Pharmacokinetics of isosorbide dinitrate and its mononitrate metabolites after intravenous infusion

Plasma concentrations of isosorbide dinitrate (ISDN) and its two active metabolites 2-isosorbide mononitrate (2-ISMN) and 5-isosorbide mononitrate (5-ISMN) have been measured during and for 6 hr after intravenous infusion at a rate of 2.5mg/hr during 1.75 hr in six cardiac patients, by a capillary gas chromatographic method. Data were analyzed by simultaneous modeling of the observed kinetics of the three compounds. Two or three phases were detected on the postinfusion ISDN concentration-time curves. ISDN concentrations declined with a mean terminal half-life of 2.81 hr±0.7 SD. The mean systemic clearance of ISDN (2.9 L/min ±0.7 SD) and its mean total volume of distribution (259 L +- 48 SD) were relatively high. Plasma 5-ISMN concentrations were 5- to 6-fold greater than those of 2-ISMN during the whole observation period. Maximum levels of 2-ISMN (6.7 ng/ml ± 0.9 SD) and of 5-ISMN (27 ng/ml ± 6 SD) occurred within a few minutes after the end of infusion. The mean half-lives of 2-ISMN (1.59 hr± 0.19 SD) and of 5-ISMN (3.78 hr± 0.79 SD) estimated by the model were smaller than those calculated by a model-independent method (2.95 hr± 0.41 SD and 5.98 hr± 2.22, respectively), but were in good agreement with those reported in the literature following separate administration of both metabolites to man. This study shows how such modeling can distinguish between metabolite formation and elimination processes and allow the determination of metabolite half-lives after administration of the precursor drug.     

The value of transesophageal echocardiography in the investigation and management of cryptogenic cerebral ischemia: a single-center experience

The diagnostic utility of transesophageal echocardiography (TEE) has often been challenged in patients with cryptogenic stroke (CS). We estimated the prevalence of different findings on TEE examination of CS patients, their impact on secondary stroke prevention and the presence of potential age or gender disparities. We reviewed all TEE examinations that were performed in a single echocardiography laboratory during a 7-year-old period to identify CS patients that underwent investigation with TEE. Of the 518 total TEE examinations, we identified 88 CS patients. TEE revealed abnormal findings in 69.3 % of them. Patent foramen ovale (PFO) and atrial septal aneurysm (ASA) were identified in 30.6 and 22.7 % of the patients. Ascending aorta and aortic arch atheromatosis was present in 26.1 % of the patients, with complex atheromatosis diagnosed in 14.7 % of them. Cardiac myxomas were uncovered in 2.3 %. Thrombi in the left atrium and in cardiac valves were reported in 3.4 and 2.3 % of the patients, respectively. Based on TEE findings, the therapeutic management would be very likely modified in 9.1 % of the patients. Subgroup analysis revealed no gender disparities on the prevalence of TEE findings and in secondary stroke prevention, while linear regression analyses revealed significant associations of age with the prevalence of PFO, ASA, aorta atheromatosis and complex aorta atheromatosis. TEE examination should be included in the diagnostic work-up of all CS patients, irrespective of age and gender status, since it can reveal potential sources of embolism and has a significant impact for secondary stroke prevention.     

Transcranial Doppler versus transthoracic echocardiography for the detection of patent foramen ovale in patients with cryptogenic cerebral ischemia: A systematic review and diagnostic test accuracy meta‐analysis

Schwannomatosis is a genetic disorder characterized by the occurrence of multiple peripheral schwannomas. Segmental schwannomatosis is diagnosed when schwannomas are restricted to 1 extremity and is thought to be caused by genetic mosaicism. We studied 5 patients with segmental schwannomatosis through microstructural magnetic resonance neurography and mutation analysis of NF2, SMARCB1, and LZTR1. In 4 of 5 patients, subtle fascicular nerve lesions were detected in clinically unaffected extremities. Two patients exhibited LZTR1 germline mutations. This appears contrary to a simple concept of genetic mosaicism and suggests more complex and heterogeneous mechanisms underlying the phenotype of segmental schwannomatosis than previously thought. Ann Neurol 2016;80:625–628     

The power and promise of "rewiring" the mitogen-activated protein kinase network in prostate cancer therapeutics

Prostate cancer is the most frequently diagnosed cancer among men and the second leading cause of male cancer deaths. Initially, tumor growth is androgen dependent and thus responsive to pharmacologic androgen deprivation, but there is a high rate of treatment failure because the disease evolves in an androgen-independent state. Growing evidence suggests that the Ras/mitogen-activated protein kinase (MAPK) signaling cascade represents a pivotal molecular circuitry participating directly or indirectly in prostate cancer evolution. The crucial role of the protein elements comprising this complex signal transduction network makes them potential targets for pharmacologic interference. Here, we will delineate the current knowledge regarding the involvement of the Ras/MAPK pathway in prostate carcinogenesis, spotlight ongoing research concerning the development of novel targeted agents such as the Ras/MAPK inhibitors in prostate cancer, and discuss the future perspectives of their therapeutic efficacy.     

Alginate microencapsulation of human mesenchymal stem cells as a strategy to enhance paracrine‐mediated vascular recovery after hindlimb ischaemia

Stem cell‐based therapies hold great promise as a clinically viable approach for vascular regeneration. Preclinical studies have been very encouraging and early clinical trials have suggested favourable outcomes. However, significant challenges remain in terms of optimizing cell retention and maintenance of the paracrine effects of implanted cells. To address these issues, we have proposed the use of a cellular encapsulation approach to enhance vascular regeneration. We contained human mesenchymal stem cells (hMSCs) in biocompatible alginate microcapsules for therapeutic treatment in the setting of murine hindlimb ischaemia. This approach supported the paracrine pro‐angiogenic activity of hMSCs, prevented incorporation of hMSCs into the host tissue and markedly enhanced their therapeutic effect. While injection of non‐encapsulated hMSCs resulted in a 22 ± 10% increase in vascular density and no increase in perfusion, treatment with encapsulated hMSCs resulted in a 70 ± 8% increase in vascular density and 21 ± 7% increase in perfusion. The described cellular encapsulation strategy may help to better define the mechanisms responsible for the beneficial effects of cell‐based therapies and provide a therapeutic strategy for inducing vascular growth in the adult. As hMSCs are relatively easy to isolate from patients, and alginate is biocompatible and already used in clinical applications, therapeutic cell encapsulation for vascular repair represents a highly translatable platform for cell‐based therapy in humans. Copyright © 2012 John Wiley & Sons, Ltd.     

Laparoendoscopic rendezvous: an effective alternative to a failed preoperative ERCP in patients with cholecystocholedocholithiasis

Background  

Although the ideal management of cholelithiasis and concomitant choledocholithiasis is controversial, the two-stage approach [endoscopic retrograde cholangiopancreatography (ERCP), sphincterotomy, and common bile duct (CBD) clearance followed by laparoscopic cholecystectomy] is the most popular treatment regimen worldwide. However, sometimes ERCP fails to solve the problem of choledocholithiasis preoperatively. The aim of this study was to evaluate the use of intraoperative ERCP using the laparoendoscopic “rendezvous” technique in patients in whom preoperative ERCP has failed or was not possible to attempt.