-
1.
Combination therapy with vancomycin-loaded calcium sulfate and vancomycin-loaded PMMA in the treatment of chronic osteomyelitis.
Luo, S, Jiang, T, Yang, Y, Yang, X, Zhao, J
BMC musculoskeletal disorders. 2016;(1):502
Abstract
BACKGROUND Chronic post-traumatic and postoperative osteomyelitis is a refractory disease which results in significant morbidity and mortality. The effect of combination therapy with vancomycin-loaded calcium sulfate and vancomycin-loaded polymethyl methacrylate (PMMA) was unknown. METHODS Fifty-one patients suffering from chronic post-traumatic or postoperative osteomyelitis of the lower extremities were included in the retrospective investigation. The patients were assigned to the study group of the combination therapy with antibiotic-loaded calcium sulfate and antibiotic-loaded PMMA or the control group of the antibiotic-loaded PMMA. Hematological parameters, eradication of infection, rate of infection recurrence and reoperation rate were evaluated during the follow-up. RESULTS The cases were followed up for an average of 24 months (range, 15-48 months) after the first-stage surgical operation. In the study group, all the patients revealed complete calcium sulfate resorption at an average of 6 weeks (range, 30-60 days). In the study group, infection was primarily eradicated in 92.31% (24 of 26) of patients and re-operation rate of 7.69% (2 of 26) after the first-stage surgery. Two patients underwent further surgical operation in the study group. One case achieved infection eradication in the recurrent two cases, with a secondary infection eradication rate of 96.15% (25 of 26). There was no persistent infection in the study group. In the control group, infection was eradicated in 64.00% (16 of 25) of patients and re-operation rate was 36.00% (9 of 25) after the first-stage surgery. Nine patients in the control group underwent further surgical operation. Two case achieved infection eradication in these cases who suffered from persistent or recurrent infection, with a secondary infection eradication rate of 72.00% (18 of 25). There was more re-operation rate in the control group (PMMA group, 9 vs combination therapy group, 2; P = 0.034). CONCLUSION The combination therapy with vancomycin-loaded calcium sulfate and vancomycin-loaded PMMA possibly achieved more effective control of infection in the treatment of osteomyelitis through synergistic effect. The immediate structural stabilization and higher concentration of antibiotic at the local site of infection may be achieved through the combination of biodegradable and non-biodegradable devices in the treatment of chronic post-traumatic and postoperative osteomyelitis. The study was retrospectively registered at 11/16/2016 (TRN: NCT02968693).
-
2.
Structure-based ligand discovery for the Large-neutral Amino Acid Transporter 1, LAT-1.
Geier, EG, Schlessinger, A, Fan, H, Gable, JE, Irwin, JJ, Sali, A, Giacomini, KM
Proceedings of the National Academy of Sciences of the United States of America. 2013;(14):5480-5
-
-
Free full text
-
Abstract
The Large-neutral Amino Acid Transporter 1 (LAT-1)--a sodium-independent exchanger of amino acids, thyroid hormones, and prescription drugs--is highly expressed in the blood-brain barrier and various types of cancer. LAT-1 plays an important role in cancer development as well as in mediating drug and nutrient delivery across the blood-brain barrier, making it a key drug target. Here, we identify four LAT-1 ligands, including one chemically novel substrate, by comparative modeling, virtual screening, and experimental validation. These results may rationalize the enhanced brain permeability of two drugs, including the anticancer agent acivicin. Finally, two of our hits inhibited proliferation of a cancer cell line by distinct mechanisms, providing useful chemical tools to characterize the role of LAT-1 in cancer metabolism.
-
3.
Optimization of a dual mechanism gastrofloatable and gastroadhesive delivery system for narrow absorption window drugs.
Murphy, C, Pillay, V, Choonara, YE, du Toit, LC, Ndesendo, VM, Chirwa, N, Kumar, P
AAPS PharmSciTech. 2012;(1):1-15
-
-
Free full text
-
Abstract
In order to overcome poor bioavailability of narrow absorption window drugs, a gastrosphere system comprising two mechanisms of gastric retention, namely buoyancy and gastroadhesion, has been investigated in this study employing poly(lactic-co-glycolic acid) (PLGA), polyacrylic acid (PAA), alginate, pectin, and a model drug metformin hydrochloride. Fifteen formulations were obtained using a Box-Behnken statistical design. The gastrosphere yield was above 80% in all cases; however, due to the high water solubility of metformin, drug entrapment efficacy was between 18% and 54%. Mean dissolution time and gastroadhesive strength were used as the formulation responses in order to optimize the formulation. Furthermore, the molecular mechanics force field simulations were performed to corroborate the experimental findings. Drug release profiles revealed three different release kinetics, namely, burst, first-order and zero-order release. Varying gastroadhesive results were obtained, and were highly sensitive to changes in polymer concentrations. FTIR revealed that strong bonds of PAA and PLGA were retained within the gastrosphere. Surface area and porosity analysis provided supporting evidence that the lyophilization process resulted in a significant increase in the porosity. Analysis of the surface morphology by SEM revealed that air pockets were spread over the entire surface of the gastrosphere, providing a visual proof of the high porosity and hence low density of the gastrosphere. The spatial disposition and energetic profile of the sterically constrained and geometrically optimized multi-polymeric complex of alginate, pectin, PAA, and PLGA corroborated the experimental results in terms of in vitro drug release and gastroadhesive strength of the fabricated gastrospheres.
-
4.
[A 32P application device for the treatment of condyloma acuminatum in the rectum].
Ma, YB, Liu, YW, Gu, AC, Xu, F, Liu, PA, Yuan, SF, Zhai, CT
Zhonghua nan ke xue = National journal of andrology. 2011;(1):47-51
Abstract
OBJECTIVE To investigate the use of a 32P application device (AD) in the treatment of condyloma acuminatum (CA) in the rectum, and to compare its clinical effect with that of the microwave therapy. METHODS This study included 107 cases of CA in the rectum, 99 males and 8 females, aged 21-58 (33.6 +/- 9.4) years. Forty-six of the patients (the AD group) were treated with a self-made 32P application device, which, as a tube-shaped carrier of radionuclide 32P colloid, was fixed in the rectum at the diseased part for medication at 4.9-8.2 Gy for 3-5 hours once and 1-2 times a week. The other 61 (the microwave group) were treated by microwave burning under local anesthesia. Both groups of patients were followed up for over 3 months for comparison of the therapeutic results and observation of the stability and reliability of the 32P application device. RESULTS The rates of cure, reoccurrence and adverse reaction were 84, 8%, 13.0% and 8.7% in the AD group, compared with 40.3%, 55.7% and 75.4% in the microwave group, with statistically significant differences between the two groups (P < 0.01). CONCLUSION The 32P application device, with its advantages of low cost, easy operation, good effect, high safety and reliability, low recurrence, fewer adverse events and good acceptability, is highly valuable for the treatment of CA in the rectum.
-
5.
Paclitaxel-eluting balloon angioplasty and cobalt-chromium stents versus conventional angioplasty and paclitaxel-eluting stents in the treatment of native coronary artery stenoses in patients with diabetes mellitus.
Ali, RM, Degenhardt, R, Zambahari, R, Tresukosol, D, Ahmad, WA, Kamar, Hb, Kui-Hian, S, Ong, TK, bin Ismail, O, bin Elis, S, et al
EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology. 2011;:K83-92
Abstract
AIMS: Coronary lesions in diabetics (DM) are associated with a high recurrence following percutaneous coronary intervention (PCI), even after drug-eluting stent (DES) deployment. Encouraging clinical data of the drug-eluting balloon catheter (DEB) SeQuent Please warrant its investigation in these patients. METHODS AND RESULTS Eighty-four diabetic patients (60.8 ± 9.1 years, 76.2% male) were randomised to either the DEB SeQuent Please or the DES Taxus Liberté to compare the 9-month clinical and angiographic outcome of PCI in native coronary arteries. Comparing the DEB vs. the DES the 9-month results (follow-up DEB 39/45 [86.7%], DES 36/39 [92.3%]) are statistically not different at the 0.05 level for the primary endpoint of in-segment (0.37 ± 0.59 mm vs. 0.35 ± 0.63 mm) and in-stent (0.51 ± 0.61 mm vs. 0.53 ± 0.67 mm) late lumen loss, overall and cardiac deaths (2/45 [4.4%] and 3/45 [6.7%] vs. 0), target lesion revascularisation (3/45 [8.9%] vs. 4/39 [10.3%]), the total MACE rate (6/45 [13.3%] vs. 6/39 [15.4%]), and the event free survival after 10.2 ± 3.8 months (Kaplan-Meier analysis, p<0.80, log rank test). CONCLUSIONS The clinical and angiographic outcome of the combination of the drug-eluting balloon SeQuent Please with a cobalt chromium stent compared to the drug eluting Taxus stent are similar.
-
6.
Impact of system L amino acid transporter 1 (LAT1) on proliferation of human ovarian cancer cells: a possible target for combination therapy with anti-proliferative aminopeptidase inhibitors.
Fan, X, Ross, DD, Arakawa, H, Ganapathy, V, Tamai, I, Nakanishi, T
Biochemical pharmacology. 2010;(6):811-8
Abstract
Amino acids activate nutrient signaling via the mammalian target of rapamycin (mTOR), we therefore evaluated the relationship between amino acid transporter gene expression and proliferation in human ovarian cancer cell lines. Expression of three cancer-associated amino acid transporter genes, LAT1, ASCT2 and SN2, was measured by qRT-PCR and Western blot. The effects of silencing the LAT1 gene and its inhibitor BCH on cell growth were evaluated by means of cell proliferation and colony formation assays. The system L amino acid transporter LAT1 was up-regulated in human ovarian cancer SKOV3, IGROV1, A2780, and OVCAR3 cells, compared to normal ovarian epithelial IOSE397 cells, whereas ASCT2 and SN2 were not. BCH reduced phosphorylation of p70S6K, a down-stream effector of mTOR, in SKOV3 and IGROV1 cells, and decreased their proliferation by 30% and 28%, respectively. Although proliferation of SKOV3 (S1) or IGROV1 (I10) cells was unaffected by LAT1-knockdown, plating efficiency in colony formation assays was significantly reduced in SKOV3(S1) and IGROV1(I10) cells to 21% and 52% of the respective plasmid transfected control cells, SKOV3(SC) and IGROV(IC), suggesting that LAT1 affects anchorage-independent cell proliferation. Finally, BCH caused 10.5- and 4.3-fold decrease in the IC(50) value of bestatin, an anti-proliferative aminopeptidase inhibitor, in IGROV1 and A2780 cells, respectively, suggesting that the combined therapy is synergistic. Our findings indicate that LAT1 expression is increased in human ovarian cancer cell lines; LAT1 may be a target for combination therapy with anti-proliferative aminopeptidase inhibitors to combat ovarian cancer.
-
7.
Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer disease.
Fleisher, AS, Raman, R, Siemers, ER, Becerra, L, Clark, CM, Dean, RA, Farlow, MR, Galvin, JE, Peskind, ER, Quinn, JF, et al
Archives of neurology. 2008;(8):1031-8
-
-
Free full text
-
Abstract
OBJECTIVE To evaluate the safety, tolerability, and amyloid beta (Abeta) response to the gamma-secretase inhibitor LY450139 in Alzheimer disease. DESIGN Multicenter, randomized, double-blind, dose-escalation, placebo-controlled trial. SETTING Community-based clinical research centers. Patients Fifty-one individuals with mild to moderate Alzheimer disease were randomized to receive placebo (n=15) or LY450139 (100 mg [n=22] or 140 mg [n=14]), with 43 completing the treatment phase. Intervention The LY450139 groups received 60 mg/d for 2 weeks, then 100 mg/d for 6 weeks, and then either 100 or 140 mg/d for 6 additional weeks. MAIN OUTCOME MEASURES Primary outcome measures were adverse events, plasma and cerebrospinal fluid Abeta levels, vital signs, electrocardiographic data, and laboratory safety test results. Secondary outcome measures included the Alzheimer's Disease Assessment Scale cognitive subscale and the Alzheimer's Disease Cooperative Study Activities of Daily Living Scale. RESULTS Group differences were seen in skin and subcutaneous tissue concerns (P=.05), including 3 possible drug rashes and 3 reports of hair color change in the treatment groups. There were 3 adverse event-related discontinuations, including 1 transient bowel obstruction. The plasma Abeta(40) concentration was reduced by 58.2% for the 100-mg group and 64.6% for the 140-mg group (P<.001). No significant reduction was seen in cerebrospinal fluid Abeta levels. No group differences were seen in cognitive or functional measures. CONCLUSIONS LY450139 was generally well tolerated at doses of up to 140 mg/d for 14 weeks, with several findings indicating the need for close clinical monitoring in future studies. Decreases in plasma Abeta concentrations were consistent with inhibition of gamma-secretase. Trial Registration clinicaltrials.gov Identifier: NCT00244322.
-
8.
Nasal residence of insulin containing lyophilised nasal insert formulations, using gamma scintigraphy.
McInnes, FJ, O'Mahony, B, Lindsay, B, Band, J, Wilson, CG, Hodges, LA, Stevens, HN
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. 2007;(1):25-31
Abstract
Bioadhesive dosage forms are a potential method for overcoming rapid mucociliary transport in the nose. A lyophilised nasal insert formulation previously investigated in sheep demonstrated prolonged absorption of nicotine hydrogen tartrate suggestive of extended nasal residence, and increased bioavailability. The current study was performed to quantify nasal residence of the formulations using gamma scintigraphy, and to investigate the absorption of a larger molecule, namely insulin. A four-way crossover study was conducted in six healthy male volunteers, comparing a conventional nasal spray solution with three lyophilised nasal insert formulations (1-3% hydroxypropylmethylcellulose (HPMC)). The conventional nasal spray deposited in the posterior nasal cavity in only one instance, with a rapid clearance half-life of 9.2 min. The nasal insert formulations did not enhance nasal absorption of insulin, however an extended nasal residence time of 4-5 h was observed for the 2% HPMC formulation. The 1% HPMC insert initially showed good spreading behaviour; however, clearance was faster than for the 2% formulation. The 3% HPMC nasal insert showed no spreading, and was usually cleared intact from the nasal cavity within 90 min. In conclusion, the 2% HPMC lyophilised insert formulation achieved extended nasal residence, demonstrating an optimum combination of rapid adhesion without over hydration.
-
9.
Effects of high-dose atorvastatin on cerebrovascular events in patients with stable coronary disease in the TNT (treating to new targets) study.
Waters, DD, LaRosa, JC, Barter, P, Fruchart, JC, Gotto, AM, Carter, R, Breazna, A, Kastelein, JJ, Grundy, SM
Journal of the American College of Cardiology. 2006;(9):1793-9
Abstract
OBJECTIVE We sought to assess the effects on cerebrovascular events of treating patients with stable coronary disease with low-density lipoprotein cholesterol (LDL-C) levels substantially below 100 mg/dl. BACKGROUND Lowering LDL-C with statins has been shown to reduce the risk of stroke in patients with stable coronary disease. In observational studies, naturally low cholesterol levels have been associated with an increased risk of hemorrhagic stroke. The cerebrovascular benefits of treating patients with stable coronary disease to LDL-C levels substantially below 100 mg/dl have not been previously investigated. METHODS We describe an analysis of cerebrovascular events in the Treating to New Targets study, a trial where 10,001 patients with documented coronary disease were randomized to treatment with atorvastatin at 10 mg/day or 80 mg/day and followed for a median of 4.9 years. RESULTS Mean LDL-C levels were 101 mg/dl on 10 mg atorvastatin and 77 mg/dl on 80 mg. In addition to the reduction in major cardiovascular events (hazard ratio 0.78, 95% confidence interval [CI] 0.69 to 0.89; p = 0.0002), the primary end point of the trial, patients in the 80-mg arm experienced a reduction in cerebrovascular events (hazard ratio 0.77, 95% CI 0.64 to 0.93; p = 0.007) and stroke (hazard ratio 0.75, 95% CI 0.59 to 0.96; p = 0.02). Each 1-mg/dl reduction in LDL-C with treatment was associated with a 0.6% relative risk reduction in cerebrovascular events (p = 0.002) and a 0.5% relative risk reduction in stroke (p = 0.041). The incidence of hemorrhagic stroke was similar in the 80-mg and 10-mg groups, 16 and 18 respectively, and the hemorrhagic strokes were distributed evenly across quintiles of achieved LDL-C during treatment. CONCLUSIONS Among patients with established coronary disease, treating to an LDL-cholesterol substantially below 100 mg/dl with 80 mg/day atorvastatin reduces both stroke and cerebrovascular events by an additional 20% to 25% compared with the 10 mg/day dose. An increase in hemorrhagic stroke was not seen at low LDL-C levels. (Treating to New Targets; http://www.clinicaltrials.gov; NCT00327691).
-
10.
Comparison of intratumoral bolus injection and convection-enhanced delivery of radiolabeled antitenascin monoclonal antibodies.
Sampson, JH, Akabani, G, Friedman, AH, Bigner, D, Kunwar, S, Berger, MS, Bankiewicz, KS
Neurosurgical focus. 2006;(4):E14
Abstract
OBJECTIVES Convection-enhanced delivery (CED) is a novel technique used to deliver agents to the brain parenchyma for treatment of neoplastic, infectious, and degenerative conditions. The purpose of this study was to determine if CED would provide a larger volume of distribution (Vd) of a radiolabeled monoclonal antibody (mAb) than a bolus injection. METHODS Patients harboring a recurrent glioblastoma multiforme that reacted with the antitenascin mAb 81C6 during immunohistochemical analysis were randomized to receive an intratumoral injection of the human-murine chimeric mAb Ch81C6, which had been labeled with the 123I tracer. The mAb was administered by either a bolus injection or CED via a stereotactically placed catheter; between 48 and 72 hours later the mAb was again administered using the other technique. Injections of escalating doses of a 131I-labeled therapeutic mAb were then delivered using the technique shown to produce the largest Vd by single-photon emission computerized tomography. CONCLUSIONS Convection-enhanced delivery has enormous potential for administering drugs to sites within the central nervous system. For the relatively small volumes injected in this study, however, CED did not provide a significant increase in the Vd when compared with the bolus injection. Nevertheless, a clear cross-over effect was seen, which was probably related to the temporal proximity of the two infusions.