Sub-optimal proton pump inhibitor dosing is prevalent in patients with poorly controlled gastro-oesophageal reflux disease

BACKGROUND: Proton pump inhibitors are the most potent drug treatment for gastro-oesophageal reflux disease. Pre-meal dosing maximizes efficacy while sub-optimal dose timing may limit efficacy. AIM: To determine the prevalence of sub-optimal proton pump inhibitor dosing in a community-based gastro-oesophageal reflux disease population. MATERIALS AND METHODS: One hundred patients on proton pump inhibitors referred for persistent gastro-oesophageal reflux disease symptoms were questioned about their proton pump inhibitor dosing habits and classified as optimal or sub-optimal dosers. Optimal dosers took proton pump inhibitors with or up to 60 min before meals. Sub-optimal dosers took proton pump inhibitors >60 min before meals, after meals, as needed, or at bedtime. RESULTS: Forty-six percent dosed optimally. Fifty-four percent dosed sub-optimally with 21 of 54 (39%) dosing >60 min before meals, 16 (30%) after meals, 15 (28%) at bedtime and two (4%) as needed. Only 6% of the subjects on once-daily proton pump inhibitor regimens and 33% of subjects taking proton pump inhibitors two- to three times daily dosed in a manner that maximized acid suppression (15-30 min before a meal). CONCLUSIONS: In this study, 54% of patients dosed proton pump inhibitors sub-optimally and only 12% dosed in a manner that maximized acid suppression. As sub-optimal proton pump inhibitor dose timing can limit efficacy, patients with refractory symptoms should be asked about dose timing to avoid inappropriate and costly dose escalations.     

Discovery, synthesis, and insecticidal activity of cycloaspeptide E

Several Penicillia and one Tricothecium strain produced a new, insecticidally active member of the cycloaspeptide family, with the proposed name cycloaspeptide E (1). The structure, which was determined on the basis of spectroscopic (NMR, UV, MS) data and Marfey amino acid analysis, was the tyrosine desoxy version of cycloaspeptide A (2). Two synthetic routes to compound 1 were developed: one a partial synthesis from 2 and the other a total synthesis from methyl alaninate hydrochloride. Cycloaspeptide E, the first member of this series not to contain a tyrosine moiety, is also the first to be reported with insecticidal activity.     

Detection of the breakage of pharmaceutical tablets in pneumatic transport

Pneumatic transport of pharmaceutical tablets is very convenient, compact and greatly reduces contamination. A potential problem, however, is the breakage of a significant fraction of the transported tablets, causing serious product quality problems. Since the flowrate of tablets transported through a given pneumatic transport line increases with gas velocity, lines are often operated at gas velocities slightly below the velocity at which tablets break. Minor changes in operating conditions can have a large effect on the impact resistance of tablets and on the observed tablet breakage rate. Therefore, maintaining a constant gas velocity is not sufficient to keep the tablet breakage rate below an acceptable level. The objective of the present study was to develop a reliable and non-invasive on-line method for the detection of tablet breakage. Pharmaceutical acetaminophen tablets were transported pneumatically in a 0.1 m diameter pipeline consisting of a 5 m vertical and a 4.0 m horizontal section made of either re-enforced PVC or steel. The pipeline flow regime was determined by visual observation through clear pipeline sections. Tablet breakage was quantified by screening tablet samples. Acoustic measurements were recorded at different locations along the pipeline. Analysis of the signals from microphones attached to the wall of the elbow and horizontal section provided a reliable detection of conditions leading to tablet breakage.     

Guanidino N-substituted and N,N-disubstituted derivatives of the kappa-opioid antagonist GNTI

Derivatives of the highly selective kappa-opioid receptor antagonist GNTI (2a) have been prepared. Binding and functional studies conducted on cloned human opioid receptors expressed in Chinese hamster ovarian (CHO) cells suggested that adding a benzyl or a substituted benzyl group to the guanidino moiety led, in general, to a retention of high kappa-affinity and antagonist potency. Disubstitution of the guanidino moiety led to reduced kappa-selectivity.     

Safety and efficacy of switching psychiatric patients from a delayed-release to an extended-release formulation of divalproex sodium

This study evaluated the safety and efficacy of divalproex sodium extended-release (ER) when patients were switched from therapy with divalproex sodium delayed-release (DR) to divalproex sodium ER. This open-label, 7-day study included 55 patients with bipolar disorder, major depression, schizophrenia, schizoaffective disorder, Alzheimer's disease, dementia, or intermittent explosive disorder. Baseline plasma valproate concentrations were determined, and patients received their usual morning dose of divalproex sodium DR. At 9:00 p.m. the same day, they received divalproex sodium ER at a dose equal to their total daily dose of divalproex sodium DR. Valproate concentrations were monitored, and efficacy was measured with the Positive and Negative Syndrome Scale (PANSS). Side effects were assessed using the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale. Valproate concentrations for 52 patients remained within the therapeutic range. Inpatient PANSS scores significantly improved from baseline to final evaluation on all subscales. For the combined inpatient and outpatient populations, a small but statistically significant improvement from baseline to final evaluation was seen for positive, general, and total PANSS subscale scores. At study's end, patients reported a significant decrease in the number and severity of adverse events; 54 of 55 patients elected to continue therapy with once-daily divalproex sodium ER. This study suggests that divalproex sodium ER is at least as effective as the DR formulation for treating patients with psychiatric illness and may be better tolerated. The ER formulation offers the advantage of once-daily dosing, which may help improve compliance.     

Vesicular disruption of myelin in autoimmune demyelination

A pattern of autoimmune demyelination in EAE and EAN has been described which was encountered consistently and was sometimes more common than the better known phenomenon of active stripping of myelin by macrophages. This pattern involved the rapid dissolution of myelin into a vesicular network which was later degraded by macrophages. It occurred early in the disease, was not accentuated perivascularly, and was usually associated with the presence of macrophages. The underlying mechanisms are not known but several alternatives have been discussed, viz., activity of locally released antibody, cytotoxic factors, or hydrolytic enzymes.     

Differences between the nodes of Ranvier of large and small diameter fibres in the P.N.S.

Summary The architecture of nodes of Ranvier in the spinal nerve roots of the rabbit has been examined. It has been shown that the nodes of large diameter fibres (mean 12 m) are structurally different from those of small diameter fibres (mean 3 m) on the basis of differences in the degree of axonal constriction, the frequent packing of axoplasmic constituents on one side of the node in large fibres, and the complexity of the arrangement of Schwann cell fingers which abut the nodal axolemma. Schwann cell fingers were seen to traverse a granular nodal gap substance which was web-like and came to rest upon a supra-axonal granular layer. Fine strands (5–6 nm in diameter) apparently formed bridges between some Schwann cell fingers and the nodal axolemma. The picture which emerges from this study is that the nodal apparatus might have orientation and structural stability which contribute to its efficiency as an electrogenic pump and is structurally distinct in small and large diameter fibres.     

Experimental allergic encephalomyelitis: Characterization of serum factors causing demyelination and swelling of myelin

Serum factors in rabbits with white matter-induced experimental allergic encephalomyelitis (WM-EAE) were studied with respect to their role in demyelination in vitro in organotypic central nervous system (CNS) tissue cultures and in vivo in the myelinated retina of the rabbit eye. By absorption with staphylococcal protein A, IgG was quantitatively separated from the other serum proteins. No IgG was demonstrable in the absorbed IgG-depleted sera by Ouchterlony double diffusion, immunoelectrophoresis and SDS-polyacrylamide gel electrophoresis. Both the IgG-depleted WM-EAE sera and the IgG fractions had complement-dependent demyelinating activity on CNS cultures, and both contained immunoglobulin binding to myelin and oligodendroglia of the cultures, as demonstrated by an immunoperoxidase technique. However, only the purified IgG fractions in the absence of complement induced swelling of myelin and proliferation of oligodendroglial processes with redundant myelin in tissue cultures. The IgG-depleted complement-inactivated WM-EAE sera produced no morphological changes. In the rabbit eye model, antibody-dependent cell-mediated demyelination was observed only with the IgG fractions but not with the IgG-depleted EAE sera. No oligodendroglial proliferation occurred. These studies demonstrate for the first time that in CNS cultures, non-IgG immunoglobulins as well as IgG mediate complement-dependent demyelination and that these bind to myelin and oligodendrocytes, whereas only IgG causes myelin swelling and oligodendrocyte proliferation.     

Specific Binding of Peroxidase-Labeled Myelin Basic Protein in Allergic Encephalomyelitis

A conjugate of horseradish peroxidase and the encephalitogenic basic protein from myelin has been used to study the antigen reactivity of tissue in the autoimmune disease, experimental allergic encephalomyelitis. Control conjugates were also prepared of peroxidase and bovine serum albumin and of peroxidase and lysozyme, another basic protein. The basic protein from myelin conjugate was specifically bound by lymph node cells from rabbits immunized against the basic protein. Some of these cells appeared to be plasma cells. The conjugate was also specifically bound by occasional cells in the spinal-cord infiltrates of animals with early signs of allergic encephalomyelitis. These cells resembled large lymphocytes and plasma cells. There was no difference between the binding of basic protein of bovine and rabbit origin. The findings suggest the possibility that a local release of antibody within the target organ may play a role in the pathogenesis of allergic encephalomyelitis.