rate of cholesteryl ester transfer protein (CETP)-mediated flow of cholesterol from HDL. There is some evidence that the statin effects on HDL reduce progression of atherosclerosis and risk of cardiovascular disease independently of reductions in LDL.
Statins cause modest increases in HDL-C and apo A-I probably mediated by reductions in CETP activity. It is plausible that such changes independently contribute to the cardiovascular benefits of the statin class but more studies are needed to further explore this possibility.
PMCID: PMC2493531  PMID: 18553127
Atherosclerosis; Cardiovascular disease; Cholesterol; High-density lipoprotein; Lipid-lowering therapy; Statin
16.  Intensive statin therapy in acute coronary syndromes and stable coronary heart disease: a comparative meta‐analysis of randomised controlled trials 
Heart  2007;93(8):914-921.
Intensive statin therapy reduces major adverse cardiovascular events (MACE), but the effect on mortality is unclear.
To determine whether intensive statin therapy reduces all‐cause mortality compared with moderate statin therapy in patients with recent acute coronary syndromes (ACS) and stable coronary heart disease (CHD).
Medline, Embase, the Cochrane Database, the internet, and conference proceedings from 1966 to 2006 were searched to identify relevant trials. Selection criteria were randomised allocation to intensive statin therapy (atorvastatin 80 mg/day, simvastatin 80 mg/day, or rosuvastatin 20–40 mg/day) versus moderate statin therapy, recent ACS or stable CHD at the time of randomisation, and ⩾6 months of follow‐up.
Six trials, encompassing 110 271 patient‐years, were pooled. In patients with recent ACS, intensive statin therapy reduced all‐cause mortality from 4.6% to 3.5% over 2.0 years (OR = 0.75, 95% CI 0.61 to 0.93). In patients with stable CHD, intensive statin therapy had no effect on all‐cause mortality over 4.7 years (OR = 0.99, 95% CI 0.89 to 1.11). Overall, intensive statin therapy was associated with a reduction in MACE (OR = 0.84, 95% CI 0.77 to 0.91) and admissions to hospital for heart failure (OR = 0.72, 95% CI 0.62 to 0.83). Intensive statin therapy was also associated with an increase in hepatic transaminases >3 times normal (OR = 3.73, 95% CI 2.11 to 6.58) and a trend towards increased creatine kinase >10 times normal and/or rhabdomyolysis (OR = 1.96, 95% CI 0.50 to 7.63).
Compared with moderate statin therapy, intensive statin therapy reduces all‐cause mortality in patients with recent ACS but not in patients with stable CHD.
PMCID: PMC1994400  PMID: 17277349
mortality; meta‐analysis; lipids; cholesterol; coronary disease
17.  Experimental evaluation of analgesic and anti-inflammatory activity of simvastatin and atorvastatin 
Indian Journal of Pharmacology  2012;44(4):475-479.
The aim of this study is to evaluate the analgesic and anti-inflammatory activities of atorvastatin and simvastatin in different experimental models in mice and rats.
Materials and Methods:
Analgesic activity of simvastatin and atorvastatin was assessed in tail flick model in rats (n = 6), where it was compared with aspirin and tramadol and in acetic acid induced writhing in mice (n = 6), where it was compared with aspirin. Anti-inflammatory activity of statins was evaluated using carrageenin induced paw edema and formalin induced arthritis in rats.
In the tail flick method, analgesic effect of tramadol was significantly more than the other drugs except at two observation times, when it was comparable to simvastatin and atorvastatin. Effect of simvastatin was found to be comparable to aspirin. In acetic acid induced writhing method, analgesic activity of simvastatin was comparable to that of aspirin while that of atorvastatin was significantly less. In carrageenin induced paw edema in rats, both simvastatin and atorvastatin showed anti-inflammatory activity which was comparable to aspirin. Both the statins exhibited significant anti-inflammatory activity (P < 0.01) in formalin induced arthritis model though less than aspirin (P < 0.05).
The results of this study if substantiated by further experimental and clinical research suggest that simvastatin and atorvastatin may play an adjuvant role, which may be particularly beneficial in the treatment of inflammatory disorders, especially when there is coexisting dyslipidemia.
PMCID: PMC3469950  PMID: 23087508
Formalin induced arthritis; paw edema; statins; tail-flick method; writhing
18.  Cost-effectiveness of the use of low- and high-potency statins in people at low cardiovascular risk 
Although statins have been shown to reduce the risk of cardiovascular events in patients at low cardiovascular risk, their absolute benefit is small in the short term, which may adversely affect cost-effectiveness. We sought to determine the long-term cost-effectiveness (beyond the duration of clinical trials) of low- and high-potency statins in patients at low cardiovascular risk and to estimate the impact on Canada’s publicly funded health care system.
Using Markov modelling, we performed a cost-utility analysis in which we compared low-potency statins (fluvastatin, lovastatin, pravastatin and simvastatin) and high-potency statins (atorvastatin and rosuvastatin) with no statins in a simulated cohort of low-risk patients over a lifetime horizon. Model outcomes included costs (in 2010 Canadian dollars), quality-adjusted life-years (QALYs) gained and the cost per QALY gained.
Over a lifetime horizon, the cost of managing a patient at low cardiovascular risk was estimated to be about $10 100 without statins, $15 200 with low-potency statins and $16 400 with high-potency statins. The cost per QALY gained with high-potency statins (v. no statins) was $21 300; the use of low-potency statins was not considered economically attractive. These results were robust to sensitivity analyses, although their use became economically unattractive when the duration of benefit from statin use was assumed to be less than 10 years.
Use of high-potency statins in patients at low cardiovascular risk was associated with a cost per QALY gained that was economically attractive by current standards, assuming that the benefit from statin use would continue for at least 10 years. However, the overall expenditure on statins would be substantial, and the ramifications of this practice should be carefully considered by policy-makers.
PMCID: PMC3216439  PMID: 21989469
19.  Comparative In Vitro Activities and Postantibiotic Effects of the Oxazolidinone Compounds Eperezolid (PNU-100592) and Linezolid (PNU-100766) versus Vancomycin against Staphylococcus aureus, Coagulase-Negative Staphylococci, Enterococcus faecalis, and Enterococcus faecium 
The activities of the oxazolidinone antibacterial agents eperezolid (PNU-100592) and linezolid (PNU-100766) were compared with that of vancomycin against clinical isolates of methicillin-susceptible and -resistant Staphylococcus aureus (n = 200), coagulase-negative staphylococci (n = 100), and vancomycin-susceptible and -resistant Enterococcus faecalis and Enterococcus faecium (n = 50). Eperezolid and linezolid demonstrated good in vitro inhibitory activity, regardless of methicillin susceptibility for staphylococci (MIC at which 90% of the isolates are inhibited [MIC90] range, 1 to 4 μg/ml) or vancomycin susceptibility for enterococci (MIC90 range, 1 to 4 μg/ml). In time-kill studies, eperezolid and linezolid were bacteriostatic in action. A postantibiotic effect of 0.8 ± 0.5 h was demonstrated for both eperezolid and linezolid against S. aureus, S. epidermidis, E. faecalis, and E. faecium.
PMCID: PMC105529  PMID: 9517963
20.  Cardiovascular and Economic Outcomes After Initiation of Lipid-Lowering Therapy With Atorvastatin vs Simvastatin in an Employed Population 
Mayo Clinic Proceedings  2009;84(12):1065-1072.
OBJECTIVE: To compare the risk of cardiovascular-related hospitalization, statin adherence, and direct (medical and drug) and indirect (disability and medically related absenteeism) costs in US employees in whom atorvastatin or simvastatin was newly prescribed.
PATIENTS AND METHODS: Active employees aged 18 to 64 years with a new atorvastatin or simvastatin prescription were identified from a deidentified claims database for 23 privately insured US companies from January 1, 1999, through December 31, 2006. Employees given atorvastatin were matched to those given simvastatin according to propensity scores based on patient characteristics, index statin dose, preindex cardiovascular events, and wage. Outcomes were compared between matched cohorts during the 2-year postindex period, including the risk of cardiovascular-related hospitalization, adherence to the index statin, use of other lipid-lowering drugs, direct medical costs for third-party payers, and indirect costs to employers. Indirect costs were computed as follows: Disability Payments + Daily Wage × Days of Medically Related Absenteeism. Atorvastatin and simvastatin drug costs were imputed using recent pricing to account for the availability of lower-cost generic simvastatin after the study period.
RESULTS: Among 13,584 matched pairs, treatment with atorvastatin vs simvastatin was associated with a reduced risk of cardiovascular-related hospitalization, higher adherence, and less use of other lipid-lowering drugs. The increase in statin costs associated with atorvastatin vs simvastatin therapy was almost completely offset by reductions in medical service and indirect costs.
CONCLUSION: In this study, treatment with atorvastatin compared with simvastatin was associated with a reduced risk of cardiovascular events, reduced indirect costs, and a minimal difference in total costs to employers.
Among 13,584 matched pairs in this study, treatment with atorvastatin compared with simvastatin was associated with a reduced risk of cardiovascular-related hospitalization, higher adherence, reduced indirect costs, and a minimal difference in total costs to employers.
PMCID: PMC2787392  PMID: 19955243
21.  Survival of Vancomycin-Resistant and Vancomycin-Susceptible Enterococci on Dry Surfaces 
Journal of Clinical Microbiology  1998;36(12):3734-3736.
We compared the abilities of Enterococcus faecium strains (three vancomycin-resistant enterococci [VRE] and five vancomycin-susceptible enterococci [VSE]) and Enterococcus faecalis strains (one VRE and 10 VSE) to survive under dry conditions. Bacterial suspensions of the strains were inoculated onto polyvinyl chloride and stored under defined conditions for up to 16 weeks. All strains survived for at least 1 week, and two strains survived for 4 months. A statistical model was used to distribute the 19 resulting survival curves between two types of survival curves. The type of survival curve was not associated with the species (E. faecalis versus E. faecium), the source of isolation (patient versus environment), or the susceptibility to vancomycin (VRE versus VSE). Resistance to dry conditions may promote the transmissibility of a strain, but VRE have no advantages over VSE with respect to their ability to survive under dry conditions.
PMCID: PMC105279  PMID: 9817912
22.  The effect of statins on testosterone in men and women, a systematic review and meta-analysis of randomized controlled trials 
BMC Medicine  2013;11:57.
Statins are extensively used for cardiovascular disease prevention. Statins reduce mortality rates more than other lipid-modulating drugs, although evidence from randomized controlled trials also suggests that statins unexpectedly increase the risk of diabetes and improve immune function. Physiologically, statins would be expected to lower androgens because statins inhibit production of the substrate for the local synthesis of androgens and statins' pleiotropic effects are somewhat similar to the physiological effects of lowering testosterone, so we hypothesized that statins lower testosterone.
A meta-analysis of placebo-controlled randomized trials of statins to test the a priori hypothesis that statins lower testosterone. We searched the PubMed, Medline and ISI Web of Science databases until the end of 2011, using '(Testosterone OR androgen) AND (CS-514 OR statin OR simvastatin OR atorvastatin OR fluvastatin OR lovastatin OR rosuvastatin OR pravastatin)' restricted to randomized controlled trials in English, supplemented by a bibliographic search. We included studies with durations of 2+ weeks reporting changes in testosterone. Two reviewers independently searched, selected and assessed study quality. Two statisticians independently abstracted and analyzed data, using random or fixed effects models, as appropriate, with inverse variance weighting.
Of the 29 studies identified 11 were eligible. In 5 homogenous trials of 501 men, mainly middle aged with hypercholesterolemia, statins lowered testosterone by -0.66 nmol/l (95% confidence interval (CI) -0.14 to -1.18). In 6 heterogeneous trials of 368 young women with polycystic ovary syndrome, statins lowered testosterone by -0.40 nmol/l (95% CI -0.05 to -0.75). Overall statins lowered testosterone by -0.44 nmol/l (95% CI -0.75 to -0.13).
Statins may partially operate by lowering testosterone. Whether this is a detrimental side effect or mode of action warrants investigation given the potential implications for drug development and prevention of non-communicable chronic diseases.
See commentary article here
PMCID: PMC3621815  PMID: 23448151
androgen; cardiovascular; cholesterol; diabetes; inflammation; statins; testosterone
23.  Disparate Effects of Atorvastatin Compared With Simvastatin on C-Reactive Protein Concentrations in Patients With Type 2 Diabetes 
Diabetes Care  2010;33(9):1948-1950.
Reduction in LDL and high sensitivity (hs) C-reactive protein (CRP) are independent indicators of successful cardiovascular risk reduction with statins. This study compared the effect of equivalent LDL-lowering doses of simvastatin and atorvastatin on hsCRP in type 2 diabetic patients.
A crossover study of 26 patients with type 2 diabetes taking either 40 mg simvastatin or 10 mg atorvastatin was undertaken. After 3 months on one statin, lipids and hsCRP were measured on 10 occasions over a 5-week period. The same procedure was then followed taking the other statin.
LDL was comparable on either treatment: atorvastatin 2.2 ± 0.2 vs. 2.1 ± 0.3 mmol/l (mean ± SD; P = 0.19). CRP of individuals taking atorvastatin was significantly lower than when they were taking simvastatin (median 1.08 vs. 1.47 mg/l, P = 0.0002) and was less variable (median SD of logCRP 0.0036 vs. 0.178, P = 0.0001).
Compared with simvastatin, atorvastatin reduced hsCRP and its variability in type 2 diabetic patients. This enhanced anti-inflammatory effect may prove beneficial if lower CRP is associated with improved cardiovascular risk.
PMCID: PMC2928339  PMID: 20805273
24.  Antibacterial Activity of Extracts of Acacia Aroma Against Methicillin-Resistant And Methicillin-Sensitive Staphylococcus 
Brazilian Journal of Microbiology  2010;41(3):581-587.
Antibacterial activity of organic and aqueous extracts of Acacia aroma was evaluated against methicillin-resistant Staphylococcus aureus (MRSA), methicillin sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus epidermidis. Inhibition of bacterial growth was determined using agar diffusion and bioautographic methods. Among all assayed organic extracts only ethanolic and ethyl acetate extracts presented highest activities against all tested Staphylococcus strains with minimal inhibitory concentration (MIC) values ranging from 2.5 to 10 mg/ml and from 2.5 to 5 mg/ml respectively. The aqueous extracts show little antibacterial activity against Staphylococcus strains. The bioautography assay demonstrated well-defined growth inhibition zones against S. aureus in correspondence with flavonoids and saponins. A. aroma would be an interesting topic for further study and possibly for an alternative treatment for skin infections.
PMCID: PMC3768637  PMID: 24031532
Acacia aroma; Antibacterial activity; Staphylococcus; Tusca
25.  Consistency of effect of ezetimibe/simvastatin compared with intensified lipid-lowering treatment strategies in obese and non-obese diabetic subjects 
This post hoc analysis assessed switching to ezetimibe/simvastatin 10/20 mg vs doubling the baseline statin dose to simvastatin 40 mg or atorvastatin 20 mg or switching to rosuvastatin 10 mg in subgroups of obese (BMI ≥30 kg/m2) and non-obese (BMI <30 kg/m2) diabetic subjects.
This was a randomized, double-blind, 12-week study of adults 18–79 years with cardiovascular disease with low-density lipoprotein cholesterol (LDL-C) ≥70 and ≤160 mg/dl. Percent change in LDL-C and other lipids was estimated.
In obese subjects (n = 466), percent changes in LDL-C and most other lipids were greater with ezetimibe/simvastatin vs doubling the baseline statin dose or switching to rosuvastatin. In non-obese subjects (n = 342), percent changes in LDL-C, total cholesterol, non-HDL-C, Apo B and Apo A-I were greater with ezetimibe/simvastatin vs doubling the baseline statin dose or switching to rosuvastatin; and treatment with ezetimibe/simvastatin resulted in greater changes in triglycerides vs rosuvastatin and HDL-C vs doubling the baseline statin dose. The safety profiles were generally similar.
Regardless of baseline obesity status, switching to ezetimibe/simvastatin was more effective at reducing LDL-C, total cholesterol, non-HDL-C, and Apo B vs doubling the baseline statin dose to simvastatin 40 mg or atorvastatin 20 mg or switching to rosuvastatin 10 mg.
PMCID: PMC3722050  PMID: 23866306
Atorvastatin; Ezetimibe; Diabetes; Obesity; Rosuvastatin; Statin

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