Intrathecal drug delivery in the era of nanomedicine.

Administration of substances directly into the cerebrospinal fluid (CSF) that surrounds the brain and spinal cord is one approach that can circumvent the blood-brain barrier to enable drug delivery to the central nervous system (CNS). However, molecules that have been administered by intrathecal injection, which includes intraventricular, intracisternal, or lumbar locations, encounter new barriers within the subarachnoid space. These barriers include relatively high rates of turnover as CSF clears and potentially inadequate delivery to tissue or cellular targets. Nanomedicine could offer a solution. In contrast to the fate of freely administered drugs, nanomedicine systems can navigate the subarachnoid space to sustain delivery of therapeutic molecules, genes, and imaging agents within the CNS. Some evidence suggests that certain nanomedicine agents can reach the parenchyma following intrathecal administration. Here, we will address the preclinical and clinical use of intrathecal nanomedicine, including nanoparticles, microparticles, dendrimers, micelles, liposomes, polyplexes, and other colloidalal materials that function to alter the distribution of molecules in tissue. Our review forms a foundational understanding of drug delivery to the CSF that can be built upon to better engineer nanomedicine for intrathecal treatment of disease.

Quantification of wear, hemolysis and coagulation deficits in patients with Beall mitral valves.

Fifty-five patients (35 females and 20 males) were studied by noninvasive means 3.5-8.6 years after isolated mitral valve replacement with Models 103 and 104 Beall prostheses. History and physical exams by three physicians, complete hemograms, SMA 18, iron excretion rates, and coagulation profiles were performed. Additionally, electrocardiograms, echocardiograms, phonocardiograms, cardiac series, and high-speed cinefluorography of the prostheses were obtained. Valve wear was assessed by the disc/cage ratio measured from a "three-legged view" with magnification. At a mean duration of 5.85 years after operation, the entire group had a mean disc/cage ratio of operation, the entire group had a mean disc/cage ratio of 0.906 +/- 0.031 vs a normal value of 0.944 +/- 0.014. The group was mildly anemic and had a urinary iron loss that was 40 times normal. The lactic dehydrogenase (LDH) concentration was more than five times normal. The coagulation profiles were abnormal with respect to the bleeding and stypven times, antiheparin activity, fibrin degradation products, and megathrombocyte index. These abnormalities were unrelated to sex, degree of valve wear, and history of thromboembolism. Males were less anemic and had higher urine iron losses than females. Nine patients with severe valve wear (disc/cage ratio less than or equal to 0.87) were significantly more anemic with large urine iron losses and had elevated total bilirubin, serum glutamic oxaloacetic transaminase, and LDH concentrations (ninefold), when compared to nine patients with minimal wear (disc/cage ratio greater than or equal to 0.925). It is emphasized that the findings of a significant anemia, an LDH concentration greater than 1500 mU/ml, and a disc/cage ratio of less than 0.87 in a patient with an isolated Beall mitral valve prosthesis are indicators for the need to replace the prosthesis in the near future. Re-replacement is urged before significant clinical deterioration.