Ultrasound-directed enzyme-prodrug therapy (UDEPT) using self-immolative doxorubicin derivatives

Background: Enzyme-activatable prodrugs are extensively employed in oncology and beyond. Because enzyme concentrations and their (sub)cellular compartmentalization are highly heterogeneous in different tumor types and patients, we propose ultrasound-directed enzyme-prodrug therapy (UDEPT) as a means to increase enzyme access and availability for prodrug activation locally. Methods: We synthesized β-glucuronidase-sensitive self-immolative doxorubicin prodrugs with different spacer lengths between the active drug moiety and the capping group. We evaluated drug conversion, uptake and cytotoxicity in the presence and absence of the activating enzyme β-glucuronidase. To trigger the cell release of β-glucuronidase, we used high-intensity focused ultrasound to aid in the conversion of the prodrugs into their active counterparts. Results: More efficient enzymatic activation was observed for self-immolative prodrugs with more than one aromatic unit in the spacer. In the absence of β-glucuronidase, the prodrugs showed significantly reduced cellular uptake and cytotoxicity compared to the parent drug. High-intensity focused ultrasound-induced mechanical destruction of cancer cells resulted in release of intact β-glucuronidase, which activated the prodrugs, restored their cytotoxicity and induced immunogenic cell death. Conclusion: These findings shed new light on prodrug design and activation, and they contribute to novel UDEPT-based mechanochemical combination therapies for the treatment of cancer

Assessment of the relationship between functional capacity and right ventricular ultrasound tissue characterization by integrated backscatter in patients with isolated mitral stenosis

Aim: The aim of the present study was to investigate right ventricular (RV) myocardial textural properties in asymptomatic and symptomatic mitral stenosis (MS) patients with normal RV systolic function using integrated backscatter (IBS). Methods: The study included 40 patients with MS of moderate or severe degree. Patients were classified into 2 groups according to NYHA class (asymptomatic group, NYHA class I, symptomatic group, NYHA class II-III). RV pulsed-wave tissue Doppler imaging (TDI) and IBS analyses were performed in all patients. Isovolumic contraction time (IVCT), systolic wave velocity (S), isovolumic relaxation time (IVRT), early diastolic wave velocity (E), and late diastolic wave velocity (A) were measured by TDI. IBS amplitude (IB) and cyclic variation (CV) of the RV lateral wall in the parasternal long-axis view were measured by IBS. CV was calculated by subtracting systolic IB from diastolic IB. Results: IVRT (54.2 ± 11.9 ms versus 86.2 ± 16.2 ms, P < 0.001) and A wave amplitude (10.2 ± 2.1 cm/s versus 13.6 ± 1.8 cm/s, P < 0.05) were higher whereas E wave amplitude (11.7 ± 1.6 cm/s and 10.3 ± 1.5 cm/s, P < 0.05) and E/A ratio (1.3 ± 0.3 versus 0.7 ± 0.1, P < 0.001) were lower in group 2. Symptomatic patients had a lower CV value of RV (9.5 ± 3.4 dB versus 6.7 ± 1.9 dB, P = 0.004). There was a positive correlation between CV and E/A (r = 0.964, P < 0.001) Conclusion: Symptomatic isolated MS patients had RV echo texture changes and diastolic dysfunction in comparison to asymptomatic ones with similar mitral valve areas in the presence of normal RV systolic function. In isolated MS, both pulsed-wave TDI and IBS may aid in the detection of RV diastolic pathology

Fistulous connection between internal mammary graft and pulmonary vasculature after coronary artery bypass grafting: a rare cause of continuous murmur

A 58-year-old male who had undergone coronary artery bypass grafting (CABG) using left internal mammary artery and a sequential saphenous vein graft 2 years ago presented with new onset angina. His initial physical examination revealed an unexpected continuous murmur over the left sternal border, and two-dimensional echocardiography has failed to identy the cause. Cardiac catheterization then performed and revealed patent left internal mammary artery and saphenous vein grafts. Besides, selective injection of the left internal mammary artery graft also showed a fistula formation between left internal mammary artery graft and pulmonary vasculature of the left upper lobe. He was managed conservatively because of the severely diseased left anterior descending artery distal to internal mammary artery anastomosis and low pulmonary artery pressure. The development of fistulous connection between internal mammary artery and pulmonary vasculature is an extremely rare complication following CABG. Patients with such fistulae usually present with chest pain due to coronary steal syndrome. A new heart sound, especially a continuous murmur, may be detected during, physical examination. Surgical correction is indicated in the event of refractory angina, growing fistula causing heart failure or endarteritis. Otherwise, a conservative approach with instruction of the patient for prophylactic precautions of subacute bacterial endocarditis may be recommended for asymptomatic patients. (C) 2003 Elsevier Ireland Ltd. All rights reserved

Alginate microgels loaded with temperature sensitive liposomes for magnetic resonance imageable drug release and microgel visualization

The objective of this study was to prepare and characterize alginate microgels loaded with temperature sensitive liposomes, which release their payload after mild hyperthermia. It is further aimed that by using these microgels both the drug release and the microgel deposition can be visualized by magnetic resonance imaging (MRI) after their administration (e.g. in the vicinity of a tumor). To this end, temperature sensitive (TSL) and non-temperature sensitive liposomes (NTSL) loaded with fluorescein (drug mimicking dye) and a T1 MRI contrast agent (Prohance®, [Gd(HPDO3A)(H2O)]) were encapsulated in alginate microgels crosslinked by holmium ions (T2∗ MRI contrast agent). The drug release could be monitored by the release of [Gd(HPDO3A)(H2O)] while the microgels could be visualized using MRI via the holmium ions in the microgels. The microgels were prepared with a JetCutter and had an average size of 325 μm and contained ∼0.6 wt% Ho3+. Microgels loaded with NTSL (NTSL-Ho-microgels) were stable at 37 and 42 °C with only a minimal release of fluorescein and [Gd(HPDO3A)(H2O)]. Microgels encapsulating TSL (TSL-Ho-microgels) released fluorescein and [Gd(HPDO3A)(H2O)] only marginally at 37 °C while, importantly, their payload was co-released within 2 min at 42 °C. TSL-Ho-microgels were administered in an ex vivo sheep kidney via a catheter. Clusters of TSL-Ho-microgels could be visualized via MRI and were deposited in the interlobular blood vessels. In conclusion, these alginate TSL-Ho-microgels are promising systems for real-time, MR-guided embolization and triggered release of drugs in vivo

The effects of octreotide in a patient with Nelson's syndrome.

We have administered octreotide, 100 micrograms tid, to a 27-year-old man with Nelson's syndrome. After seven days of therapy, adrenocorticotropin levels fell to 54% of initial values, and some shrinkage of the tumour was observed. This study indicates that octreotide therapy may have a role in the treatment of Nelson's syndrome

Turkey 2017 Clinical Practice Guidelines on recommendations for screning diagnosing and managing hepatitis C virus

The present guideline updates the Turkish recommendations for the screening, diagnosis and management of Hepatitis C virus (HCV) infection prepared by the Turkish Association for the Study of the Liver (TASL) and Viral Hepatitis Society (VHS). The aim of this guidance was to provide updates recommendations to physicians, who are interested in HCV care on the optimal screening, diagnosis and pre-treatment management for patients with HCV infection in Turkey. These recommendations, produced by panel experts, were aimed to addresses the management issues ranging from diagnosis and linkage to care, to the optimal treatment regimen in patients with HCV infection. Recommendations are based on evidence and opinions of more than 70% of the panelists. This guidance is supported by the memberships of two societies and not by pharmaceutical companies. This guidance will be updated frequently as new data become available

Ultrasound-directed enzyme-prodrug therapy (UDEPT) using self-immolative doxorubicin derivatives

Background: Enzyme-activatable prodrugs are extensively employed in oncology and beyond. Because enzyme concentrations and their (sub)cellular compartmentalization are highly heterogeneous in different tumor types and patients, we propose ultrasound-directed enzyme-prodrug therapy (UDEPT) as a means to increase enzyme access and availability for prodrug activation locally. Methods: We synthesized β-glucuronidase-sensitive self-immolative doxorubicin prodrugs with different spacer lengths between the active drug moiety and the capping group. We evaluated drug conversion, uptake and cytotoxicity in the presence and absence of the activating enzyme β-glucuronidase. To trigger the cell release of β-glucuronidase, we used high-intensity focused ultrasound to aid in the conversion of the prodrugs into their active counterparts. Results: More efficient enzymatic activation was observed for self-immolative prodrugs with more than one aromatic unit in the spacer. In the absence of β-glucuronidase, the prodrugs showed significantly reduced cellular uptake and cytotoxicity compared to the parent drug. High-intensity focused ultrasound-induced mechanical destruction of cancer cells resulted in release of intact β-glucuronidase, which activated the prodrugs, restored their cytotoxicity and induced immunogenic cell death. Conclusion: These findings shed new light on prodrug design and activation, and they contribute to novel UDEPT-based mechanochemical combination therapies for the treatment of cancer