A new aliphatic amino prodrug system for the delivery of small molecules and proteins utilizing novel PEG derivatives

A new amino PEG prodrug system, based entirely on aliphatic structures, has been designed using ester derivatives easily synthesized from N-modified bis-N-2-hydroxyethylglycinamides. Hydrolysis of the various promoiety bonds, in vivo, regenerated amine in a predictable manner. Thus, a novel new methodology for controlled release of amino-containing drugs, peptides, and proteins has been accomplished. This work demonstrates the usefulness of a PEG prodrug strategy that results in solubilization of insoluble amino-containing drugs and provides prodrugs with relatively long circulating half-lives. It can be appreciated that this novel system should also be applicable for nonpolymer-containing prodrugs as well.     

Integrated microsystems for controlled drug delivery

Efficient drug delivery and administration are needed to realize the full potential of molecular therapeutics. Integrated microsystems that incorporate extremely fast sensory and actuation capabilities can fulfill this need for efficient drug delivery tools. Photolithographic technologies borrowed from the semiconductor industry enable mass production of such microsystems. Rapid prototyping allows for the quick development of customized devices that would accommodate for diverse therapeutic requirements. This paper reviews the capabilities of existing microfabrication and their applications in controlled drug delivery microsystems. The next generation of drug delivery systems--fully integrated and self-regulating--would not only improve drug administration, but also revolutionize the health-care industry.     

Drug-exposed infants and developmental outcome: effects of a home intervention and ongoing maternal drug use

OBJECTIVE: To evaluate the effects of a home intervention and ongoing maternal drug use on the developmental outcome of drug-exposed infants. DESIGN: Longitudinal randomized cohort study of a home intervention with substance-abusing mothers and their infants. Mother-infant dyads were randomly assigned to a control or intervention group at 2 weeks' post partum. Control families received brief monthly tracking visits. Intervention families received weekly home visits from 0 to 6 months and biweekly visits from 6 to 18 months by trained lay visitors. PARTICIPANTS: One hundred eight low-income, inner-city, drug-exposed children (control, 54; intervention, 54) who underwent developmental testing at 6, 12, and 18 months post partum and who remained with their biological mothers through 18 months. MAIN OUTCOME MEASURES: Infant scores from the Bayley Scales of Infant Development (BSID) at 6, 12, and 18 months post partum. Maternal report of drug use during the pregnancy and ongoing drug use through 18 months post partum was assessed. RESULTS: In the repeated-measures analyses, intervention infants had significantly higher BSID Mental Developmental Index (MDI) and Psychomotor Developmental Index scores than control infants. Ongoing maternal cocaine and/or heroin use was associated with lower MDI scores. Finally, MDI scores decreased significantly in both groups. CONCLUSIONS: Ongoing maternal drug use is associated with worse developmental outcomes among a group of drug-exposed infants. A home intervention led to higher BSID scores among drug-exposed infants. However, BSID MDI scores decreased during the first 18 months post partum among inner-city, low-socioeconomic-status infants in the present study.     

Dexamethasone regulates endothelin-1 and endothelin receptors in human non-pigmented ciliary epithelial (HNPE) cells

Endothelin-1 (ET-1) lowers intraocular pressure (IOP) in animal models by regulating aqueous humour dynamics through both inflow and outflow mechanisms. Moreover, ET's concentration is elevated in glaucoma patients and in animal models of glaucoma. Glucocorticoid therapy often can lead to increase IOP in susceptible individuals including patients with primary open angle glaucoma (POAG). In this study, we examined the effects of dexamethasone (Dex), a frequently used anti-inflammatory glucocorticoid, on the synthesis and release of endothelin-1 and on the expression of endothelin receptors in human non-pigmented ciliary epithelial (HNPE) cells, an established source for ET-1 in the anterior chamber. As measured by ET-1 immunoreactivity, ET-1 was concentration-dependently increased following 24hr Dex treatment, with a maximum concentration (100 nM) causing a threefold increase of ET-1 release. Western blot analysis of HNPE cells showed the expression of endothelin receptor A (ET(A)) and endothelin receptor B (ET(B)) with approximate molecular weights of 40 kDa. Dex treatment decreased ET(A) receptor expression at all Dex doses, but up-regulated ET(B) receptors with 10nM Dex having the greatest effect. Quantitative PCR demonstrated that Dex also increased the mRNA of pre-pro-ET-1 (ppET-1) and ET(B) but decreased the mRNA of ET(A). RU486, a glucocorticoid receptor antagonist, was able to block Dex's actions on ET release and ET(B) receptor expression, but did not block its action on ET(A) receptor expression. Endothelin receptors were minimally expressed in HNPE cells as determined in binding experiments (B(max): ET(A) 17, ET(B) 25 fmolmg(-1) membrane protein). However Dex treatment stimulated a dramatic increase in ET(B) receptor density while decreasing ET(A) receptors (B(max): ET(A) 11, ET(B) 116 fmolmg(-1) membrane protein). The regulation of endothelin and its receptors could be a novel mechanism associated with glucocorticoid's effects on intraocular pressure. The increase in ET-1 and disproportionate regulation in ET receptor expression by Dex could promote dysregulation in ET's mechanism on both inflow and outflow, thus affecting aqueous humour dynamics in the anterior chamber of the eye.     

Use of a vaccine strain of measles virus genetically engineered to produce carcinoembryonic antigen as a novel therapeutic agent against glioblastoma multiforme

Despite the most aggressive medical and surgical treatments, glioblastoma multiforme remains incurable with a median survival of <1 year. We investigated the antitumor potential of a novel viral agent, an attenuated strain of measles virus (MV), derived from the Edmonston vaccine lineage, genetically engineered to produce carcinoembryonic antigen (CEA). CEA production as the virus replicates can serve as a marker of viral gene expression. Infection of a variety of glioblastoma cell lines including U87, U118, and U251 at MOIs 0.1, 1, and 10 resulted in significant cytopathic effect consisting of excessive syncycial formation and massive cell death at 72-96 h from infection. terminal deoxynucleotidyltransferase-mediated nick end labeling assays demonstrated the mechanism of cell death to be predominantly apoptotic. The efficacy of this approach in vivo was examined in BALB/c nude mice by using both s.c. and intracranial orthotopic U87 tumor models. In the s.c. U87 model, mice with established xenografts were treated with a total dose of 8 x 10(7) plaque forming units of MV-CEA, administered i.v. Mice treated with UV light inactivated MV, and untreated mice with established U87 tumors were used as controls. There was statistically significant regression of s.c. tumors (P < 0.001) and prolongation of survival (P = 0.007) in MV-CEA treated animals compared with the two control groups. In the intracranial orthotopic U87 model, there was significant regression of intracranial U87 tumors treated with intratumoral administration of MV-CEA at a total dose of 1.8 x 10(6) plaque forming units as assessed by magnetic resonance image (P = 0.002), and statistically significant prolongation of survival as compared with mice that received UV-inactivated virus and untreated mice (P = 0.02). Histological examination of brains of MV-CEA-treated animals revealed complete regression of the tumor with the presence of a residual glial scar and reactive changes, mainly presence of hemosiderin-laden macrophages. In addition, CEA levels in the peripheral blood in both the s.c. and orthotopic models increased before tumor regression, indicating viral gene expression, and returned to normal when the tumors regressed. Ifnar(ko) CD46 Ge transgenic mice, susceptible to MV infection, were used to assess central nervous system toxicity of MV-CEA. Intracranial administration of MV-CEA into the caudate nucleus of Ifnar(ko) CD46 Ge did not result in clinical neurotoxicity. Pathologic examination demonstrated limited microglial infiltration surrounding the injection site. In summary, MV-CEA has potent antitumor activity against gliomas in vitro, as well as in both s.c. and orthotopic U87 animal models. Monitoring CEA levels in the serum can serve as a low-risk method of detecting viral gene expression during treatment, and could allow dose optimization and individualization of treatment.     

Occult spinal dysraphism: evidence-based diagnosis and treatment

This article reviews the scientific evidence behind the diagnostic tools available for the appropriate workup and management of patients with occult spinal dysraphism (OSD). The diagnostic tools include the use of detailed history and physical examination, plain films, ultrasound, MR imaging, and neurophysiologic tests. In addition, the article discusses the epidemiology of the most common causes of OSD in children, which will allow physicians caring for children to develop a pretest probability of disease and make a more educated decision as to when additional diagnostic testing is required.     

Dependence of insulin secretion from permeabilized pancreatic beta-cells on the activation of Ca(2+)/calmodulin-dependent protein kinase II. A re-evaluation of inhibitor studies

Previous studies utilizing inhibitors of the Ca(2+)/calmodulin-dependent protein kinase II (CaM kinase II) to address the role of this enzyme in insulin secretion have produced contradictory results. In the current study, these inconsistencies have been addressed by evaluating the effect of various CaM kinase II inhibitors to decrease Ca(2+)-induced insulin secretion from permeabilized beta-cells. KN-93 (2-[N-(2-hydroxyethyl)-N-(4-methoxy-benzenesulfonyl)]-amino-N-(4-chlo rocinnamyl)-N-methylbenzylamine) markedly inhibited both CaM kinase II activation and insulin secretion in parallel in alpha-toxin-permeabilized beta-cells. These effects were specific since they were not mimicked by the inactive analog, KN-92 (2-[N-(4-methoxy-benzenesulfonyl)]-amino-N-(4-chlorocinnamyl)-N-methy lbenzylamine). In contrast, KN-62 (1-[N, O-bis(5-isoquinolinesulfonyl)-N-methyl-l-tyrosyl]-4-phenylpiperazine) , while reported to be similar to KN-93 with respect to mechanism of action, did not inhibit Ca(2+)-induced activation of CaM kinase II or insulin secretion in these cell preparations. All three agents suppressed Ca(2+) influx in intact beta-cells induced by depolarization in the presence of elevated extracellular potassium although to different extents. The synthetic peptide inhibitors of CaM kinase II, [Ala(286)]CaMK 281-302 and AIP (autocamtide-2-related inhibitory peptide), strongly inhibited Ca(2+)-induced insulin secretion from electropermeabilized islets, an effect that also correlated with an equivalent inhibition of CaM kinase II activation. This re-evaluation (i) explains a lack of effect of KN-62 on insulin secretion from permeabilized cells based on its inability to inhibit CaM kinase II activation in these preparations; (ii) has revealed that CaM inhibitors, either chemical or peptide in nature, that are capable of preventing enzyme activation uniformly suppress Ca(2+)-sensitive insulin secretion; and (iii) cautions the use of KN-62/93/92 as selective inhibitors of CaM kinase II in intact cell studies. These observations reinforce the suggestion that CaM kinase II plays an important role in insulin exocytosis in the beta-cell.     

Exposure to Human and Bovine Noroviruses in a Birth Cohort in Southern India from 2002 to 2006

Human and bovine norovirus virus-like particles were used to evaluate antibodies in Indian children at ages 6 and 36 months and their mothers. Antibodies to genogroup II viruses were acquired early and were more prevalent than antibodies to genogroup I. Low levels of IgG antibodies against bovine noroviruses indicate possible zoonotic transmission.     

Confusion,Urea, Respiratory Rate and Shock Index or Adjusted Shock Index (CURSI or CURASI) criteria predict mortality in community-acquired pneumonia

BackgroundCommunity-acquired pneumonia (CAP) is common and associated with a significant mortality. Shock index, heart rate divided by systolic blood pressure, has been shown to be associated with outcome in sepsis.ObjectiveTo examine the usefulness of two new criteria CURSI (confusion, urea, respiratory rate and shock index), and CURASI where shock index is replaced by temperature adjusted shock index in mortality assessment of CAP.MethodsA prospective study was conducted in Norfolk and Suffolk, UK. We explored the usefulness of CURSI and CURASI which we derived and performed mapping exercise using a different cohort. In this study we compared these new indices with the CURB-65 criteria in correctly predicting mortality in CAP.ResultsA total of 190 patients were included (males = 53%). The age range was 18–101 years (median = 76 years). There were a total of 54 deaths during a six-week follow-up. All died within 30-days. Sixty-five (34%) had severe pneumonia by CURB-65. Using CURSI and CURASI, 71(37%) and 69(36%) had severe pneumonia, respectively. The sensitivity, specificity, positive and negative predictive values in predicting death during six-week follow-up were comparable among three indices examined. The Receiver Operating Characteristic curve values (95%CI) for the criteria were 0.67(0.60–0.75) for CURB-65, 0.67(0.59–0.74) for CURSI and 0.66(0.58–0.74) for CURASI (p > 0.05). There were strong agreements between these three indices (Kappa values ≥0.75 for all). Repeating analyses in those who were aged 65 years and over (n = 135) did not alter the results.ConclusionsBoth CURSI and CURASI are similarly useful to CURB-65 in predicting deaths associated with CAP including older patients.     

The Location of Maxillary Sinus Ostium and Its Clinical Application

The endoscopic sinus surgeons must have a detailed knowledge of inconsistent location of maxillary sinus openings in any interventional maxillary sinus surgeries as it relates to the orbital floor, ethmoid infundibulum and the nasolacrimal duct. Forty cadaver head and neck specimens had been cut sagittally through the nose, such that the lateral nasal wall had been preserved. The findings were documented with an emphasis on location of the maxillary sinus openings. In the present study maxillary sinus ostium opened more commonly into posterior third of the hiatus semilunaris. Accessory maxillary ostium was another variation seen in nearly three-fourths of the cases which opened into membranous meatus inferior to the uncinate process.