Novel bone-anchored vascular access on the mastoid for hemodialysis: concept and preclinical trials

GOAL We present the development of a boneanchored port for the painless long-term hemodialytic treatment of patients with renal failure. This port is implanted behind the ear. METHODS The port was developed based on knowledge obtained from long-term experience with implantable hearing devices, which are firmly anchored to the bone behind the ear. This concept of bone anchoring was adapted to the requirements for a vascular access during hemodialysis. The investigational device is comprised of a base plate that is firmly fixed with bone screws to the bone behind the ear (temporal bone). A catheter leads from the base plate valve block through the internal jugular vein and into the right atrium. The valves are opened using a special disposable adapter, without any need to puncture the blood vessels. Between hemodialysis sessions the port is protected with a disposable cover. RESULTS Flow rate, leak tightness and purification were tested on mockups. Preoperative planning and the surgical procedure were verified in 15 anatomical human whole head specimens. CONCLUSION Preclinical evaluations demonstrated the technical feasibility and safety of the investigational device. SIGNIFICANCE Approximately 1.5 million people are treated with hemodialysis worldwide, and 25% of the overall cost of dialysis therapy results from vascular access problems. New approaches towards enhancing vascular access could potentially reduce the costs and complications of hemodialytic therapy.

Development of Drugs Targeting the PI3K Signalling Pathway in Leukaemias and Lymphomas

The phosphoinositide 3-kinase (PI3K) family of signalling enzymes play a key role in the transduction of signals from activated cell surface receptors controlling cell growth and proliferation, survival, metabolism, and migration. The intracellular signalling pathway from activated receptors to PI3K and its downstream targets v-akt murine thymoma viral oncogene homolog (Akt) and mechanistic target of rapamycin (mTOR) is very frequently deregulated by genetic and epigenetic mechanisms in human cancer, including leukaemia and lymphoma. In the past decade, an arsenal of small molecule inhibitors of key enzymes in this pathway has been developed and evaluated in pre-clinical studies and clinical trials in cancer patients. These include pharmacological inhibitors of Akt, mTOR, and PI3K, some of which are approved for the treatment of leukaemia and lymphoma. The PI3K family comprises eight different catalytic isoforms in humans, which have been subdivided into three classes. Class I PI3K isoforms have been extensively studied in the context of human cancer, and the isoforms p110α and p110δ are validated drug targets. The recent approval of a p110δ-specific PI3K inhibitor (idelalisib/Zydelig®) for the treatment of selected B cell malignancies represents the first success in developing these molecules into anti-cancer drugs. In addition to PI3K inhibitors, mTOR inhibitors are intensively studied in leukaemia and lymphoma, and temsirolimus (Torisel®) is approved for the treatment of a type of lymphoma. Based on these promising results it is hoped that additional novel PI3K pathway inhibitors will in the near future be further developed into new drugs for leukaemia and lymphoma.

Report from the National Institute of Allergy and Infectious Diseases workshop on drug allergy

Allergic reactions to drugs are a serious public health concern. In 2013, the Division of Allergy, Immunology, and Transplantation of the National Institute of Allergy and Infectious Diseases sponsored a workshop on drug allergy. International experts in the field of drug allergy with backgrounds in allergy, immunology, infectious diseases, dermatology, clinical pharmacology, and pharmacogenomics discussed the current state of drug allergy research. These experts were joined by representatives from several National Institutes of Health institutes and the US Food and Drug Administration. The participants identified important advances that make new research directions feasible and made suggestions for research priorities and for development of infrastructure to advance our knowledge of the mechanisms, diagnosis, management, and prevention of drug allergy. The workshop summary and recommendations are presented herein.

Drug-induced torsades de pointes in an underserved urban population. Methadone: is there therapeutic equipoise?

BACKGROUND Although it has been well established that methadone use can result in prolonged QTc/torsades de pointes (TdP) and has been labeled as one of the main drugs that cause TdP, it is still prescribed indiscriminately, and several cases of methadone-associated TdP have been seen in our community. METHODS Our objective was to determine the associated factors for prolonged QTc and the development of torsades de pointes (TdP) in our underserved patient population. We found 12,550 ECGs with prolonged QTc between 2002 and 2013. Medical records were reviewed in order to identify precipitating factors for prolonged QTc and to detect incidence of TdP. RESULTS We identified 2735 patients with prolonged QTc who met the inclusion criteria. Of these, 89 (3%) experienced TdP. There was a greater prevalence of HIV infection in the TdP group (11.2 vs. 3.7%, p < 0.001). Furosemide, hydrochlorothiazide, selective serotonin reuptake inhibitors (SSRIs), amiodarone, ciprofloxacin, methadone, haloperidol, and azithromycin were the drugs most often associated with prolonged QTc (31, 8.2, 7.6, 7.1, 3.9, 3.4 and 3.3%, respectively). However, the agents most commonly associated with TdP were furosemide (39.3%), methadone (27%), SSRIs (19.1%), amiodarone (18%), and dofetilide (9%). The medications with statistical significance in the multivariate analysis for TdP development in descending order were as follows: ranolazine (odds ratios [OR] = 53.61, 95% confidence interval [CI] 5.4-524, p < 0.001), dofetilide (OR = 25, CI 6.47-103.16, p < 0.001), voriconazole (OR = 21.40, CI 3.24-124.25, p < 0.001), verapamil (OR = 10.98, CI 2.62-44.96, p < 0.001), sotalol (OR = 12.72, 1.95-82.81, p = 0.008), methadone (OR = 9.89, CI 4.05-24.15, p < 0.001), and SSRI (OR = 2.26, CI 1.10-5.96, p < 0.001). This multivariate analysis revealed that amiodarone and HIV infection were not implicated in TdP. CONCLUSION Methadone was by far the leading medication implicated in the development of TdP and an independent predictor in both univariate and multivariate analyses despite the fact that it was not the most common QT-prolonging medication in our population.

The proteasome inhibitor MLN-273 blocks exoerythrocytic and erythrocytic development of Plasmodium parasites.

Protein degradation is regulated during the cell cycle of all eukaryotic cells and is mediated by the ubiquitin-proteasome pathway. Potent and specific peptide-derived inhibitors of the 20S proteasome have been developed recently as anti-cancer agents, based on their ability to induce apoptosis in rapidly dividing cells. Here, we tested a novel small molecule dipeptidyl boronic acid proteasome inhibitor, named MLN-273 on blood and liver stages of Plasmodium species, both of which undergo active replication, probably requiring extensive proteasome activity. The inhibitor blocked Plasmodium falciparum erythrocytic development at an early ring stage as well as P. berghei exoerythrocytic progression to schizonts. Importantly, neither uninfected erythrocytes nor hepatocytes were affected by the drug. MLN-273 caused an overall reduction in protein degradation in P. falciparum, as demonstrated by immunoblots using anti-ubiquitin antibodies to label ubiquitin-tagged protein conjugates. This led us to conclude that the target of the drug was the parasite proteasome. The fact that proteasome inhibitors are presently used as anti-cancer drugs in humans forms a solid basis for further development and makes them potentially attractive drugs also for malaria chemotherapy.