Correlating in Vitro Solubilization and Supersaturation Profiles with in Vivo Exposure for Lipid Based Formulations of the CETP Inhibitor CP-532,623.

Lipid based formulations (LBFs) are a promising formulation strategy for many poorly water-soluble drugs and have been shown previously to enhance the oral exposure of CP-532,623, an oral cholesteryl ester transfer protein inhibitor. In the current study, an in vitro lipid digestion model was used to probe the relationship between drug solubilization and supersaturation on in vitro dispersion and digestion of LBF containing long chain (LC) lipids and drug absorption in vivo. After in vitro digestion of LBF based on LC lipids, the proportion of CP-532,623 maintained in the solubilized state in the aqueous phase of the digest was highest in formulations containing Kolliphor RH 40, and in most cases outperformed equivalent formulations based on MC lipids.

Lymphatic Transport and Lymphocyte Targeting of a Triglyceride Mimetic Prodrug Is Enhanced in a Large Animal Model: Studies in Greyhound Dogs.

In previous studies, a triglyceride (TG) mimetic prodrug of the model immunomodulator mycophenolic acid (MPA) was shown to significantly enhance lymphatic transport of MPA-related species in the rat. The rat gastrointestinal tract, however, is somewhat different from that in higher order species such as dogs and humans and may underestimate lymphatic transport. Here the effectiveness of the prodrug strategy has been examined in conscious greyhound dogs, the GI physiology of which is more representative of that in humans.

Plasma Ion Activated Expanded Polytetrafluoroethylene Vascular Grafts with a Covalently Immobilized Recombinant Human Tropoelastin Coating Reducing Neointimal Hyperplasia.

Expanded polytetrafluoroethylene (ePTFE) vascular conduits with less than or equal to 6 mm internal diameter typically occlude due to a combination of thrombus formation and neointimal hyperplasia. We hypothesized that by layering the polymerized elastin precursor, human tropoelastin, in the synthetic vessel lumen we could mimic the internal elastic lamina and so maintain low thrombogenicity while significantly reducing smooth muscle cell proliferation. The luminal surfaces of ePTFE conduits were activated with plasma immersion ion implantation (PIII) treatment to facilitate covalent attachment of tropoelastin.

New engineering treatment of bovine pericardium confers outstanding resistance to calcification in mitral and pulmonary implantations in a juvenile sheep model.

Objective: To conduct a test of noninferiority for CardioCel (Admedus, Brisbane, Australia), a chemically engineered bovine pericardium over autologous pericardium treated intraoperatively with glutaraldehyde in a chronic juvenile sheep model of pulmonary valve (PV) and mitral valve (MV) reconstruction.

Methods: We replaced the posterior leaflet of the MV and of 1 PV cusp with patches in ewes aged 10 months. There were 2 groups: CardioCel (n = 6) and control (n = 4).

In vitro-in vivo evaluation of lipid based formulations of the CETP inhibitors CP-529,414 (torcetrapib) and CP-532,623.

The present study investigated the use of lipid based drug delivery systems to enhance the oral bioavailability of the CETP inhibitors CP-532,623 and torcetrapib. A series of self-emulsifying lipid based drug delivery systems (SEDDS) were assembled and examined using an in vitro lipid digestion model to evaluate patterns of drug precipitation under simulated intestinal conditions. Drug exposure after oral administration of the same formulations was subsequently assessed in beagle dogs.

Non-linear increases in danazol exposure with dose in older vs. younger beagle dogs: the potential role of differences in bile salt concentration, thermodynamic activity, and formulation digestion.

Purpose: To explore the possibility that age-related changes in physiology may result in differences in drug bioavailability after oral administration of lipid based formulations of danazol.

Methods: Danazol absorption from lipid formulations with increasing drug load was examined in younger (9 months) and older (8 years) beagles. Age related changes to hepatic function were assessed via changes to systemic clearance and serum bile acid concentrations.

Silica-lipid hybrid (SLH) formulations enhance the oral bioavailability and efficacy of celecoxib: An in vivo evaluation.

This study is the first to demonstrate in canines the ability of silica-lipid hybrid (SLH) microparticles to enhance the bioavailability and efficacy of a poorly water-soluble drug after oral administration. Spray-dried SLH microparticles comprising Capmul MCM (mono-diglycerides of C8/C12 fatty acids) and silica nanoparticles (Aerosil® 380) were shown to significantly enhance the fasted state oral bioavailability of celecoxib (CEL) (6.5 fold, relative to an aqueous suspension and more than 2-fold higher relative to the fed state) after oral administration to beagle dogs.

Lipid digestion as a trigger for supersaturation: evaluation of the impact of supersaturation stabilization on the in vitro and in vivo performance of self-emulsifying drug delivery systems.

The generation of supersaturation in the gastrointestinal (GI) tract is an increasingly popular means of promoting oral absorption for poorly water-soluble drugs. The current study examined the impact of changes to the quantities of medium-chain (MC) lipid (Captex 300:Capmul MCM), surfactant (Cremophor EL) and cosolvent (EtOH), and the addition of polymeric precipitation inhibitors (PPI), on supersaturation during the dispersion and digestion of MC self-emulsifying drug delivery systems (SEDDS) containing danazol. The data suggest that digestion acts as a "trigger" for enhanced supersaturation and that solubilization/precipitation behavior is correlated with the degree of supersaturation on dispersion (S(M)DISP) or digestion (S(M)DIGEST).

A highly elastic and adhesive gelatin tissue sealant for gastrointestinal surgery and colon anastomosis.

Background: We describe the development of a highly elastic and adhesive surgical tissue sealant, based on photochemically crosslinked gelatin, for sealing sutured incisions in the gastrointestinal (GI) tract in a rabbit surgical model and in a canine colon anastomosis study.

Methods: The study included in vitro assessment of mechanical parameters of the tissue sealant and in vivo analysis of burst strength and histology at 24 h, 3 days and 7 days post surgery, in a rabbit model, to assess progress of wound healing at the suture sites. Utility of this sealant to repair and seal a lower colonic resection and anastomosis procedure in a canine model was also investigated.

A highly elastic tissue sealant based on photopolymerised gelatin.

Gelatin is widely used as a medical biomaterial because it is readily available, cheap, biodegradable and demonstrates favourable biocompatibility. Many applications require stabilisation of the biomaterial by chemical crosslinking, and this often involves derivatisation of the protein or treatment with cytotoxic crosslinking agents. We have previously shown that a facile photochemical method, using blue light, a ruthenium catalyst and a persulphate oxidant, produces covalent di-tyrosine crosslinks in resilin and fibrinogen to form stable hydrogel biomaterials.

Atrial electrophysiology is altered by acute hypercapnia but not hypoxemia: implications for promotion of atrial fibrillation in pulmonary disease and sleep apnea.

Background: Chronic pulmonary disease and sleep apnea have been associated with the development of atrial fibrillation (AF).

Objective: The purpose of this study was to characterize the atrial electrical changes that occur with hypercapnia and hypoxemia and to determine their role in AF development.

Methods: Seventeen sheep (6 control, 5 hypercapnia, 6 hypoxemia) underwent open chest electrophysiologic evaluation under autonomic blockade.

The role of the intestinal lymphatics in the absorption of two highly lipophilic cholesterol ester transfer protein inhibitors (CP524,515 and CP532,623).

Purpose: To evaluate the potential role of intestinal lymphatic transport in the absorption and oral bioavailability of members of an emerging class of anti-atherosclerosis drugs (CETP inhibitors). CP524,515 and CP532,623 are structurally related with eLogD(7.4) >5; however, only CP524,515 (and not CP532,623) had sufficient solubility (>50 mg/g) in long-chain triglyceride (LCT) to be considered likely to be lymphatically transported.

Human cord blood stem cells enhance neonatal right ventricular function in an ovine model of right ventricular training.

Background: Nonischemic right ventricular dysfunction and cardiac failure is a source of considerable morbidity in children with congenital heart disease. Cell transplantation has not previously been studied in the pediatric setting in which enhancing ventricular function in response to supraphysiologic workloads might be beneficial.

Methods: Engraftment and differentiation of human cord blood stem cells were studied in an immunosuppressed neonatal ovine model of right ventricular training.

Lymphatic transport of Methylnortestosterone undecanoate (MU) and the bioavailability of methylnortestosterone are highly sensitive to the mass of coadministered lipid after oral administration of MU.

The contribution of lymphatic transport to the oral bioavailability of methylnortestosterone (M) after oral administration of the lipophilic prodrug methylnortestosterone undecanoate (MU) has been evaluated, and the sensitivity of lymphatic MU transport to lymphatic lipid transport has been investigated. M and MU were administered intravenously and orally to greyhound dogs to determine absolute bioavailability after oral dosing of MU. MU was also administered orally with differing quantities of food (lipid) to lymph duct-cannulated greyhound dogs to investigate the relative roles of lymph versus blood transport on M bioavailability and the effect of lipid load on systemic exposure.

Intestinal lymphatic transport enhances the post-prandial oral bioavailability of a novel cannabinoid receptor agonist via avoidance of first-pass metabolism.

Purpose: To examine the effect of food on the oral bioavailability of a highly lipophilic, cannabinoid receptor agonist (CRA13) and to explore the basis for the food effect in lymph-cannulated and non-cannulated dogs.

Methods: Oral bioavailability was assessed in fasted and fed human volunteers and in lymph-cannulated dogs. In fasted dogs, the extent of absorption and oral bioavailability was also examined following administration of radiolabelled CRA13.

Expert systems for clinical pathology reporting.

* Conventional automated interpretative reporting systems use standard or "canned" comments for patient reports. These are result-specific and do not generally refer to the patient context. * Laboratory information systems (LIS) are limited in their application of patient-specific content of reporting.

Evaluation of the impact of surfactant digestion on the bioavailability of danazol after oral administration of lipidic self-emulsifying formulations to dogs.

Lipid-based formulations of danazol with varying quantities of included surfactant have been examined in vitro and in vivo. Formulations comprising fatty acid ester surfactants were readily hydrolysed during in vitro digestion, although Cremophor RH40 (CrRH) was less effectively hydrolysed than Cremophor EL (CrEL). Formulations comprising high quantities of digestible surfactant also appeared to less effectively prevent danazol precipitation during in vitro evaluation.

Lymphatic absorption of subcutaneously administered proteins: influence of different injection sites on the absorption of darbepoetin alfa using a sheep model.

The relative contribution of the lymph and blood in the absorption of darbepoetin alfa (DA) from different s.c. injection sites was determined using a central lymph-cannulated sheep model.

Increasing the proportional content of surfactant (Cremophor EL) relative to lipid in self-emulsifying lipid-based formulations of danazol reduces oral bioavailability in beagle dogs.

Purpose: To investigate the impact of a change in the proportions of lipid, surfactant and co-solvent on the solubilisation capacity of self-emulsifying formulations of danazol during in vitro dispersion and digestion studies and correlation with in vivo bioavailability in beagle dogs.

Methods: Formulations from within the phase diagram of the pseudo-ternary system composed of soybean oil:maisine 35-1 (1:1 w/w), Cremophor EL and ethanol were assessed in vitro on dispersion and digestion. The relative bioavailability of danazol after administration of a series of these formulations was also determined.

Atrial electrical and structural abnormalities in an ovine model of chronic blood pressure elevation after prenatal corticosteroid exposure: implications for development of atrial fibrillation.

Aims: Elevated blood pressure (EBP) is the most prevalent and potentially modifiable risk factor for AF, yet little is known of its atrial effects. We aimed to characterize the atrial electrical and structural changes in a chronic ovine model of EBP after prenatal corticosteroid exposure.

Methods And Results: Twelve sheep with chronically EBP (mean arterial pressure 94+/-3 mmHg) and six controls (71+/-4 mmHg, P<0.

The absorption of darbepoetin alfa occurs predominantly via the lymphatics following subcutaneous administration to sheep.

Purpose: To determine the contribution of the lymphatics to the systemic availability of darbepoetin alfa (DA) using an established sheep model.

Materials And Methods: DA was administered either by intravenous (IV) injection (0.2, 0.

Lymphatic absorption is the primary contributor to the systemic availability of epoetin Alfa following subcutaneous administration to sheep.

The contribution of the lymphatics to the absorption and systemic availability of recombinant human epoetin alfa (rHuEPO) following s.c. injection was examined using a cannulated sheep model.

Susceptibility to lipase-mediated digestion reduces the oral bioavailability of danazol after administration as a medium-chain lipid-based microemulsion formulation.

Purpose: To investigate the impact of lipidic formulation type on in vitro dispersion and digestion properties and the relationship to oral bioavailability, using danazol as a model lipophilic poorly water-soluble drug.

Methods: Three lipid-based danazol formulations [a long-chain triglyceride solution (LCT-solution) and self-microemulsifying drug delivery systems (SMEDDS) based on long-chain (C18) lipids (LC-SMEDDS) and medium-chain (C8-C10) lipids (MC-SMEDDS)] were administered to fasted beagle dogs and compared with a micronized danazol formulation administered postprandially and in the fasted state. In vitro dispersion and particle size data for the two SMEDDS were compared, and the distribution/solubilization patterns of danazol across the various phases produced during in vitro digestion quantified.

Autoaugmentation gastrocystoplasty: further studies of the sheep model.

Objective: To report our experience with autoaugmentation gastrocystoplasty (AAGC, reported to result in an inconsistent augmentation effect in children) in a sheep model, specifically addressing issues of surgical techniques and postoperative bladder drainage that may affect the augmentation result, as many factors have been implicated in the poor outcome.

Materials And Methods: Ten 6-month-old male lambs had a suprapubic catheter placed by an open laparotomy. Intraoperative urodynamics were evaluated before and after detrusorotomy for autoaugmentation and after completing AAGC.

Use of in vitro lipid digestion data to explain the in vivo performance of triglyceride-based oral lipid formulations of poorly water-soluble drugs: studies with halofantrine.

The relative oral bioavailability (BA) of halofantrine base (Hf) was assessed in male beagle dogs after administration of a medium chain triglyceride (MCT), a long chain triglyceride (LCT), and a blended LCT/MCT lipid solution formulation of Hf (Study 1) and after administration of suspensions of Hf base and Hf. HCl in LCT (Study 2). A series of in vitro lipid digestion experiments were also performed in an attempt to clarify the data obtained.