Effect of practitioner education on adherence to asthma treatment guidelines

OBJECTIVE: To determine whether a letter-based intervention program submitted to prescribers and pharmacists would improve drug therapy in users of high-dose beta(2)-agonists (HDBs). STUDY DESIGN: Retrospective drug utilization review. PATIENTS AND METHODS: The intervention group consisted of 135 asthmatic patients (identified through ICD-9-CM codes) in the Connecticut Medicaid Program who submitted >1 claim per month for short-acting beta(2)-agonists (over a 6-mo period). Patient-specific intervention packets were mailed to the patients' prescribers and pharmacists, and their use of long-term control agents and healthcare utilization was evaluated over 6 months. These variables were compared with a comparison group (n = 510) of asthmatics drawn from the same Medicaid program who were not considered to be high-dose users of short-acting beta(2)-agonists at baseline. RESULTS: Prior to the intervention, the intervention group used fewer long-term asthma control agents as compared with the comparison group (58% vs. 96%; p < 0.001); there was no significant difference after the intervention program (65% vs. 71%; p = 0.169). The acquisition of spacers was greater in the intervention group than in the control group after the intervention (7% vs. 2%; p = 0.007). At the end of the 6-month intervention period, 46% of patients in the intervention group were no longer HDB users (p < 0.001). The higher frequency of prescriber office visits in the intervention group than the comparison group before the intervention (0.46 +/- 0.82 vs. 0.25 +/- 0.66; p < 0.001) was not evident after the intervention program (0.24 +/- 0.63 vs. 0.18 +/- 0.60; p = 0.283). CONCLUSIONS: This intervention program had modest impact on improving the use of long-term control agents and reducing prescriber office visits.     

Adenosine is the primary precursor of all purine nucleotides in Trichomonas vaginalis

Trichomonas vaginalis, a parasitic protozoan and the causative agent of trichomoniasis, lacks de novo purine nucleotide synthesis and possesses a unique purine salvage pathway, consisting of a bacterial type purine nucleoside phosphorylase and a purine nucleoside kinase. It is generally believed that adenine and guanine are converted to their corresponding nucleosides and then further phosphorylated to form AMP and GMP, respectively, as the main as well as the essential pathway of replenishing the purine nucleotide pool in the organism. Formycin A, an analogue of adenosine, inhibits both enzymes as well as the in vitro growth of T. vaginalis with an estimated IC(50) of 0.27 microM. This growth inhibition was reversed by adding adenine to the culture medium but not by adding guanine or hypoxanthine. Furthermore, T. vaginalis can grow in semi-defined medium supplemented with only adenine but not with guanine or hypoxanthine. Radiolabeling experiments followed by HPLC analysis of the purine nucleotide pool in T. vaginalis demonstrated incorporation of [8-14C]adenine into both adenine and guanine nucleotides, whereas [8-14C]guanine was incorporated only into guanine nucleotides. Substantial adenosine deaminase activity and significant IMP dehydrogenase and GMP synthetase activities were identified in T. vaginalis lysate, suggesting a pathway capable of converting adenine to GMP via adenosine. This purine salvage scheme depicts adenosine the primary precursor of the entire purine nucleotide pool in T. vaginalis and the purine nucleoside kinase one of the most pivotal enzymes in purine salvage and a potential target for anti-trichomoniasis chemotherapy.     

Withaferin A induces p53-dependent apoptosis by repression of HPV oncogenes and upregulation of tumor suppressor proteins in human cervical cancer cells

Cervical cancer is caused by human papilloma virus (HPV) expressing E6 and E7 oncoproteins, which are known to inactivate tumor suppressor proteins p53 and pRb, respectively. Repression of HPV oncoproteins would therefore result in reactivation of tumor suppressor pathways and cause apoptosis in cancer cells. Withaferin A (WA), the active component of the medicinal plant Withania Somnifera, has exhibited inhibitory effects against several different cancers. We examined the activity of WA on human cervical cancer cells in vitro and in vivo. WA potently inhibited proliferation of the cervical cancer cells, CaSki (IC(50) 0.45 ± 0.05 μM). Mechanistically, WA was found to (i) downregulate expression of HPV E6 and E7 oncoproteins, (ii) induce accumulation of p53, (iii) increase levels of p21(cip1/waf1) and its interaction with proliferating cell nuclear antigen (PCNA), (iv) cause G(2)/M cell cycle arrest, associated with modulation of cyclin B1, p34(cdc2) and PCNA levels, (v) decrease the levels of STAT3 and its phosphorylation at Tyr(705) and Ser(727) and (vi) alter expression levels of p53-mediated apoptotic markers-Bcl2, Bax, caspase-3 and cleaved PARP. In vivo, WA resulted in reduction of nearly 70% of the tumor volume in athymic nude mice with essentially similar trend in the modulation of molecular markers as in vitro. This is the first demonstration indicating that WA significantly downregulates expression of HPV E6/E7 oncogenes and restores the p53 pathway, resulting in apoptosis of cervical cancer cells. Together, our data suggest that WA can be exploited as a potent therapeutic agent for the treatment and prevention of cervical cancer without deleterious effects.     

Cucurbitacin B potently suppresses non-small-cell lung cancer growth: Identification of intracellular thiols as critical targets

Cucurbitacin B (CuB), has recently emerged as a potent anticancer agent; however, its efficacy in non-small-cell lung cancer (NSCLC) and the mechanism(s) initiating its biological effects remain largely unclear. In this study, CuB potently suppressed the growth of four NSCLC cells (H1299, A549, HCC-827 and H661) in vitro and the highly aggressive H1299 xenograft in vivo. CuB significantly altered the actin cytoskeletal assembly, induced G2/M cell-cycle arrest and mitochondrial apoptosis through the modulation of several key molecular targets mediating the aforementioned processes. Interestingly, all cellular effects of CuB were completely attenuated only by the thiol antioxidant N-acetylcysteine (NAC). Furthermore, pretreatment with glutathione synthesis inhibitor butithione-sulfoxime (BSO), significantly exacerbated CuB’s cytotoxic effects. To this end, cells treated with CuB revealed a rapid and significant decrease in the levels of protein thiols and GSH/GSSG ratio, suggesting disruption of cellular redox balance as the primary event in CuB’s cytotoxic arsenal. Using UV and FTICR mass spectrometry we also demonstrate for the first time a physical interaction of CuB with NAC and GSH in a cell-free system suggesting that CuB interacts with and modulates cellular thiols to mediate its anti-cancer effects. Collectively, our data sheds new light on the working mechanisms of CuB and demonstrate its therapeutic potential against NSCLC.     

Controlled-release systemic delivery - a new concept in cancer chemoprevention

Many chemopreventive agents have encountered bioavailability issues in pre-clinical/clinical studies despite high oral doses. We report here a new concept utilizing polycaprolactone implants embedded with test compounds to obtain controlled systemic delivery, circumventing oral bioavailability issues and reducing the total administered dose. Compounds were released from the implants in vitro dose dependently and for long durations (months), which correlated with in vivo release. Polymeric implants of curcumin significantly inhibited tissue DNA adducts following the treatment of rats with benzo[a]pyrene, with the total administered dose being substantially lower than typical oral doses. A comparison of bioavailability of curcumin given by implants showed significantly higher levels of curcumin in the plasma, liver and brain 30 days after treatment compared with the dietary route. Withaferin A implants resulted in a nearly 60% inhibition of lung cancer A549 cell xenografts, but no inhibition occurred when the same total dose was administered intraperitoneally. More than 15 phytochemicals have been tested successfully by this formulation. Together, our data indicate that this novel implant-delivery system circumvents oral bioavailability issues, provides continuous delivery for long durations and lowers the total administered dose, eliciting both chemopreventive/chemotherapeutic activities. This would also allow the assessment of activity of minor constituents and synthetic metabolites, which otherwise remain uninvestigated in vivo.     

The natriuretic peptides in cardiovascular medicine

Within the last five years, assay systems for measurement of plasma levels of brain natriuretic peptide (BNP) have been approved as a diagnostic aid for heart failure (HF). Similarly, nesiritide, a recombinant form of human BNP, has been approved for the treatment of acutely decompensated HF. Both BNP as a diagnostic test and a therapeutic modality are rapidly becoming integrated into clinical practice. The purpose of this review is to provide a brief overview of the physiology of the natriuretic peptides relevant to their informed clinical use. The current literature regarding the utility of measuring BNP for the diagnosis and management of HF is reviewed and practical recommendations regarding the interpretation of BNP levels are offered. The clinical literature regarding the use of recombinant BNP for the treatment of HF is reviewed, underscoring current gaps in our knowledge regarding the indications for and benefits of this novel agent.     

Coronary revascularization for acute myocardial infarction in the HIV population

Objective

To analyze trends in management and outcomes of patients infected with the human immunodeficiency virus (HIV) undergoing percutaneous coronary intervention (PCI) for an acute myocardial infarction (AMI) in the United States.

Background

Infection with HIV is an independent risk factor for accelerated atherosclerosis associated with higher rates of AMI. Current trends and outcomes of HIV‐infected individuals presenting with AMI in the United States remain unknown.

Methods

Using the Healthcare Cost and Utilization Project National Inpatient Sample database we identified HIV‐infected individuals who underwent PCI for an AMI from 2002 to 2013. Multivariable logistic regression and propensity‐score matching were performed to analyze outcomes.

Results

We identified a total of 59 194 patients of which 7841 underwent PCI during index hospitalization (13.3%). Most patients were men (71%), ≥50 years of age (82%), and white (74%). ST‐elevation myocardial infarction was present in 21% of cases. Charlson comorbidity index (CCI) was 5.67 ± 0.4. Predictors of post‐procedural complications included female sex, black race, higher CCI, and placement of a bare metal stent, whereas predictors of mortality included occurrence of a complication, ST‐elevation myocardial infarction, age ≥70 years, and higher CCI. Conversely, placement of a drug‐eluting stent was associated with a reduced risk of complications and mortality. After propensity‐score matching, HIV‐infected individuals were less likely to undergo PCI and receive a drug‐eluting stent, while having longer length of stay, higher hospitalization costs, and higher in‐hospital mortality when compared to non‐infected individuals.

Conclusion

Significant disparities continue to affect HIV‐infected individuals undergoing PCI for AMI in the United States.