Nitinol Stents in the Femoropopliteal Artery: A Mechanical Perspective on Material,Design, and Performance

Endovascular stenting has matured into a commonly used treatment for peripheral arterial disease (PAD) due to its minimally invasive nature and associated reductions in short-term morbidity and mortality. The mechanical properties of the superelastic Nitinol alloy have played a major role in the explosion of peripheral artery stenting, with modern stents demonstrating reasonable resilience and durability. Yet in the superficial femoral and popliteal arteries, even the newest generation Nitinol stents continue to demonstrate clinical outcomes that leave significant room for improvement. Restenosis and progression of native arterial disease often lead to recurrence of symptoms and reinterventions that increase morbidity and health care expenditures. One of the main factors thought to be associated with stent failure in the femoropopliteal artery (FPA) is the unique and highly dynamic mechanical environment of the lower limb. Clinical and experimental data demonstrate that the FPA undergoes significant deformations with limb flexion. It is hypothesized that the inability of many existing stent designs to conform to these deformations likely plays a role in reconstruction failure, as repetitive movements of the leg and thigh combine with mechanical mismatch between the artery and the stent and result in mechanical damage to both the artery and the stent. In this review we will identify challenges and provide a mechanical perspective of FPA stenting, and then discuss current research directions with promise to provide a better understanding of Nitinol, specific features of stent design, and improved characterization of the biomechanical environment of the FPA to facilitate development of better stents for patients with PAD.     

Aggregation induced emission by pyridinium–pyridinium interactions

Non-covalent intermolecular interactions between pyridinium subunits in a crystal-state are an efficient means to accomplish aggregation induced emission and avoid aggregation caused quenching.

Non-covalent intermolecular pyridinium–pyridinium and pyridinium–arene-π system interactions result in aggregation induced emission (AIE).     

The Global Drug Facility as an intervention in the market for tuberculosis drugs

Objective

To investigate funding for the Global Drug Facility since 2001 and to analyse the facility’s influence on the price of high-quality tuberculosis drugs.

Methods

Data on the price of tuberculosis drugs were obtained from the Global Drug Facility for 2001 to 2012 and, for the private sector in 15 countries, from IMS Health for 2002 to 2012. Data on funding of the facility were also collected.

Findings

Quality-assured tuberculosis drugs supplied by the Global Drug Facility were generally priced lower than drugs purchased in the private sector. In 2012, just three manufacturers accounted for 29.9 million United Stated dollars (US$) of US$ 44.5 million by value of first-line drugs supplied. The Global Fund to Fight AIDS, Tuberculosis and Malaria provided 73% (US$ 32.5 million of US$ 44.5 million) and 89% (US$ 57.8 million of US $65.2 million) of funds for first- and second-line drugs, respectively. Between 2010 and 2012, the facility’s market share of second-line tuberculosis drugs increased from 26.1% to 42.9%, while prices decreased by as much as 24% (from US$ 1231 to US$ 939). Conversely, the facility’s market share of first-line drugs fell from 37.2% to 19.2% during this time, while prices increased from US$ 9.53 to US$ 10.2.

Conclusion

The price of tuberculosis drugs supplied through the facility was generally less than that on the private market. However, to realize its full potential and meet the needs of more tuberculosis patients, the facility requires more diverse and stable public funding and greater flexibility to participate in the private market.     

Microdialysis sampling of the isothiazolone, PD-161374, and its thiol and disulfide metabolites

A method based on microdialysis sampling combined with high-performance liquid chromatography (HPLC) has been developed for monitoring the anti-HIV agent PD-161374 (isothiazolone) and its thiol and disulfide metabolites in blood. It was demonstrated that unlike blood withdraw and extraction, microdialysis sampling can preserve the distribution among the isothiazolone and its metabolites in blood. The use of a narrow-bore HPLC system, combined with the relatively high probe extraction efficiency (approximately 50%) from the flexible probe design in this work, allows the direct and quantitative determination of the drug and its major metabolites at submicromolar level.     

Application of capillary electrophoresis with pH-mediated sample stacking to analysis of coumarin metabolites in microsomal incubations

A sensitive method for the analysis of metabolites of coumarin by capillary electrophoresis (CE), incorporating pH-mediated sample stacking, was developed. The analytes were detected in phosphate buffer (pH 7.5; 25 mM), the matrix of the microsomal incubations. Detection was by direct UV absorbance. The three metabolites studied were 7-hydroxycoumarin (7-OHC), 4-hydroxycoumarin (4-OHC) and 2-hydroxyphenylacetic acid (HPAA), and the limits of detection of the analytes were 0.1, 0.5 and 0.3 microM, respectively. The developed method was then applied to microsomal incubations of coumarin. Male Cynomologus monkey microsomes were used in the study and 7-OHC was detected in the incubation mixture.     

Determination of the Dermal Penetration of Esterom Components Using Microdialysis Sampling

PURPOSE: Esterom Solution, an investigational pharmaceutical product, is derived from the esterification of benzoylmethylecgonine (cocaine) in 1.2 propanediol. The resulting solution contains a mixture of components. Esterom Solution is intended to be a topical analgesic to relieve pain and increase the range of motion in patients suffering from acute inflammation of the shoulder or back. Although the components of Esterom are known, the components that are responsible for analgesia have only recently been identified. The purpose of this research is to evaluate which components have the ability to penetrate the skin, how much actually penetrates, and if and/or how each component is metabolized and distributed locally. METHODS: Linear microdialysis probes were implanted into rat dermis. The individual components present in the Esterom Solution were applied separately to the dermis directly over a probe. Dermal dialysis samples were collected to evaluate the dermal penetration of each compound following topical application. RESULTS: Following a 10 mg/50 microL application. 1.8 +/- 0.6 mM benzoic acid was detected at the plateau after approximately 220 min. Following hydroxypropyl benzoic acid application, complete hydrolysis to benzoic acid was observed with a plateau concentration of 137 +/- 19 microM (150 min plateau). When applied separately, hydroxypropyl benzoylecgonine and ecgonine penetrate the skin with plateau concentrations of 32 +/- 9 microM (15 h plateau) and 36 +/- 5 microM (150 min plateau) respectively. Benzoylecgonine, the hydrolytic product of HP-BE, was also detected with a plateau concentration of 3.9 +/- 0.1 microM (16 h plateau) Applied topically, ecgonidine, methylecgonidine, benzoylecgonine, and hydroxypropyl ecgonidine were not detected. CONCLUSIONS: Of the components with analgesic activity, the only compound that penetrates the skin is hydroxypropyl benzoylecgonine. Dermal microdialysis was shown to be an effective technique to monitor the skin penetration of topically applied compounds.     

Correlation of the Capacity Factor in Vesicular Electrokinetic Chromatography with the Octanol: Water Partition Coefficient for Charged and Neutral Analytes

Purpose. The aim of this study was to develop a method based upon electrokinetic chromatography (EKC) using oppositely charged surfactant vesicles as a buffer modifier to estimate hydrophobicity (log P) for a range of neutral and charged compounds.Methods. Vesicles were formed from cetyltrimethylammonium bromide (CTAB) and sodium n-octyl sulfate (SOS). The size and polydispersity of the vesicles were characterized by electron microscopy, dynamic light scattering, and pulsed-field gradient NMR (PFG-NMR). PFG-NMR was also used to determine if ion-pairing between cationic analytes and free SOS monomer occurred. The CTAB/SOS vesicles were used as a buffer modifier in capillary electrophoresis (CE). The capacity factor (log k) was calculated by determining the mobility of the analytes both in the presence and absence of vesicles. Log k was determined for 29 neutral and charged analytes.Results. There was a linear relationship between the log of capacity factor (log k) and octanol/water partition coefficient (log P) for both neutral and basic species at pH 6.0, 7.3, and 10.2. This indicated that interaction between the cation and vesicle was dominated by hydrophobic forces. At pH 4.3, the log k values for the least hydrophobic basic analytes were higher than expected, indicating that electrostatic attraction as well as hydrophobic forces contributed to the overall interaction between the cation and vesicle. Anionic compounds could not be evaluated using this system.Conclusion. Vesicular electrokinetic chromatography (VEKC) using surfactant vesicles as buffer modifiers is a promising method for the estimation of hydrophobicity.     

Regional pharmacokinetics of amifostine in anesthetized dogs: role of the liver, gastrointestinal tract, lungs, and kidneys.

Amifostine is a prodrug in which selectivity is largely determined by the preferential formation and uptake of its cytoprotective metabolite, WR-1065, in normal tissues as a result of differences in membrane-bound alkaline phosphatase activity. In this study, we characterized the sites and extent of organ-specific activation by the liver, gastrointestinal tract, lungs, and kidneys after systemic administrations of amifostine. A total of 10 dogs were infused via the cephalic vein using sequential dose rates of drug at 0.125, 0.500, and 1.00 micro mol/min/kg. Infusion of each dose rate lasted 2 h, at which time steady-state plasma concentrations were obtained (i.e., portal vein, carotid artery, hepatic vein, pulmonary artery, and renal vein). The hepatic arterial, portal venous, and renal arterial blood flows, and cardiac output, were measured. The hepatic and splanchnic extraction of amifostine remained high at 90%, whereas gastrointestinal extraction decreased from 43 to 12 to 15% with increasing dose. Pulmonary extraction of amifostine was low at 7%, whereas renal extraction was intermediate at 57%. Because blood flow measurements were relatively constant during the drug infusions, clearance parameters paralleled that of organ extraction. As a result, saturability was observed in the gastrointestinal blood clearance (i.e., from 9.8 to 2.8-3.3 ml/min/kg) and total body plasma clearance of amifostine (i.e., from 52.6 to about 37.3 ml/min/kg), as the doses increased. Due to the drug's high activation in liver, these findings suggest that amifostine may offer good protection of this organ against the toxicities of chemotherapy and radiation.     

Evaluation of an osmotic pump for microdialysis sampling in an awake and untethered rat

The feasibility of using an osmotic pump in place of a syringe pump for microdialysis sampling in rat brain was investigated. The use of an osmotic pump permits the rat to be free from the constraints of the standard tethered system. The in vitro flow rates of a microdialysis syringe pump (set at 10.80 μl/h) and the osmotic pump (pump specifications were 11.35 μl/h) with no probe attached were compared, yielding results of 10.87 μl/h ± 1.7% and 10.95 μl/h ± 8.0%, respectively. The average of four flow rate experiments in vivo yielded R.S.D.s less than 10% and an average flow rate of 11.1 μl/h. Following the flow rate studies, in vivo sampling of neurotransmitters was accomplished with the osmotic pump coupled to a microdialysis probe implanted in the brain. Finally, after determination of basal levels of 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindole-3-acetic acid (5-HIAA) in the rats, the rats were dosed with benserazide followed by l-3,4-dihydroxyphenylalanine (l-DOPA). The results from the dosing study showed at least a 10-fold increase in compounds in the l-DOPA metabolic pathway (DOPAC and HVA) and a slight or no increase in 5-HIAA (serotonin metabolic pathway.) These results indicate that the osmotic pump is a viable alternative to the syringe pump for use in microdialysis sampling.     

Dermal Microdialysis Sampling in Vivo

Microdialysis sampling of the dermis in vivo was accomplished using a linear microdialysis probe. In contrast to previous studies using a commercial cannula-style microdialysis probe, the linear probe had no effect on the flux of drug through the skin in vitro. The extent of tissue damage in vivo due to probe implantation was evaluated by histological examination and microdialysis delivery studies. Tissue damage due to implantation of the linear probe was minimal with no bleeding or edema observed. Infiltration of lymphocytes into the tissue was observed beginning 6 hours after probe implantation with scar tissue beginning to form after approximately 32 hours. The infiltration of lymphocytes had no effect on the behavior of implanted microdialysis probes. Delivery of 5-fluorouracil was between 20 and 25% for six different probes implanted in six different animals demonstrating good probe-to-probe and implantation-to-implantation reproducibility. Constant delivery was maintained for at least 24 hours in all cases indicating that experiments of at least 24 hour duration are feasible. The dermal concentration of topically applied 5-FU cream, Efudex^®, was continuously monitored by an implanted microdialysis probe demonstrating the feasibility of this technique as for monitoring skin drug levels in vivo. The dermal concentration of 5-FU following topical application was approximately 40-fold higher for in vitro excised skin than for in vivo intact skin.