Diabetic Ketoalkalosis: A Case Report.

Introduction: Diabetic ketoacidosis (DKA) is a common diagnosis in the emergency department (ED). However, one must consider other causes for acid-base disturbances when the pattern is not consistent with typical presentation. Case Report: A 52-year-old female with a history of insulin-dependent diabetes mellitus type 2 presented to the ED with abdominal pain, nausea, and vomiting for three days. Her diagnostic workup revealed diabetic ketoacidosis but with concurrent metabolic alkalosis. Standard treatment for DKA was initiated, and there was improvement of her mentation and resolution of metabolic derangements. Conclusion: Overlooking a diagnosis of DKA because of alkalosis on venous blood gas testing could lead to inappropriate treatment and, therefore, increased risk of morbidity and mortality in the affected patient.

Entrapment of fractured balloon after angioplasty in an AV access using a covered stent.

Fracture of the angioplasty balloon is a known complication during endovascular procedures in arteriovenous (AV) fistulas and grafts. We describe a case of a patient with end-stage renal disease (ESRD) on dialysis with a brachiocephalic AV fistula that had become dysfunctional. After a percutaneous angioplasty procedure during balloon withdrawal, a portion of the balloon fractured and separated due to the balloon being caught in the struts of a previously placed bare metal stent. A covered stent was used to contain the segment of the fractured balloon to the wall of the fistula. The use of a covered stent in jailing the fractured balloon to prevent further complications is not well described. This strategy may be implemented in some circumstances such as this case to avoid surgical interventions.

Amorphous solid dispersions: Utilization and challenges in preclinical drug development within AstraZeneca.

The poor aqueous solubility of many active pharmaceutical ingredients (APIs) dominates much of the early drug development portfolio and poses a major challenge in pharmaceutical development. Polymer-based amorphous solid dispersions (ASDs) are becoming increasingly common and offer a promising formulation strategy to tackle the solubility and oral absorption issues of these APIs. This review discusses the design, manufacture, and utilisation of ASD formulations in preclinical drug development, with a key focus on the pre-formulation assessments and workflows employed at AstraZeneca.

Hyaluronidase Coated Molecular Envelope Technology Nanoparticles Enhance Drug Absorption via the Subcutaneous Route.

Parenteral chemotherapy is usually administered intravenously, although patient preference and health economics suggest the subcutaneous (sc) route could be an attractive alternative. However, due to the low aqueous solubility of hydrophobic drugs and injection volume limitations, the total amount of drug that can be administered in a single sc injection is frequently insufficient. We have developed hyaluronidase coated nanoparticles (NPs) that efficiently encapsulate such drugs, thus addressing both issues and allowing sufficient amounts of hydrophobic drug to be administered and absorbed effectively. CUDC-101, a poorly water-soluble multitargeted anticancer drug that simultaneously inhibits the receptor tyrosine kinases (RTKs) EGFR and HER2, as well as histone deacetylase (HDAC), was encapsulated in polymeric Molecular Envelope Technology (MET) NPs. The role of polymer chemistry, formulation parameters, and coating with hyaluronidase (HYD) on MET-CUDC-101 NP formulations was examined and optimized to yield high drug loading and colloidal stability, and, after freeze-drying, stable storage at room temperature for up to 90 days. The pharmacokinetic studies in healthy rats showed that plasma AUC0-24h after sc administration correlates tightly with formulation physical chemistry, specifically in vitro colloidal stability. Compared to uncoated NPs, the HYD-coating doubled the drug plasma exposure. In a murine A431 xenograft model, the coated HYD-MET-CUDC-101 NPs at a dose equivalent to 90 mg kg-1 CUDC-101 increased the survival time from 15 days (control animals treated with hyaluronidase alone) to 43 days. Polymer MET nanoparticles coated with hyaluronidase enabled the subcutaneous delivery of a hydrophobic drug with favorable therapeutic outcomes.

Nanoparticulate peptide delivery exclusively to the brain produces tolerance free analgesia.

The delivery of peptide drugs to the brain is challenging, principally due to the blood brain barrier and the low metabolic stability of peptides. Exclusive delivery to the brain with no peripheral exposure has hitherto not been demonstrated with brain quantification data. Here we show that polymer nanoparticles encapsulating leucine5-enkephalin hydrochloride (LENK) are able to transport LENK exclusively to the brain via the intranasal route, with no peripheral exposure and nanoparticle localisation is observed within the brain parenchyma. Animals dosed with LENK nanoparticles (NM0127) showed a strong anti-nociceptive response in multiple assays of evoked and on going pain whereas animals dosed intranasally with LENK alone were unresponsive. Animals did not develop tolerance to the anti-hyperalgesic activity of NM0127 and NM0127 was active in morphine tolerant animals. A microparticulate formulation of clustered nanoparticles was prepared to satisfy regulatory requirements for nasal dosage forms and the polymer nanoparticles alone were found to be biocompatible, via the nasal route, on chronic dosing.

Safety and efficacy of placing internal jugular dialysis catheter tip in the inferior vena cava.

PURPOSE: To assess the efficacy and safety of placing the tip of the internal jugular (IJ) hemodialysis catheter in the inferior vena cava (IVC) in situations where it does not work well when placed in the right atrium. METHODS: The medical records of chronic hemodialysis patients at an outpatient vascular intervention facility were retrospectively reviewed. Out of the 831 patients who had dialysis catheters exchanged over a 4-year period, 13 patients were identified who underwent catheter exchanges where the tip of the catheter was placed in the IVC via the IJ approach. These were all patients where the catheters had poor flows when placed in the right atrium earlier. RESULTS: Adequate flow (>350 mL/min) was achieved in all 13 cases with the catheter placed in the IVC with no significant complications. CONCLUSIONS: This study suggests that exchanging the catheter and placing the tip in the IVC is effective and safe in certain situations especially when the tip placement in the conventional position (i.e. the right atrium) does not work well.

Direct in vivo evidence on the mechanism by which nanoparticles facilitate the absorption of a water insoluble, P-gp substrate.

Here we examine the mechanisms by which nanoparticles enable the oral absorption of water-insoluble, P-glycoprotein efflux pump (P-gp) substrates, without recourse to P-gp inhibitors. Both 200nm paclitaxel N-(2-phenoxyacetyl)-6-O-glycolchitosan (GCPh) nanoparticles (GCPh-PTX) and a simulated Taxol formulation, facilitate drug dissolution in biorelevant media, unlike paclitaxel nanocrystals. Verapamil (40mgkg-1) increased the oral absorption from low dose Taxol (6 or 10mgkg-1) by 100%, whereas the oral absorption from high dose Taxol (20mgkg-1) or low dose GCPh-PTX (6 or 10mgkg-1) was largely unchanged by verapamil. There was virtually no absorption from control paclitaxel nanocrystals (20mgkg-1). Imaging of ex-vivo rat ileum samples showed that fluorescently labelled GCPh nanoparticles are mucoadhesive and are taken up by ileum epithelial cells. GCPh nanoparticles were also found to open Caco-2 cell tight junctions. In conclusion, mucoadhesive, drug solubilising GCPh nanoparticles enable the oral absorption of paclitaxel via the saturation of the P-gp pump (by high local drug concentrations) and by particle uptake and tight junction opening mechanisms.

Retrograde dissection of the axillary artery during arteriogram via arteriovenous access.

INTRODUCTION: Retrograde arterial dissection is a recognized complication of endovascular intervention but has not been well reported especially in the context of dialysis arteriovenous access procedures. The management of this complication is also not well defined. CASE PRESENTATION: We report the case of an 80-year-old female with end-stage renal disease (ESRD) on dialysis who developed an asymptomatic retrograde dissection of the left axillary artery during an arteriogram performed via a retrograde approach as part of access dysfunction evaluation. The condition was managed conservatively with no other intervention and close follow-up. No surgical intervention or stenting was needed in this case. DISCUSSION: Conservative management of retrograde arterial dissection in the arm may be a viable option especially in asymptomatic patients due to the nature of the injury. The force of blood flow in the antegrade direction limits the expansion of the false lumen and likely promotes the spontaneous healing of the vessel.

Physical characterisation and long-term stability studies on quaternary ammonium palmitoyl glycol chitosan (GCPQ)--a new drug delivery polymer.

N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ) is a self-assembling polymer, which enables the oral bioavailability of peptide and hydrophobic drugs. In preparation for clinical testing, here we examine GCPQ's synthesis reproducibility, pKa, thermal, and rheological properties. GCPQ was synthesised by acid degradation of glycol chitosan (GC), reaction with palmitic acid N-hydroxysuccinimide (PNS) and methylation. A GC monomer, PNS molar feed ratio of 0.92 together with a gravimetric feed ratio for N-palmitoyl-6-O-glycolchitosan, methyl iodide of 3.3, reproducibly produces GCPQ48 (Mw = 19.9 ± 9.9 kDa, Mn = 13.1 ± 2.4 kDa, mol % palmitoylation = 23 ± 2.7, mol % quaternisation = 10 ± 0.23, n = 56). GCPQ48 decomposes at 218 ± 4.3 °C, is glassy at room temperature (Tg = 164.4 ± 8.5 °C), is a weak base (pKa = 5.99 ± 0.15), and produces micellar dispersions at neutral pH. Below a concentration of 0.07 g mL(-1) , GCPQ48 dispersions showed Newtonian rheological behaviour but at higher concentrations, the polymer undergoes shear thinning because of the chain disentanglement at high shear rates. GCPQ48 forms a network of micelles and concentrated (0.09 g mL(-1) ) dispersions are viscoelastic, with the storage modulus exceeding the loss modulus at high frequencies. Solid GCPQ48 was stable when stored at room temperature for 18 months.

Claw amphiphiles with a dendrimer core: nanoparticle stability and drug encapsulation are directly proportional to the number of digits.

There are numerous pharmaceutical, food, and consumer product applications requiring the incorporation of hydrophobic solutes within aqueous media. Often amphiphiles and/or polymers are used to produce encapsulating nanostructures. Because the encapsulation efficiencies of these nanostructures directly impact on the process or product, it is often desirable to optimize this parameter. To produce these advanced functional materials, we hypothesized that an amphiphile with a claw shape would favor polymer aggregation into nanoparticles and hydrophobic compound encapsulation. Claw amphiphiles were prepared by attaching one end of comb-shaped chitosan amphiphile chains [N,N,N-trimethyl, N,N-dimethyl, N-monomethyl, N-palmitoyl, N-acetyl, 6-O-glycol chitosan (GCPQA)] to a central dendrimer core [generation 3 diaminobutane poly(propylenimine) dendrimer (DAB)] to give DAB-GCPQA. The linear chitosan amphiphile (GCPQA) forms the digits of the claw. These claw amphiphiles were very stable and had a high encapsulating efficiency. DAB-GCPQAs (Mn = 30 and 70 kDa) had extremely low critical micelle concentrations [CMCs = 0.43 µg mL(-1) (13 nM) and 0.093 µg mL(-1) (0.9 nM), respectively], and their CMCs were lower than that of linear GCPQA [Mn = 14 kDa, CMC = 0.77 µg mL(-1) (38 nM)]. The claw amphiphile CMCs decreased linearly with the number of digits (r(2) = 0.98), and drug encapsulation (hydrophobic drug propofol) in 4 mg mL(-1) dispersions of the amphiphiles increased linearly (r(2) = 0.94) with the number of digits. DAB-GCPQA70 (4 mg mL(-1), 0.058 mM) encapsulated propofol (7.3 mg mL(-1), 40 mM). Finally, despite their stability, claw amphiphile nanoparticles are able to release the encapsulated drug in vivo, as shown with the claw amphiphile-propofol formulations in a murine loss of righting reflex model.

Efficacy and safety results with the LifeSite hemodialysis access system versus the Tesio-Cath hemodialysis catheter at 12 months.

PURPOSE: To compare the performance and safety of a fully subcutaneous vascular access device, the LifeSite hemodialysis access system, versus a tunneled hemodialysis catheter, the Tesio-Cath, at 1 year after implantation. MATERIALS AND METHODS: Sixty-eight patients who required hemodialysis received implantation of the LifeSite device or a Tesio-Cath device as a part of this multicenter study. Thirty-four patients were treated in each group. The endpoints observed included blood flow rates and associated venous pressures, overall and device-related adverse events, the need for thrombolytic infusions, device-related infections (DRIs) and associated hospitalizations, and technical device survival. RESULTS: During the 12-month observation period, significantly higher venous pressures were required in patients with the Tesio-Cath to achieve blood flow rates comparable with those achieved with the LifeSite device. Patients in the LifeSite group experienced a significantly lower rate of non-device-related adverse events (P < .001), device-related adverse events (P < .016), need for thrombolytic infusions (P < .002), and DRIs (P < .013) compared with patients in the Tesio-Cath group. There was a trend toward a lower number of hospital days per month for DRIs in the LifeSite group, with the rate for the Tesio-Cath group being twice that in the LifeSite group. The use of the LifeSite device was also associated with a significantly higher probability of device survival for 12 months after censoring for planned removals (P < .031). CONCLUSIONS: The results of the present study demonstrate superior device performance and technical device survival, reduced complications, and the need for fewer interventions with the LifeSite hemodialysis access system compared with a standard hemodialysis catheter during a 1-year time period after implantation.

Multicenter clinical trial results with the LifeSite hemodialysis access system.

BACKGROUND: The LifeSite Hemodialysis Access System is a subcutaneous access device designed to maximize blood flow while minimizing access-related complications. The purpose of this study was to compare the efficacy and safety of the LifeSite System to a similar but transcutaneous access device, the Tesio-Cath Hemodialysis Catheter. METHODS: The study was conducted in two phases. A multi-center randomized prospective design was utilized for the first phase (Phase 1) where thirty-four patients were enrolled in the Tesio-Cath group and 36 patients into the LifeSite group where 0.2% sodium oxychlorosene was used as an antimicrobial solution for the LifeSite. A nonrandomized, but otherwise identical, second phase of the study followed where a 70% isopropyl alcohol solution was utilized as the antimicrobial solution for 34 additional LifeSite patients (Phase 2). RESULTS: Device function was evaluated in Phase 1 of the trial. Actual blood flow (determined by ultrasound dilution) was greater in the LifeSite versus the Tesio-Cath group (358.7 vs. 331.8 mL/min, P < 0.001 for machine-indicated blood flow of 400 mL/min). Infection comparisons were performed for all three groups encompassing Phase 1 and 2 of the trial; Tesio-Catheter, LifeSite System with oxychlorosene, and LifeSite System with 70% isopropyl alcohol. Device-related infections were defined as systemic bacteremia without another obvious site of origin and exit site infections requiring systemic antibiotics or device removal. This revealed infection rates per 1000 device use days of 1.3 for the LifeSite alcohol group, 3.3 for the Tesio-Cath group, and 3.4 per for the LifeSite oxychlorosene group. There was no statistically significant difference in device related infection rates between the Tesio-Cath and the LifeSite oxychlorosene groups. There were significant differences in infection rate between LifeSite alcohol group and the other two groups (P < 0.05). Device thrombosis was defined by the need for instillation of thrombolytic agents to maintain blood flow>300 mL/min. There was no difference in the need for thrombolytic infusions between the LifeSite oxychlorosene group and the Tesio-Cath group (P = 0.1496); however, the LifeSite alcohol group required significantly fewer thrombolytic infusions than the Tesio-Cath group (P = 0.0295) to maintain adequate blood flow. Device survival at 6 months after stratification by diabetic status and adjusting for age was significantly better in the LifeSite alcohol group (89.9%) than in the LifeSite oxychlorosene group (64.8%, P = 0.0286) and in the Tesio-Cath (69.1%, P = 0.0292) group. CONCLUSIONS: The LifeSite Hemodialysis Access System, when used with 70% isopropyl alcohol as an antimicrobial solution, provides superior performance with a lower infection rate and better device survival than a standard cuffed tunneled hemodialysis catheter.