3D printing injectable microbeads using a composite liposomal ink for local treatment of peritoneal diseases.

The peritoneal cavity offers an attractive administration route for challenging-to-treat diseases, such as peritoneal carcinomatosis, post-surgical adhesions, and peritoneal fibrosis. Achieving a uniform and prolonged drug distribution throughout the entire peritoneal space, though, is difficult due to high clearance rates, among others. To address such an unmet clinical need, alternative drug delivery approaches providing sustained drug release, reduced clearance rates, and a patient-centric strategy are required. Here, we describe the development of a 3D-printed composite platform for the sustained release of the tyrosine kinase inhibitor gefitinib (GEF), a small molecule drug with therapeutic applications for peritoneal metastasis and post-surgical adhesions. We present a robust method for the production of biodegradable liposome-loaded hydrogel microbeads that can overcome the pharmacokinetic limitations of small molecules with fast clearance rates, a current bottleneck for the intraperitoneal (IP) administration of these therapeutics. By means of an electromagnetic droplet printhead, we 3D printed microbeads employing an alginate-based ink loaded with GEF-containing multilamellar vesicles (MLVs). The sustained release of GEF from microbeads was demonstrated. In vitro studies on an immortalized human hepatic cancer cell line (Huh-7) proved concentration-dependent cell death. These findings demonstrate the potential of 3D-printed alginate microbeads containing liposomes for delivering small drug compounds into the peritoneum, overcoming previous limitations of IP drug delivery

Microcirculatory changes and skeletal muscle oxygenation measured at rest by non-infrared spectroscopy in patients with and without diabetes undergoing haemodialysis

Introduction: Haemodialysis has direct and indirect effects on skin and muscle microcirculatory regulation that are severe enough to worsen tolerance to physical exercise and muscle asthenia in patients undergoing dialysis, thus compromising patients' quality of life and increasing the risk of mortality. In diabetes these circumstances are further complicated, leading to an approximately sixfold increase in the incidence of critical limb ischaemia and amputation. Our aim in this study was to investigate in vivo whether haemodialysis induces major changes in skeletal muscle oxygenation and blood flow, microvascular compliance and tissue metabolic rate in patients with and without diabetes. Methods: The study included 20 consecutive patients with and without diabetes undergoing haemodialysis at Sant Andrea University Hospital, Rome from March to April 2007. Near-infrared spectroscopy (NIRS) quantitative measurements of tissue haemoglobin concentrations in oxygenated [HbO(2)] and deoxygenated forms [HHb] were obtained in the calf once hourly for 4 hours during dialysis. Consecutive venous occlusions allowed one to obtain muscular blood flow (mBF), microvascular compliance and muscle oxygen consumption (mVO(2)). The tissue oxygen saturation (StO(2)) and content (CtO(2)) as well as the microvascular bed volume were derived from the haemoglobin concentration. Nonparametric tests were used to compare data within each group and among the groups and with a group of 22 matched healthy controls. Results: The total haemoglobin concentration and [HHb] increased significantly during dialysis in patients without and with diabetes. Only in patients with diabetes, dialysis involved a [HbO(2)], CtO(2) and mVO(2) increase but left StO(2) unchanged. Multiple regression analysis disclosed a significant direct correlation of StO(2) with HbO(2) and an inverse correlation with mVO(2). Dialysis increased mBF only in diabetic patients. Microvascular compliance decreased rapidly and significantly during the first hour of dialysis in both groups. Conclusions: Our NIRS findings suggest that haemodialysis in subjects at rest brings about major changes in skeletal muscle oxygenation, blood flow, microvascular compliance and tissue metabolic rate. These changes differ in patients with and without diabetes. In all patients haemodialysis induces changes in tissue haemoglobin concentrations and microvascular compliance, whereas in patients with diabetes it alters tissue blood flow, tissue oxygenation (CtO(2), [HbO(2)]) and the metabolic rate (mVO(2)). In these patients the mVO(2) is correlated to the blood supply. The effects of haemodialysis on cell damage remain to be clarified. The absence of StO(2) changes is probably linked to an opposite [HbO(2)] and mVO(2) pattern

Cyclic Peptides Acting as Allosteric Inhibitors of Human Thymidylate Synthase and Cancer Cell Growth

Thymidylate synthase (TS) is a prominent drug target for different cancer types. However, the prolonged use of its classical inhibitors, substrate analogs that bind at the active site, leads to TS overexpression and drug resistance in the clinic. In the effort to identify anti-TS drugs with new modes of action and able to overcome platinum drug resistance in ovarian cancer, octapeptides with a new allosteric inhibition mechanism were identified as cancer cell growth inhibitors that do not cause TS overexpression. To improve the biological properties, 10 cyclic peptides (cPs) were designed from the lead peptides and synthesized. The cPs were screened for the ability to inhibit recombinant human thymidylate synthase (hTS), and peptide 7 was found to act as an allosteric inhibitor more potent than its parent open-chain peptide [Pro3]LR. In cytotoxicity studies on three human ovarian cancer cell lines, IGROV-1, A2780, and A2780/CP, peptide 5 and two other cPs, including 7, showed IC50 values comparable with those of the reference drug 5-fluorouracil, of the open-chain peptide [d-Gln4]LR, and of another seven prolyl derivatives of the lead peptide LR. These promising results indicate cP 7 as a possible lead compound to be chemically modified with the aim of improving both allosteric TS inhibitory activity and anticancer effectiveness

Liposomal aggregates sustain the release of rapamycin and protect cartilage from friction.

Liposomes show promise as biolubricants for damaged cartilage, but their small size results in low joint and cartilage retention. We developed a zinc ion-based liposomal drug delivery system for local osteoarthritis therapy, focusing on sustained release and tribological protection from phospholipid lubrication properties. Our strategy involved inducing aggregation of negatively charged liposomes with zinc ions to extend rapamycin (RAPA) release and improve cartilage lubrication. Liposomal aggregation occurred within 10 min and was irreversible, facilitating excess cation removal. The aggregates extended RAPA release beyond free liposomes and displayed irregular morphology influenced by RAPA. At nearly 100 µm, the aggregates were large enough to exceed the previously reported size threshold for increased joint retention. Tribological assessment on silicon surfaces and ex vivo porcine cartilage revealed the system's excellent protective ability against friction at both nano- and macro-scales. Moreover, RAPA was shown to attenuate the fibrotic response in human OA synovial fibroblasts. Our findings suggest the zinc ion-based liposomal drug delivery system has potential to enhance OA therapy through extended release and cartilage tribological protection, while also illustrating the impact of a hydrophobic drug like RAPA on liposome aggregation and morphology

Liposomal aggregates sustain the release of rapamycin and protect cartilage from friction

Liposomes show promise as biolubricants for damaged cartilage, but their small size results in low joint and cartilage retention. We developed a zinc ion-based liposomal drug delivery system for local osteoarthritis therapy, focusing on sustained release and tribological protection from phospholipid lubrication properties. Our strategy involved inducing aggregation of negatively charged liposomes with zinc ions to extend rapamycin (RAPA) release and improve cartilage lubrication. Liposomal aggregation occurred within 10 min and was irreversible, facilitating excess cation removal. The aggregates extended RAPA release beyond free liposomes and displayed irregular morphology influenced by RAPA. At nearly 100 µm, the aggregates were large enough to exceed the previously reported size threshold for increased joint retention. Tribological assessment on silicon surfaces and ex vivo porcine cartilage revealed the system's excellent protective ability against friction at both nano- and macro-scales. Moreover, RAPA was shown to attenuate the fibrotic response in human OA synovial fibroblasts. Our findings suggest the zinc ion-based liposomal drug delivery system has potential to enhance OA therapy through extended release and cartilage tribological protection, while also illustrating the impact of a hydrophobic drug like RAPA on liposome aggregation and morphology

[Atypical mycobacterial infection after kidney transplant: two clinical cases]

Infections are an important cause of morbidity and mortality during kidney transplant. In areas where tuberculosis is not endemic, Mycobacteria other than tuberculosis (MOOT), also known as 'atypical' Mycobacteria, are more frequently involved in mycobacterial infections than M. tuberculosis. The incidence of MOOT infection in renal transplant recipients ranges from 0.16 to 0.38 percent. This low rate of reported incidence is, however, often due to delay in diagnosis and lack of therapeutic protocols. Further difficulty is caused by the interaction of antimycobacterial drugs with the post-transplant immunosuppressive regimen, necessitating close monitoring of plasma concentrations and careful dose modification. We present two cases of Mycobacterium Chelonae infection in kidney transplant recipients which differ in both clinical presentation and pharmacological approach

Mild and moderate renal dysfunction: impact on short-term outcome

Background: Preoperative renal dysfunction is an important risk factor in cardiac surgery. Thus, the association between creatinine clearance (ClCr) and mechanical ventilation time and ICU length of stay, independent of other established preoperative risk indicators, was analyzed. Methods: In our study, 156 consecutive patients underwent open-heart surgery at the Department of Cardiac Surgery, University Hospital St. Andrea, Rome, and were prospectively studied for the relation between the ClCr, using the formula develop by Cockroft and Gault, and ICU length of stay and mechanical ventilation time. The 156 patients were divided into two groups in relation of ClCr: group A (n = 78) ClCr 70 ml/min. Results: In multivariate analysis, ICU length of stay was influenced by ClCr < 70 ml/min, hypertension and COPD. ICU stay was median 48 h (range 24-72) in group A versus 24 h (range 20.7-44) in group B (p = 0.0001). In multivariate analysis, only ClCr < 70 ml/min and EuroScore were associated with increasing VAM. VAM was median 8 h (range 5.7-13.2) in group A versus 6 h (range 4-10) in group B (p = 0.001). Conclusions: Our study demonstrates that after short-term outcome follow-up, preoperative mild renal dysfunction is an independent predictor of ICU length of stay and mechanical ventilation time. © 2007 European Association for Cardio-Thoracic Surgery

Creation of autogenous radial cephalic direct wrist access for hemodialysis in the elderly using microsurgery

Purpose: Guidelines recommend autogenous radial-cephalic AV fistula (RCAVF) as the first choice for hemodialysis. Concern has been raised that this is not suitable in the elderly. We assessed the results of microsurgery for RCAVF creation comparatively in patients older and younger than 70 years. Methods: We prospectively followed 126 patients for three years. After systematic clinical and ultrasound assessment, a RCAVF was created using a surgical microscope. Patency was assessed immediately, at one week, one month and one year. Outcomes were recorded and stratified into two groups: 70y. Results: RCAVF was created in 75.4% and 70.8% of the 70y groups, respectively. Incidence of early failure was 11% (70y). Primary and secondary patency at one year was 67% and 84% (70y). Conclusions: Microsurgery enabled the creation of RCAVF in >70y with acceptable risk of failure and slight differences by comparison with <70y. Older age should not preclude RCAVF creation