Publications

Acid-reducing agents (ARAs) are the most commonly prescribed medications in North America and Western Europe. There are currently no data describing the prevalence of their use among cancer patients. However, this is a paramount question due to the potential for significant drug-drug interactions (DDIs) between ARAs, most commonly proton pump inhibitors (PPIs), and orally administered cancer therapeutics that display pH-dependent solubility, which may lead to decreased drug absorption and decreased therapeutic benefit. Of recently approved orally administered cancer therapeutics, >50% are characterized as having pH-dependent solubility, but there are currently no data describing the potential for this ARA-DDI liability among targeted agents currently in clinical development. The objectives of this study were to (1) determine the prevalence of ARA use among different cancer populations and (2) investigate the prevalence of orally administered cancer therapeutics currently in development that may be liable for an ARA-DDI. To address the question of ARA use among cancer patients, a retrospective cross-sectional analysis was performed using two large healthcare databases: Thomson Reuters MarketScan (N = 1,776,443) and the U.S. Department of Veterans Affairs (VA, N = 1,171,833). Among all cancer patients, the total prevalence proportion of ARA use (no. of cancer patients receiving an ARA/total no. of cancer patients) was 20% and 33% for the MarketScan and VA databases, respectively. PPIs were the most commonly prescribed agent, comprising 79% and 65% of all cancer patients receiving a prescription for an ARA (no. of cancer patients receiving a PPI /no. of cancer patients receiving an ARA) for the MarketScan and VA databases, respectively. To estimate the ARA-DDI liability of orally administered molecular targeted cancer therapeutics currently in development, two publicly available databases, (1) Kinase SARfari and (2) canSAR, were examined. For those orally administered clinical candidates that had available structures, the pKa's and corresponding relative solubilities were calculated for a normal fasting pH of 1.2 and an "ARA-hypochlorhydric" pH of 4. Taking calculated pKa's and relative solubilities into consideration, clinical candidates were classified based on their risk for an ARA-DDI. More than one-quarter (28%) of the molecules investigated are at high risk for an ARA-DDI, and of those high risk molecules, nearly three-quarters (73%) are being clinically evaluated for at least one of five cancer types with the highest prevalence of ARA use (gastrointestinal, pancreatic, lung, glioblastoma multiforme, gastrointestinal stromal tumor (GIST)). These data strongly suggest that with the clinical development of ARA-DDI-susceptible cancer therapeutics will come continued challenges for drug-development scientists, oncologists, and regulatory agencies in ensuring that patients achieve safe and efficacious exposures of their cancer therapeutics and thus optimal patient outcomes.

The objective of this study was to determine the role of A-Kinase Anchoring Protein (AKAP)-Lbc in the development of heart failure, by investigating AKAP-Lbc-protein kinase D1 (PKD1) signaling in vivo in cardiac hypertrophy. Using a gene-trap mouse expressing a truncated version of AKAP-Lbc (due to disruption of the endogenous AKAP-Lbc gene), that abolishes PKD1 interaction with AKAP-Lbc (AKAP-Lbc-ΔPKD), we studied two mouse models of pathological hypertrophy: i) angiotensin (AT-II) and phenylephrine (PE) infusion and ii) transverse aortic constriction (TAC)-induced pressure overload. Our results indicate that AKAP-Lbc-ΔPKD mice exhibit an accelerated progression to cardiac dysfunction in response to AT-II/PE treatment and TAC. AKAP-Lbc-ΔPKD mice display attenuated compensatory cardiac hypertrophy, increased collagen deposition and apoptosis, compared to wild-type (WT) control littermates. Mechanistically, reduced levels of PKD1 activation are observed in AKAP-Lbc-ΔPKD mice compared to WT mice, resulting in diminished phosphorylation of histone deacetylase 5 (HDAC5) and decreased hypertrophic gene expression. This is consistent with a reduced compensatory hypertrophy phenotype leading to progression of heart failure in AKAP-Lbc-ΔPKD mice. Overall, our data demonstrates a critical in vivo role for AKAP-Lbc-PKD1 signaling in the development of compensatory hypertrophy to enhance cardiac performance in response to TAC-induced pressure overload and neurohumoral stimulation by AT-II/PE treatment.

Alpha interferon (IFN-α) suppresses human immunodeficiency virus type 1 (HIV-1) replication in vitro by inducing cell-intrinsic retroviral restriction mechanisms. We investigated the effects of IFN-α/ribavirin (IFN-α/riba) treatment on 34 anti-HIV-1 restriction factors in vivo. Expression of several anti-HIV-1 restriction factors was significantly induced by IFN-α/riba in HIV/hepatitis C virus (HCV)-coinfected individuals. Fold induction of cumulative restriction factor expression in CD4(+) T cells was significantly correlated with viral load reduction during IFN-α/riba treatment (r(2) = 0.649; P < 0.016). Exogenous IFN-α induces supraphysiologic restriction factor expression associated with a pronounced decrease in HIV-1 viremia.

OBJECTIVE

Rifampin monoresistant tuberculosis (RMR-TB) is increasingly identified because of scale-up of rapid molecular tests. The longitudinal association of RMR-TB, multidrug-resistant TB (MDR-TB), and HIV/AIDS is incompletely described.

METHODS

We examined clinical characteristics and treatment outcomes of patients with RMR-TB, isoniazid monoresistant TB (IMR-TB), MDR-TB, and drug-susceptible TB during a 16-year period (1993-2008) in California. TB cases were cross-matched with the state HIV/AIDS registry, and HIV prevalence denominators modeled using nonparametric backcalculation.

RESULTS

Of 42,582 TB cases, 178 (0.4%), 3469 (8.1%), and 635 (1.5%) were RMR-TB, IMR-TB, and MDR-TB, respectively. From the pre-HAART (1993-1996) to HAART (2005-2008) era, RMR-TB rates declined rapidly (12.0 vs. 0.5 per 100,000) among patients with HIV infection. The proportion of patients for whom rifampin resistance indicated RMR-TB (rather than MDR-TB) decreased from 31% [95% confidence interval (CI) 26-38%] to 11% (95% CI 5-19%). In multivariate analysis controlling for HIV coinfection and other covariates, patients with RMR-TB were twice as likely to die as patients with drug-sensitive TB (relative risk 1.94, 95% CI 1.40-2.69).

CONCLUSION

RMR-TB/HIV rates declined substantially over time in association with improved TB control and HIV control in California. Mortality among patients with RMR-TB was high, even after adjusting for HIV status.