Hybrid aortic procedures for endoluminal arch replacement in thoracic aneurysms and type B dissections

The aim of this study was to report our clinical experience with and review current literature on endoluminal aortic hybrid techniques and to evaluate outcome in high-risk patients treated for complex aortic arch lesions combining conventional supra-aortic debranching bypasses with subsequent or staged thoracic endovascular grafting. Of 172 patients treated with thoracic endografts for different thoracic aortic pathologies within the last 8 years, the mid-aortic arch was involved in 25, i.e. at least the left common carotid artery had to be overstented and revascularized to provide a proper proximal landing zone. These debranching bypasses were performed as a simultaneous or a staged procedure. All patients were at high-risk and were excluded by cardiac surgeons as ineligible for conventional arch repair. After partial (n=16) or complete (n=9) supra-aortic transposition, 4 different commercially available endografts (80% TAG, WL Gore) were implanted transfemorally or via iliac conduit. Deployment success was 100% in 25 patients after simultaneous or staged supra-aortic transposition; in 32% an emergency procedure was performed due to contained rupture; in 36% more than 1 endograft system was implanted (2 in 20%, 3 in 8% und 4 in 8%). The overall perioperative thirty-day mortality was 5 of 25 (20%) due to interoperative proximal bare stent perforation (n=1), transfusion related acute lung injury (TRALI n=1), cardiac failure (n=1), embolic stroke (n=1) and pneumonia (n=1). The mean follow-up was 21 months. All endoleaks type I (n=3) were corrected with another endograft; the 2 endoleaks type II sealed spontaneously. The major adverse events were: prolonged ventilation in 5 (20%), temporary renal insufficiency with hemodialysis (n=2), bypass infection (n=1), without any complications (n=9). No cases of paraplegia were recorded. Hybrid aortic arch repair is technically challenging but feasible. This novel approach may be an alternative to standard open procedures in high-risk patients and emergency cases. However, the promising early results need to be confirmed by longer follow-up and larger series.     

A Quantitative Kinetic Study of Polysorbate Autoxidation: The Role of Unsaturated Fatty Acid Ester Substituents

Purpose  

To study the role of unsaturated fatty acid ester substituents in the autoxidation of polysorbate 80 using quantitative kinetics.     

Solid-State Nuclear Magnetic Resonance Determination of the Physical Form of BHA on Common Pharmaceutical Excipients

PURPOSE: The purpose of this study was to evaluate the physical form of 2-tert-butyl-4-methoxy-phenol (BHA) following wet granulation onto common pharmaceutical excipients. METHODS: A 13C label was incorporated into the methoxy group of BHA, the major isomer in synthetic butylated hydroxyanisole. Solutions of the labeled BHA were used to load the labeled BHA onto common pharmaceutical excipients. After air drying under ambient conditions, the mixtures were examined by 13C MAS and CP/MAS nuclear magnetic resonance (NMR) spectroscopy to evaluate the physical form of the BHA. RESULTS: The data suggested that BHA could exist as either a crystalline or an amorphous component and that amorphous material was either bound to excipients or relatively mobile during the time of the NMR experiment. At 0.1% loading, BHA appeared to be amorphous and mobile in the freshly prepared blends. At 0.5% loading, BHA was shown to be amorphous on microcrystalline cellulose (MCC) and hydroxypropylmethylcellulose (HPMC) while remaining crystalline on lactose, mannitol, calcium phosphate dihydrate, and croscarmellose sodium. CONCLUSIONS: Solid-state NMR spectroscopy has been used to probe the physical forms of 13C-labeled BHA granulated onto common pharmaceutical excipients. The techniques described in this paper may be applied to help explain stability changes in formulations containing BHA.     

Design and characterization of a surfactant-enriched tablet formulation for oral delivery of a poorly water-soluble immunosuppressive agent.

The feasibility of incorporating significant quantities of the anionic surfactant, sodium lauryl sulfate (SDS), into an immediate release tablet formulation of a poorly water-soluble immunosuppressive agent was investigated. Despite the extremely poor compressibility of SDS and poor chemical stability of the drug, a commercializable, direct-compression tablet formulation with satisfactory mechanical properties and acceptable chemical stability was achieved. Optimal in vitro release of the drug from the tablet formulation was achieved by establishing the minimum molar uptake ratio necessary to achieve complete micellar solubilization of the drug, after which formulation studies were conducted to determine the influence of formulation and process variables on the rate and extent of drug release. A model-independent analysis of dissolution results in a reduced volume (250 ml) of modified simulated gastric fluid demonstrated that the rate and extent of drug release was highly dependent on the mean particle size of the bulk drug, but independent of compression force above that required to achieve a compact of acceptable mechanical strength. Employing the Korsmeyer-Peppas model of Fickian and non-Fickian drug release, it was further shown that release of the drug from the dosage form was governed largely by surface erosion of the surfactant-enriched tablet matrix.     

Kinetics and mechanism of the hydrolytic degradation of indinavir: intramolecular catalysis

The pH-rate profile of first-order rate constants for the lactonization of Indinavir in aqueous solutions with ionic strength I = 1 (KCl) at 40 degrees C is reported. The lactonization reaction is a subject of strong buffer catalysis with a nonlinear dependence of the first-order rate constants on the concentration of the buffer. The pH-rate profile is more complex than the pH-rate profiles for the hydrolysis of simple peptides and for the intramolecular OH-catalyzed hydrolysis of gamma-hydroxyamides. This complexity appears unique to Indinavir and is a result of the cis-aminoindanol leaving group. The mechanistic pathways for the lactonization are discussed. The buffer catalysis data are consistent with kinetic general acid catalysis. The second-order rate constant for the specific-acid catalyzed hydrolysis of Indinavir at 40 degrees C (k(H) = 2.2 x 10(-4) M(-1) min(-1)) is similar to that for a simple peptide indicating similar interactions in the rate limiting transition state for both reactions.     

The co-crystal approach to improve the exposure of a water-insoluble compound: AMG 517 sorbic acid co-crystal characterization and pharmacokinetics

Co-crystals are relatively novel in the pharmaceutical field and are not reported extensively. AMG 517 is an insoluble small molecule VR1 (vanilloid receptor 1) antagonist. In animal studies, good exposure of AMG 517 is seen from a 10% (w/v) Pluronic F108 in OraPlus suspension. Investigation of the suspension formulation revealed that AMG 517 forms a co-crystal with sorbic acid, a preservative in OraPlus. This co-crystal of AMG 517 was isolated by coslurrying AMG 517 and sorbic acid; studied by DSC and XRD; and identified by solution NMR, TGA, and HPLC to be a 1:1 association of AMG 517 and sorbic acid. Single crystal structure analysis revealed a 1:1 co-crystal of AMG 517 and sorbic acid, held together by two hydrogen bonds and other noncovalent, nonionic forces. The co-crystal has better aqueous solubility initially as compared to AMG 517 free base but does revert back to a form of the free base hydrate during prolonged slurry in FaSIF (fasted simulated intestinal fluid). Pharmacokinetic evaluation of the co-crystal in rats using 10% (w/v) Pluronic F108 in OraPlus suspensions revealed that a 30 mg/kg dose in suspension had comparable exposure to a 500 mg/kg dose of the free base.     

Morphological changes in the edge structures following femtosecond laser capsulotomy with varied patient interfaces and different energy settings

Background

To ascertain the morphological changes in the edge structure of femtosecond laser-derived capsulotomy specimens using varying patient interfaces and different laser pulse energies.

Methods

In this experimental clinical study femtosecond laser-assisted capsulotomies were performed in 30 eyes using the LenSx femtosecond laser (LenSx, Alcon, Fort Worth, TX, USA). Surgery was performed using either a rigid curved contact interface (group 1, 15 eyes) or a curved interface with a soft contact lens between cornea and interface (group 2, 15 eyes). The laser pulse-energy was set to 15 μJ in group 1 and to 5 μJ in group 2. After the removal of the anterior capsule, half of the specimens from each group underwent either further staining for light microscopy (LM) or scanning electron microscopy (SEM). Cell configuration, capsule shape, and edge abnormalities were analysed on a morphological basis.

Results

LM showed continuous anterior capsular incisions with a prominent demarcation line along the cutting edge, as well as tags and bridges, which were more pronounced in group 1. SEM revealed further smaller microgrooves and sawtooth patterns in both groups, and a more regular demarcation line configuration in group 2.

Conclusion

A soft contact lens interface with a subsequent laser pulse energy of 5 μJ resulted in fewer tags and bridges, smoother edges, and a more regular and thinner demarcation line on specimens edges of femtosecond laser-performed capsulotomies compared to a rigid curved 15 μJ interface application.     

Regiospecific Intestinal Absorption of the HIV Protease Inhibitor L-735,524 in Beagle Dogs

Purpose. To evaluate regional intestinal absorption and the feasibility of sustained release dosage form development for an HIV protease inhibitor, L-735,524. Methods. L-735,524 free base or sulfate salt was administered orally as suspension, solution or in solid dosage forms to fasted or fed Beagle dogs. Delayed-release dosage forms with slow or fast in vitro dissolution rates were evaluated in vivo to assess plasma concentration profiles. In addition, drug was administered directly into the jejunum or colon of animals, and drug concentrations determined in portal circulation to characterize absorption from these sites. Results. L-735,524 sulfate was well absorbed orally from a solution or capsule formulation if fasted animals' stomachs were preacidified with citric acid solution. A free base suspension, delivered in divided doses to fed animals, was also well absorbed. Prototype extended release dosage forms of L-735,524 produced a reduction in peak plasma levels but failed to prolong absorption and extend plasma concentrations compared to an immediate release capsule. Administration of L-735,524 sulfate solution (pH<3) as bolus solution or by infusion into the jejunum resulted in rapid but incomplete absorption compared to oral gavage. The free base suspension (pH 6.5) delivered into jejunal or colonic regions did not produce measurable systemic plasma concentrations. Conclusions. Extended release formulations did not prolong absorption of L-735,524 in dogs. Optimal L-735,524 absorption was dependent on solubility in an acidic environment in the duodenum.