Outcomes of treatment for hepatitis C virus infection by primary care providers.

BACKGROUND: The Extension for Community Healthcare Outcomes (ECHO) model was developed to improve access to care for underserved populations with complex health problems such as hepatitis C virus (HCV) infection. With the use of video-conferencing technology, the ECHO program trains primary care providers to treat complex diseases. METHODS: We conducted a prospective cohort study comparing treatment for HCV infection at the University of New Mexico (UNM) HCV clinic with treatment by primary care clinicians at 21 ECHO sites in rural areas and prisons in New Mexico. A total of 407 patients with chronic HCV infection who had received no previous treatment for the infection were enrolled. The primary end point was a sustained virologic response. RESULTS: A total of 57.5% of the patients treated at the UNM HCV clinic (84 of 146 patients) and 58.2% of those treated at ECHO sites (152 of 261 patients) had a sustained viral response (difference in rates between sites, 0.7 percentage points; 95% confidence interval, -9.2 to 10.7; P=0.89). Among patients with HCV genotype 1 infection, the rate of sustained viral response was 45.8% (38 of 83 patients) at the UNM HCV clinic and 49.7% (73 of 147 patients) at ECHO sites (P=0.57). Serious adverse events occurred in 13.7% of the patients at the UNM HCV clinic and in 6.9% of the patients at ECHO sites. CONCLUSIONS: The results of this study show that the ECHO model is an effective way to treat HCV infection in underserved communities. Implementation of this model would allow other states and nations to treat a greater number of patients infected with HCV than they are currently able to treat. (Funded by the Agency for Healthcare Research and Quality and others.).

An in vitro study of liposomal curcumin: stability, toxicity and biological activity in human lymphocytes and Epstein-Barr virus-transformed human B-cells.

Curcumin is a multi-functional and pharmacologically safe natural agent. Used as a food additive for centuries, it also has anti-inflammatory, anti-virus and anti-tumor properties. We previously found that it is a potent inhibitor of cyclosporin A (CsA)-resistant T-cell co-stimulation pathway. It inhibits mitogen-stimulated lymphocyte proliferation, NFkappaB activation and IL-2 signaling. In spite of its safety and efficacy, the in vivo bioavailability of curcumin is poor, and this may be a major obstacle to its utility as a therapeutic agent. Liposomes are known to be excellent carriers for drug delivery. In this in vitro study, we report the effects of different liposome formulations on curcumin stability in phosphate buffered saline (PBS), human blood, plasma and culture medium RPMI-1640+10% FBS (pH 7.4, 37 degrees C). Liposomal curcumin had higher stability than free curcumin in PBS. Liposomal and free curcumin had similar stability in human blood, plasma and RPMI-1640+10% FBS. We looked at the toxicity of non-drug-containing liposomes on (3)H-thymidine incorporation by concanavalin A (Con A)-stimulated human lymphocytes, splenocytes and Epstein-Barr virus (EBV)-transformed human B-cell lymphoblastoid cell line (LCL). We found that dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG) were toxic to the tested cells. However, addition of cholesterol to the lipids at DMPC:DMPG:cholesterol=7:1:8 (molar ratio) almost completely eliminated the lipid toxicity to these cells. Liposomal curcumin had similar or even stronger inhibitory effects on Con A-stimulated human lymphocyte, splenocyte and LCL proliferation. We conclude that liposomal curcumin may be useful for intravenous administration to improve the bioavailability and efficacy, facilitating in vivo studies that could ultimately lead to clinical application of curcumin.

Evaluation of synthetic polymeric micelles as a stabilization medium for the handling of membrane proteins in pharmaceutical drug discovery.

PURPOSE: Polymeric micelles have been used for solubilization of insoluble drugs and as carriers for drug delivery applications. Here we evaluated an application of the synthetic polymeric micelles in experiments designed to improve the handling and stability of membrane proteins targets. METHODS: Particle sizing by dynamic light scattering was performed in a Zeta Plus Photon Correlation Spectrometer at 532 nm. UGT1A1 activity has been measured in fluorescent assay using scopoletin as a substrate. COX-2 activity has been measured in a fluorescent assay using Amplex Red. Fluorescence Resonance Energy Transfer (FRET) was monitored using either 463 nm excitation wavelength (the emission range 500-600 nm) or 395 nm excitation wavelength (the emission range 500-600 nm). RESULTS: Incorporation of membrane proteins into PreserveX-QML polymeric micelles resulted in improved homogeneity and stability of the preparation and in reduced light scattering. Stabilization of the biological activity of micelle-incorporated membrane proteins, such as the human UGT1A1 and COX-2 both during extended incubations at room temperature and during multiple freeze/thaw cycles, has been achieved. CONCLUSION: PreserveX-QML polymeric micelles help to homogenize and disperse membrane proteins preparations and stabilize the biological activity of the proteins making it more suitable for pharmaceutical assays and applications.

Bare platinum coils vs. HydroCoil in the treatment of unruptured intracranial aneurysms-A single center randomized controlled study.

PURPOSE: The HydroCoil Embolic System (HES) was developed to improve aneurysm filling to provide superior occlusion efficacy, reduce retreatment rates and enhance long-term durability. We performed a randomized clinical trial to compare the effectiveness of bare platinum coils (BPC) vs. HES for unruptured intracranial aneurysms. METHODS: Ninety-six patients underwent endovascular coiling of unruptured intracranial aneurysms. The aneurysms were randomized equally to receive BPC or HES. Immediate angiographic results, number of coils used and complications were evaluated and all cases had 12-month follow-up angiography. RESULTS: Immediate angiographic results demonstrated that 84.0% of aneurysms treated with HES were completely occluded compared to 76.1% of aneurysms treated with BPC (p=0.3310). The mean number of coils utilized to fill the aneurysm was significantly lower in the HES arm (5.04 vs. 6.93). Additional adjunctive techniques were performed in 51.1% of all cases. There were seven patients (7.3%) with postoperative complications during the study period. The coil type used during the treatment did not demonstrate any significant differences on the overall recurrence rate (HES - 18.0%, BPC - 17.4%, p=0.9712). There was a statistically significant difference in the aneurysm size and the neck width between completely occluded aneurysms and aneurysms with residual flow in both immediate angiographic and mid-term follow-up. CONCLUSIONS: Overall, aneurysm size and neck width are the main risk factors associated with aneurysm recurrence. HES compared to BPC required less total number of coils to provide a denser aneurysm filling. However, there were equivocal results with both devices, at the mid-term angiographic follow-up.

The novel highly lipophilic topoisomerase I inhibitor DB67 is effective in the treatment of liver metastases of murine CT-26 colon carcinoma.

Colorectal carcinoma occurs in 1 of 20 individuals in most developed countries. The relapse after resection with metastatic liver disease is a major cause of death. 7-t-Butyldimethylsilyl-10-hydroxycamptothecin (DB67) has been incorporated into liposomes allowing for intravenous (i.v.) administration. A preclinical efficacy study of liposomal DB67 was performed using the colon carcinoma CT-26 cell line. The therapeutic dose for DB67 and liposomal DB67 was found to be 7 mg/kg per day using the qdx5/1 schedule. The results are compared with those obtained with irinotecan. The treatment with liposomal DB67 administered intravenously was more effective in reducing the weight and volume of primary spleen tumors and the weight and extent of liver metastases than free DB67 or liposomal DB67 administered intraperitoneally, but less effective than irinotecan. When the primary tumor was resected, treatment with liposomal DB67 administered intravenously was more effective in reducing the weight and extent of liver metastases than DB67 or liposomal DB67 administered intraperitoneally, and irinotecan. DB67 showed a higher accumulation in spleen and liver after its i.v. administration in liposomal form compared with its free or liposomal form administered intraperitoneally. DB67 and liposomal DB67 are more effective than irinotecan in the treatment of liver metastases after resection of the primary tumor.

The next generation HydroCoil: initial clinical experience with the HydroFill embolic coil.

BACKGROUND: Complete packing of intracranial aneurysms has demonstrated a significant decrease in aneurysm recurrence rates with increased volumetric filling. The HydroCoil Embolization System (HES) was developed to increase volumetric filling within the aneurysm sac to maintain long term occlusion. To further enhance ease of HES deployment, a new next generation embolic coil, the HydroFill coil, was developed. OBJECTIVE: To report the first clinical experience with the HydroFill coil, focusing on safety and effectiveness, with immediate and long term follow-up on cases performed at a single institution by a single operator. METHODS: Retrospective angiographic and clinical analysis was performed on a non-randomized single arm registry of the first consecutive 11 patients with 14 intracranial saccular aneurysms treated during a 9 month period. RESULTS: The immediate angiographic occlusion rate according to the Raymond scale was 100%. Overall packing density of all coils used was 13-135% (mean 64%). The immediate complication rate was 9% (1/11 patients), secondary to a parent vessel occlusion which resolved after intravenous administration of eptifibatide (Integrilin) without neurological sequelae. The angiographic/MR angiography follow-up period for this series was 13-30 months, with an overall complete occlusion rate of 86% (12/14 aneurysms). 2/14 aneurysms (14%) converted from complete occlusion to filling of small neck remnants. Of the two, one (7%) was a cavernous aneurysm that was retreated. CONCLUSIONS: Although this initial case series is small, this study demonstrates safe deployment of the HydroFill coil in ruptured and unruptured aneurysms without major complications, and with a high rate of occlusion on long term follow-up.

Plasma and tissue disposition of non-liposomal DB-67 and liposomal DB-67 in C.B-17 SCID mice.

PURPOSE: DB-67 is a silatecan, 7-silyl-modified camptothecin, with enhanced lipophilicity and increased blood stability of the active-lactone ring. The generation of a liposomal formulation of DB-67 may be an attractive method of intravenous (IV) administration and may maintain DB-67 in the active-lactone form. We evaluated the tissue and plasma disposition of DB-67 lactone and hydroxy acid after administration of non-liposomal (NL) and liposomal (L) DB-67 in severe combined immunodeficient (SCID) mice. METHODS: NL-DB-67 and L-DB-67 10 mg/kg IV x 1 were administered via a tail vein in SCID mice. After dosing, mice (n = 3 per time point) were euthanized and blood ( approximately 1 ml) and tissue were collected from 5 min to 48 h after administration. DB-67 lactone and hydroxy acid concentrations in plasma and DB-67 total (sum of lactone and hydroxyl acid) concentrations in tissues were determined by high-performance liquid chromatography (HPLC) with fluorescence detection. RESULTS: Clearance of DB-67 lactone after administration of NL-DB-67 and L-DB-67 were 1.6 and 3.5 l/h/m(2), respectively; DB-67 lactone half-lives after administration of NL-DB-67 and L-DB-67 were 1.4 and 0.9 h, respectively. The percentages of DB-67 lactone in plasma after administration of NL-DB-67 and L-DB-67 were 92% and 89%, respectively. Liver, kidney, spleen, and lung tissues had longer exposure times to DB-67 after administration of L-DB-67 compared with NL-DB-67. CONCLUSION: In plasma, the majority of DB-67 remained in the lactone form after administration of NL-DB-67 and L-DB-67. The plasma disposition of DB-67 was similar after administration of NL-DB-67 and L-DB-67, suggesting that most of the DB-67 is immediately released from the L-DB-67 formulation. Following administration of L-DB-67, the higher and longer exposure of DB-67 in the spleen, as compared with NL-DB-67, is consistent with splenic clearance of liposomes by the reticuloendothelial system.

A versatile prodrug approach for liposomal core-loading of water-insoluble camptothecin anticancer drugs.

We describe a versatile prodrug strategy for loading the liposomal lumen with water-insoluble camptothecins. The procedure involves conversion of an active camptothecin analogue to a 20-OR omega-aminoalkanoanic ester prodrug in which R = CO[CH(2)](n)()NH(2) and n = 1-3. The basic amino group of the prodrug serves three roles. First, at pH ranges of 3-5, the amine enhances aqueous solubility. Second, it enhances responsiveness to a transmembrane ammonium sulfate gradient across the liposomal bilayer, thereby facilitating active loading of the agent into the liposomal aqueous core. Third, at a physiological pH of 7 or above (the pH to be encountered following drug release at the tumor site), the nucleophilicity of the amine manifests itself and cyclization to the C-21 carbonyl carbon occurs. This cyclization triggers a rapid and convenient nonenzymatic decomposition process that releases active camptothecin. Accordingly, this novel liposomal approach offers a potential system for tumor-targeting prodrugs of many water-insoluble camptothecins, including the highly lipophilic and clinically attractive analogues SN-38, 9-nitrocamptothecin and DB-67. The rate of formation of the active agent at the tumor site can be controlled through the selection of n (the length of the alkyl spacer group).