Inherited mutations in voltage-gated sodium channels (VGSCs; or Nav) cause many disorders of excitability, including epilepsy, chronic pain, myotonia, and cardiac arrhythmias. Understanding the functional consequences of the disease-causing mutations is likely to provide invaluable insight into the roles that VGSCs play in normal and abnormal excitability. Here, we sought to test the hypothesis that disease-causing mutations lead to increased resurgent currents, unusual sodium currents that have not previously been implicated in disorders of excitability. We demonstrated that a paroxysmal extreme pain disorder (PEPD) mutation in the human peripheral neuronal sodium channel Nav1.7, a paramyotonia congenita (PMC) mutation in the human skeletal muscle sodium channel Nav1.4, and a long-QT3/SIDS mutation in the human cardiac sodium channel Nav1.5 all substantially increased the amplitude of resurgent sodium currents in an optimized adult rat-derived dorsal root ganglion neuronal expression system. Computer simulations indicated that resurgent currents associated with the Nav1.7 mutation could induce high-frequency action potential firing in nociceptive neurons and that resurgent currents associated with the Nav1.5 mutation could broaden the action potential in cardiac myocytes. These effects are consistent with the pathophysiology associated with the respective channelopathies. Our results indicate that resurgent currents are associated with multiple channelopathies and are likely to be important contributors to neuronal and muscle disorders of excitability.

Alternative splicing is known to alter pharmacological sensitivities, kinetics, channel distribution under pathological conditions, and developmental regulation of VGSCs. Mutations that alter channel properties in Na(V)1.7 have been genetically implicated in patients with bouts of extreme pain classified as inherited erythromelalgia (IEM) or paroxysmal extreme pain disorder (PEPD). Furthermore, patients with IEM or PEPD report differential age onsets. A recent study reported that alternative splicing of Na(V)1.7 exon 5 affects ramp current properties. Since IEM and PEPD mutations also alter Na(V)1.7 ramp current properties we speculated that alternative splicing might impact the functional consequences of IEM or PEPD mutations. We compared the effects alternative splicing has on the biophysical properties of Na(V)1.7 wild-type, IEM (I136V) and PEPD (I1461T) channels. Our major findings demonstrate that although the 5A splice variant of the IEM channel had no functional impact, the 5A splice variant of the PEPD channel significantly hyperpolarized the activation curve, slowed deactivation and closed-state inactivation, shifted the ramp current activation to more hyperpolarized potentials, and increased ramp current amplitude. We hypothesize a D1/S3-S4 charged residue difference between the 5N (Asn) and the 5A (Asp) variants within the coding region of exon 5 may contribute to shifts in channel activation and deactivation. Taken together, the additive effects observed on ramp currents from exon 5 splicing and the PEPD mutation (I1461T) are likely to impact the disease phenotype and may offer insight into how alternative splicing may affect specific intramolecular interactions critical for voltage-dependent gating.

OBJECTIVE:: African-Americans have been underrepresented in most large Crohn's disease (CD) trials. This study was undertaken to assess the course and character of CD in African-Americans in comparison with whites. METHODS:: We retrospectively compared the course and character of CD in African-American and white patients at 3 Atlanta hospitals. Ninety-nine patients (55 African-American, 44 whites) were enrolled. Telephone interviews and chart reviews were used to identify disease location, presence of fistulae and perirectal disease, surgical history, and medication use. Patients with ulcerative colitis or indeterminant colitis, and all non-African-Americans or whites, were excluded. RESULTS:: The numbers of male and female patients were similar (50 and 49). Overall, men comprised 54% of white patients and 47% of African-American patients. There were no significant differences in the setting in which CD were diagnosed, number of flares per year, or duration of symptoms before diagnosis. White patients were more likely to seek care for their CD in a clinic setting, both their primary care physicians (1.31 versus 0.21 visits/yr, P < 0.001) and their gastroenterologists (3.2 versus 2.3 visits/yr, P = 0.03). Small bowel (SB) disease was present more frequently in white patients, 84% versus 65%(P = 0.03), and SB resection was more common in this group, 59% versus 16%(P < 0.01). Colonic disease was more common in African-American patients, 89% versus 63%(P = 0.002). Perirectal fistulae were more frequent in African-American patients, 58% versus 22%(P < 0.001) white patients were more likely to report complete compliance with medical therapy, 77% versus 49%(P = 0.004). African-American patients more frequently discontinued medical therapy because they "felt better"(27% versus 9%, P = 0.02). Medication usage, including immunosuppressants, was similar in both groups, except that white patients were more likely to receive multiple doses of infliximab (34% versus 11%, P = 0.005). Both groups felt equally informed about CD, but white patients felt that their disease was under good control a greater percentage of the time, 71% versus 58%(P = 0.04). CONCLUSIONS:: These data lend credence to the suggestion that the nature of CD may be different in African-Americans compared with whites. However, despite this apparent difference in disease manifestation, the contribution of socioeconomic factors, access to health care, and understanding of the disease likely play a role as well.

OBJECTIVES: To assess medication adherence, persistence, and costs between cohorts of patients in managed care settings using a fixed-dose combination (FDC) or individual components (IC) of valsartan and hydrochlorothiazide in an insurance claims database. METHODS: Medical and prescription claims for hypertensive patients using a combination of valsartan and HCTZ were identified from the IHCIS National Managed Care Benchmark Database via a retrospective cohort analysis. Study subjects had at least 110 days prior to start of study medications during which no other antihypertensive medications were prescribed, and were followed for 12 months. Claims for 8711 adult patients were analyzed for adherence, persistence and costs. General linear regression was conducted to detect differences in adherence among groups. Covariates included age, gender, persistence, number on concomitant cardiovascular drugs, and number of cardiovascular diagnoses. RESULTS: Most subjects used an FDC product (N=8150, 93.6%) vs. the IC (N=561, 6.4%). The FDC group had a larger portion of males and less concomitant cardiovascular medications or disease. A random sample of 1628 of the FDC subjects had improved values for medication adherence compared to the IC group (62.1 vs. 53.0%, p<0.001) and persistence values were improved at both 180 days (73 vs. 28%, p<0.001) and 365 days (54 vs. 19%, p<0.001). Both prescription drug costs ($1587 vs.$2050, p<0.001) and medical costs ($3343 vs.$3817, p<0.001) were lower in the FDC cohorts. CONCLUSIONS: The use of fixed-dose therapy in hypertension may lead to increased adherence and persistence with a positive financial impact on both prescription and total medical costs. As with any retrospective claims database analysis, unobserved systematic differences between the two medication groups may exist.

Objective: The aim of this analysis was to assess the impact of multiple combination therapies on medication possession ratios (MPRs) in an antihypertensivenaive population. Methods: Data were collected using the Integrated Healthcare Information Solution's National Benchmark Database (January 1997 to June 2004). Data from patients who received 2-pill pharmacotherapy with valsartan or valsartan/hydrochlorothiazide (HCTZ) in a fixed-dose combination (FDC)+ amlodipine were compared with those from patients who received 3-pill therapy with valsartan + HCTZ + amlodipine as 3 free-drug components. MPR was calculated by dividing the total days' supply for the lower value in the case of individual drug components, or the number of days' supply in the case of FDC, by 365 (the number of days during the 1-year study period the medication regimen was prescribed). A general linear regression was then performed to determine the effect of treatment group on MPR, controlling for the demographic and clinical characteristics. Results: Data from 908 patients were included (527 women, 381 men; mean age, 53.9 years; 2-pill treatment with valsartan + amlodipine, 224 patients; 2-pill treatment with valsartan/HCTZ + amlodipine, 619; and 3-pill therapy with valsartan + HCTZ + amlodipine, 65). The MPR values were 75.4%, 73.1%, and 60.5%, respectively (P = 0.005). MPR improved with age (69.6% in the subset aged 18-<36 years vs 75.2% in the subset aged >/=64 years; P = 0.023). Conclusions: In these antihypertensive-naive patients with hypertension, MPR decreased with the increase in tablets per regimen, and improved MPR was correlated with increasing age. These findings suggest patient compliance improves with simplified pharmacotherapeutic approaches.

Stromal-epithelial interactions mediated by paracrine signaling mechanisms dictate prostate development and progression of prostate cancer. The regulatory role of androgens in both the prostate stromal and epithelial compartments set the prostate apart from many other organs and tissues with regard to gene targeting. The identification of androgen-dependent prostate epithelial promoters has allowed successful gene targeting to the prostate epithelial compartment. Currently, there are no transgenic mouse models available to specifically alter gene expression within the prostate stromal compartment. As a primary metastatic site for prostate cancer is bone, the functional dissection of the bone stromal compartment is important for understanding stromal-epithelial interactions associated with metastatic tumor growth. Use of currently available methodologies for the expression or deletion of gene expression in recent research studies has advanced our understanding of the stroma. However, the complexity of stromal heterogeneity within the prostate remains a challenge to obtaining compartment or cell-lineage-specific in vivo models necessary for furthering our understanding of prostatic developmental, benign, tumorigenic, and metastatic growth.

The development of an effective pharmacological countermeasure is needed to reduce the morbidity and mortality in military and civilian populations associated with possible exposure to ionizing radiation. Previous studies in mice have shown that a single subcutaneous (sc) injection of the natural steroid androst-5-ene-3beta,17beta-diol (5-androstenediol, 5-AED), 24-48 h prior to a lethal dose of whole-body (60)Co gamma radiation, stimulated hematopoiesis and enhanced survival. These effects are consistent with our previous observation of 5-AED-induced elevations in circulating G-CSF in normal and irradiated mice. The purpose of this study was to obtain data on the pharmacokinetics of 5-AED after sc and buccal administration to mice, and to determine whether cytokine genes are induced by sc 5-AED in hematopoietic tissues (bone marrow, spleen). We studied effects on serum cytokines and chemokines, and also analyzed the pharmacokinetics of 5-AED after sc administration and compared it with buccal delivery. 5-AED was administered 24 h before irradiation or sham-irradiation. Cytokine mRNAs were quantified by quantitative real-time PCR (QRT-PCR), and cytokine levels in serum by multiplex Luminex. 5-AED administration was associated with elevation of message for GM-CSF, IL-2, IL-3, IL-6, and IL-10 in spleen, and GM-CSF and IL-2 in bone marrow. Irradiation enhanced G-CSF, GM-CSF, IFN-gamma, TPO, IL-2, IL-3, IL-6, IL-10, and IL-12 in spleen, and GM-CSF, IFN-gamma, TPO, IL-3, and IL-10 in bone marrow. Serum levels of G-CSF were significantly elevated in 5-AED-treated mice 4 h after irradiation or sham-irradiation. Serum macrophage inflammatory protein-1gamma (MIP-1gamma) was significantly elevated 4 h after irradiation in 5-AED-treated mice. Plasma 5-AED peaked 2 h after sc injection (30 mg/kg), and remained significantly above control after 4 days, but not 8 days. The time course of plasma 5-AED after buccal delivery (60 mg/kg) was similar, but levels were significantly lower compared to sc delivery. Plasma 5-AED 24 h after administration was not significantly different between sc and buccal delivery. However, in contrast to many studies showing enhanced survival after sc administration of 5-AED, we found no effect on survival of buccal 5-AED. The results suggest that radioprotection is not dependent on the 5-AED concentration at the time of irradiation, but rather on events triggered during the first few hours after administration. The current results suggest that further studies are warranted to directly test the roles of cytokines in the radioprotective effects of 5-AED.

Methylnaltrexone and alvimopan are two new and potentially useful agents in the management of opioid-induced bowel dysfunction and prevention of postoperative ileus. Both agents have promising prokinetic properties and appear to be capable of reversing the effects of opioids on delayed gastrointestinal transit. This article reviews currently available published literature to provide an overview of the clinical trials and to provide insight for the potential use of these agents for patients requiring opioid based analgesia. These compounds represent a new class of compounds that may impact the therapeutics for opioid induced bowel dysfunction as well as postoperative ileus.

INTRODUCTION:: An employer-based cost-benefit analysis for varenicline versus bupropion was conducted using clinical outcomes from a recently published trial. METHODS:: A decision tree model was developed based on the net benefit of treatment to produce a nonsmoker at 1 year. Sensitivity analyses were conducted based on quit rates with placebo and varenicline and the cost of varenicline. RESULTS:: Estimated 12-month employer cost savings per non-smoking employee were $540.60 for varenicline,$269.80 for bupropion SR generic,$150.80 for bupropion SR brand, and $81.80 for placebo. Varenicline was more cost beneficial than placebo, which had quit rates of 16.9% or less. The quit rate with varenicline would have to be </=16.9% to lose cost benefit over bupropion SR generic. CONCLUSIONS:: The economic benefit of varenicline is improved over bupropion, despite the increased initial cost of varenicline.