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Kalari S.,Johnson & Johnson Pharmaceutical Research and Development LLC
American journal of pharmaceutical education | Year: 2011

To assess US pharmacy students' knowledge and perceptions of adverse event reporting. To gauge pharmacy students' impressions of adverse event reporting, a 10-question survey instrument was administered that addressed student perceptions of the reporting procedures of the Food and Drug Administration (FDA) and pharmaceutical manufacturers, as well as student understanding of the Health Insurance Portability and Accountability Act (HIPAA) and its relationship to adverse event reporting. Two hundred twenty-eight pharmacy students responded to the survey. The majority of respondents believed that the FDA is more likely than a pharmaceutical company to take action regarding an adverse event. There were misconceptions relating to the way adverse event reports are handled and the influence of HIPAA regulations on reporting. Communication between the FDA and pharmaceutical manufacturers regarding adverse event reports is not well understood by pharmacy students. Education about adverse event reporting should evolve so that by the time pharmacy students become practitioners, they are well acquainted with the relevance and importance of adverse event reporting.


McDuffie J.E.,Johnson & Johnson Pharmaceutical Research and Development LLC
Cytokine | Year: 2010

A 28-day study was conducted to evaluate changes in urinary cytokine/chemokine expression levels in dogs with renal injury due to administration of cisplatin. Animals (n=17) were administered cisplatin at 0.75 mg/kg/day (i.v.) for five consecutive days. Urine/serum were collected at pre-dosing, 4h post-dosing and on days 2, 3, 4, 8, 10, 14, 16, 18, 21, 23, 25, 28 and unscheduled terminations. Animals were euthanized when serum creatinine (sCr) levels measured at ≥ 1.9 mg/dL, indicating significant loss of renal function (decreased glomerular filtration rate). Relevant clinical observations included lethargy and dehydration. Pre-study sCr levels ranged from 0.6 to 0.8 mg/dL; on days 1 through 4, sCr levels ranged from 0.5 and 1.1mg/dL; and terminal sCr levels ranged from 0.6 and 6.6 mg/dL. Histologically, cisplatin-related renal changes were characterized as proximal tubule dilatation, vacuolization, degeneration, regeneration, and interstitial inflammation. Increased interleukin (IL)-2, IL-8, monocyte chemoattractant protein-1 (MCP-1), granulocyte-macrophage colony-stimulating factor (GMCSF) and keratinocyte-derived chemokine (KC) occurred on days 3 through 4. Increased IL-7 occurred on day 4. This study showed for the first time that inflammatory cytokines/chemokines in urine positively identified acute renal tubular injury in dogs at time points earlier than sCr, a traditional marker of nephrotoxicity. Copyright © 2010 Elsevier Ltd. All rights reserved.


PubMed | Johnson & Johnson Pharmaceutical Research and Development LLC
Type: Journal Article | Journal: Antimicrobial agents and chemotherapy | Year: 2011

The new broad-spectrum fluoroquinolone JNJ-Q2 displays in vitro activity against Gram-negative and Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA) and ciprofloxacin-resistant MRSA isolates. Tested with isogenic methicillin-susceptible S. aureus (MSSA) and MRSA strains bearing quinolone-resistant target mutations, JNJ-Q2 displayed MICs 0.12 g/ml, values 16- to 32-fold lower than those determined for moxifloxacin. Overexpression of the NorA efflux pump did not impact JNJ-Q2 MICs. Inhibition of S. aureus DNA gyrase and DNA topoisomerase IV enzymes demonstrated that JNJ-Q2 was more potent than comparators against wild-type enzymes and enzymes carrying quinolone-resistant amino acid substitutions, and JNJ-Q2 displayed equipotent activity against both enzymes. In serial-passage studies comparing resistance selection in parallel MRSA cultures by ciprofloxacin and JNJ-Q2, ciprofloxacin readily selected for mutants displaying MIC values of 128 to 512 g/ml, which were observed within 18 to 24 days of passage. In contrast, cultures passaged in the presence of JNJ-Q2 displayed MICs 1 g/ml for a minimum of 27 days of serial passage. A mutant displaying a JNJ-Q2 MIC of 4 g/ml was not observed until after 33 days of passage. Mutant characterization revealed that ciprofloxacin-passaged cultures with MICs of 256 to 512 g/ml carried only 2 or 3 quinolone resistance-determining region (QRDR) mutations. Cultures passaged with JNJ-Q2 selection for up to 51 days displayed MICs of 1 to 64 g/ml and carried between 4 and 9 target mutations. Established in vitro biofilms of wild-type or ciprofloxacin-resistant MRSA exposed to JNJ-Q2 displayed greater decreases in bacterial counts (7 days of exposure produced 4.5 to >7 log(10) CFU decreases) than biofilms exposed to ciprofloxacin, moxifloxacin, rifampin, or vancomycin.


PubMed | Johnson & Johnson Pharmaceutical Research and Development LLC
Type: Journal Article | Journal: Antimicrobial agents and chemotherapy | Year: 2011

The in vivo efficacy of JNJ-Q2, a new broad-spectrum fluoroquinolone (FQ), was evaluated in a murine septicemia model with methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) and in a Streptococcus pneumoniae lower respiratory tract infection model. JNJ-Q2 and comparators were also evaluated in an acute murine skin infection model using a community-acquired MRSA strain and in an established skin infection (ESI) model using a hospital-acquired strain, for which the selection of resistant mutants was also determined. JNJ-Q2 demonstrated activity in the MSSA septicemia model that was comparable to that moxifloxacin (JNJ-Q2 50% effective dose [ED(50)], 0.2 mg/kg of body weight administered subcutaneously [s.c.] and 2 mg/kg administered orally [p.o.]) and activity in the MRSA septicemia model that was superior to that of vancomycin (JNJ-Q2 ED(50), 1.6 mg/kg administered s.c.). In an S. pneumoniae lower respiratory tract infection model, JNJ-Q2 displayed activity (ED(50), 1.9 mg/kg administered s.c. and 7.4 mg/kg administered p.o.) that was comparable to that of gemifloxacin and superior to that of moxifloxacin. In both MRSA skin infection models, treatment with JNJ-Q2 resulted in dose-dependent reductions in bacterial titers in the skin, with the response to JNJ-Q2 at each dose exceeding the responses of the comparators ciprofloxacin, moxifloxacin, linezolid, and vancomycin. Additionally, in the ESI model, JNJ-Q2 showed a low or nondetectable propensity for ciprofloxacin resistance selection, in contrast to the selection of ciprofloxacin-resistant mutants observed for both ciprofloxacin and moxifloxacin. JNJ-Q2 demonstrated activity that was comparable or superior to the activity of fluoroquinolone or antistaphylococcal comparators in several local and systemic skin infection models performed with both S. aureus and S. pneumoniae and is currently being evaluated in phase II human clinical trials.


PubMed | Johnson & Johnson Pharmaceutical Research and Development LLC
Type: | Journal: BMC psychiatry | Year: 2011

To compare the efficacy and tolerability of paliperidone extended-release (ER) with risperidone immediate-release using propensity score methodology.Six double-blind, randomized, placebo-controlled, short-term clinical trials for acute schizophrenia with availability of individual patient-level data were identified (3 per compound). Propensity score pairwise matching was used to balance observed covariates between the paliperidone ER and risperidone patient populations. Scores were generated using logistic regression models, with age, body mass index, race, sex, baseline Positive and Negative Syndrome Scale (PANSS) total score and baseline Clinical Global Impressions-Severity (CGI-S) score as factors. The dosage range of paliperidone ER (6-12 mg/day) was compared with 2 risperidone dosage ranges: 2-4 and 4-6 mg/day. The primary efficacy measure was change in PANSS total score at week 6 end point. Tolerability end points included adverse event (AE) reports and weight. AEs with rates 5% and with a 2% difference between paliperidone ER and risperidone were identified.Completion rates for placebo-treated subjects in paliperidone ER trials (n = 95) and risperidone trials (n = 122) groups were 36.8% and 51.6%, respectively; end point changes on PANSS total scores were similar (p = 0.768). Completion rates for subjects receiving paliperidone ER 6-12 mg/day (n = 179), risperidone 2-4 mg/day (n = 113) or risperidone 4-6 mg/day (n = 129) were 64.8%, 54.0% and 66.7%, respectively (placebo-adjusted rates: paliperidone ER vs risperidone 2-4 mg/day, p = 0.005; paliperidone ER vs risperidone 4-6 mg/day, p = 0.159). PANSS total score improvement with paliperidone ER was greater than with risperidone 2-4 mg/day (difference in mean change score, -6.7; p < 0.05) and similar to risperidone 4-6 mg/day (0.2; p = 0.927). Placebo-adjusted AEs more common with paliperidone ER were insomnia, sinus tachycardia and tachycardia; more common with risperidone were somnolence, restlessness, nausea, anxiety, salivary hypersecretion, akathisia, dizziness and nasal congestion. Weight changes with paliperidone ER and risperidone were similar (paliperidone ER vs risperidone 2-4 mg/day, p = 0.489; paliperidone ER vs risperidone 4-6 mg/day, p = 0.236).This indirect database analysis suggested that paliperidone ER 6-12 mg/day may be more efficacious than risperidone 2-4 mg/day and as efficacious as risperidone 4-6 mg/day. The AE-adjusted incidence rates suggest differences between treatments that may be relevant for individual patients. Additional randomized, direct, head-to-head clinical trials are needed to confirm these findings.


PubMed | Johnson & Johnson Pharmaceutical Research and Development L.L.C.
Type: | Journal: Current protocols in pharmacology | Year: 2012

Determining the in vivo bactericidal potential of novel agents is critical for selecting drug candidates. Described in this unit are two protocols that measure the amount of bacterial killing under very different conditions. The mouse pouch protocol is a rapid assay that provides efficacy data in an acute infection, whereas the rabbit tissue cage protocol assesses the ability of a compound to eradicate bacteria in a chronic abscess infection. Data from these tests, along with those from other qualitative and quantitative assays, are important for defining antibacterial efficacy in vivo.


PubMed | Johnson & Johnson Pharmaceutical Research and Development LLC
Type: Comparative Study | Journal: Antimicrobial agents and chemotherapy | Year: 2011

Doripenem is a carbapenem with potent broad-spectrum activity against Gram-negative pathogens, including antibiotic-resistant Enterobacteriaceae. As the incidence of extended-spectrum -lactamase (ESBL)-producing Gram-negative bacilli is increasing, it was of interest to examine the in vivo comparative efficacy of doripenem, imipenem, and meropenem against a Klebsiella pneumoniae isolate expressing the TEM-26 ESBL enzyme. In a murine lethal lower respiratory infection model, doripenem reduced the Klebsiella lung burden by 2 log(10) CFU/g lung tissue over the first 48 h of the infection. Treatment of mice with meropenem or imipenem yielded reductions of approximately 1.5 log(10) CFU/g during this time period. Seven days postinfection, Klebsiella titers in the lungs of treated mice decreased an additional 2 log(10) CFU/g relative to those in the lungs of untreated control animals. Lipopolysaccharide (LPS) endotoxin release assays indicated that 6 h postinfection, meropenem- and imipenem-treated animals had 10-fold more endotoxin in lung homogenates and sera than doripenem-treated mice. Following doripenem treatment, the maximum endotoxin release postinfection (6 h) was 53,000 endotoxin units (EU)/ml, which was 2.7- and 6-fold lower than imipenem or meropenem-treated animals, respectively. While the levels of several proinflammatory cytokines increased in both the lungs and sera following intranasal K. pneumoniae inoculation, doripenem treatment, but not meropenem or imipenem treatment, resulted in significantly increased interleukin 6 levels in lung homogenates relative to those in lung homogenates of untreated controls, which may contribute to enhanced neutrophil killing of bacteria in the lung. Histological examination of tissue sections indicated less overall inflammation and tissue damage in doripenem-treated mice, consistent with improved antibacterial efficacy, reduced LPS endotoxin release, and the observed cytokine induction profile.


PubMed | Johnson & Johnson Pharmaceutical Research and Development L.L.C.
Type: Journal Article | Journal: Journal of chemical information and modeling | Year: 2011

Stochastic proximity embedding (SPE) was developed as a method for efficiently calculating lower dimensional embeddings of high-dimensional data sets. Rather than using a global minimization scheme, SPE relies upon updating the distances of randomly selected points in an iterative fashion. This was found to generate embeddings of comparable quality to those obtained using classical multidimensional scaling algorithms. However, SPE is able to obtain these results in O(n) rather than O(n) time and thus is much better suited to large data sets. In an effort both to speed up SPE and utilize it for even larger problems, we have created a multithreaded implementation which takes advantage of the growing general computing power of graphics processing units (GPUs). The use of GPUs allows the embedding of data sets containing millions of data points in interactive time scales.


PubMed | Johnson & Johnson Pharmaceutical Research and Development L.L.C
Type: Journal Article | Journal: ACS medicinal chemistry letters | Year: 2014

HIF prolyl 4-hydroxylases (PHD) are a family of enzymes that mediate key physiological responses to hypoxia by modulating the levels of hypoxia inducible factor 1- (HIF1). Certain benzimidazole-2-pyrazole carboxylates were discovered to be PHD2 inhibitors using ligand- and structure-based methods and found to be potent, orally efficacious stimulators of erythropoietin secretion in vivo.


PubMed | Johnson & Johnson Pharmaceutical Research and Development LLC
Type: Journal Article | Journal: Statistics in medicine | Year: 2012

Expanded availability of observational healthcare data (both administrative claims and electronic health records) has prompted the development of statistical methods for identifying adverse events associated with medical products, but the operating characteristics of these methods when applied to the real-world data are unknown.We studied the performance of eight analytic methods for estimating of the strength of association-relative risk (RR) and associated standard error of 53 drug-adverse event outcome pairs, both positive and negative controls. The methods were applied to a network of ten observational healthcare databases, comprising over 130 million lives. Performance measures included sensitivity, specificity, and positive predictive value of methods at RR thresholds achieving statistical significance of p<0.05 or p<0.001 and with absolute threshold RR>1.5, as well as threshold-free measures such as area under receiver operating characteristic curve (AUC).Although no specific method demonstrated superior performance, the aggregate results provide a benchmark and baseline expectation for risk identification method performance. At traditional levels of statistical significance (RR>1, p<0.05), all methods have a false positive rate >18%, with positive predictive value <38%. The best predictive model, high-dimensional propensity score, achieved an AUC=0.77. At 50% sensitivity, false positive rate ranged from 16% to 30%. At 10% false positive rate, sensitivity of the methods ranged from 9% to 33%.Systematic processes for risk identification can provide useful information to supplement an overall safety assessment, but assessment of methods performance suggests a substantial chance of identifying false positive associations.

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