Synthesis and biological activities of potent peptidomimetics selective for somatostatin receptor subtype 2

A series of nonpeptide somatostatin agonists which bind selectively and with high affinity to somatostatin receptor subtype 2 (sst2) have been synthesized. One of these compounds, L-054,522, binds to human sst2 with an apparent dissociation constant of 0.01 nM and at least 3,000-fold selectivity when evaluated against the other somatostatin receptors. L-054,522 is a full agonist based on its inhibition of forskolin-stimulated adenylate cyclase activity in Chinese hamster ovary-K1 cells stably expressing sst2. L-054,522 has a potent inhibitory effect on growth hormone release from rat primary pituitary cells and glucagon release from isolated mouse pancreatic islets. Intravenous infusion of L-054,522 to rats at 50 μg/kg per hr causes a rapid and sustained reduction in growth hormone to basal levels. The high potency and selectivity of L-054,522 for sst2 will make it a useful tool to further characterize the physiological functions of this receptor subtype.

Iontophoresis for modulation of cardiac drug delivery in dogs.

Cardiac arrhythmias are a frequent cause of death and morbidity. Conventional antiarrhythmia therapy involving oral or intravenous medication is often ineffective and complicated by drug-associated side effects. Previous studies from our laboratory have demonstrated the advantages of cardiac drug-polymer implants for enhanced efficacy for cardiac arrhythmia therapy compared with conventional administration. However, these studies were based on systems that deliver drugs at a fixed release rate. Modulation of the drug delivery rate has the advantage of regulating the amount of the drug delivered depending upon the disease state of the patient. We hypothesized that iontophoresis could be used to modulate cardiac drug delivery. In this study, we report our investigations of a cardiac drug implant in dogs that is capable of iontophoretic modulation of the administration of the antiarrhythmic agent sotalol. We used a heterogeneous cation-exchange membrane (HCM) as an electrically sensitive and highly efficient rate-limiting barrier on the cardiac-contacting surface of the implant. Thus, electric current is passed only through the HCM and not the myocardium. The iontophoretic cardiac implant demonstrated in vitro drug release rates that were responsive to current modulation. In vivo results in dogs have confirmed that iontophoresis resulted in regional coronary enhancement of sotalol levels with current-responsive increases in drug concentrations. We also observed acute current-dependent changes in ventricular effective refractory periods reflecting sotalol-induced refractoriness due to regional drug administration. In 30-day dog experiments, iontophoretic cardiac implants demonstrated robust sustained function and reproducible modulation of drug delivery kinetics.

Composition of Aleutian forearc sediments

The ultimate composition of any sandstone is affected by a host of primary and secondary factors, including the lithologies present in source terranes, climate, depositional environment and diagenesis. In the case of a subduction complex, however, unequivocal identification of detrital provenance may be impossible because of the cumulative effects of tectonic and sedimentary transport. Long-distance sedimentary transport (> 1000 km) is common within trenches, and abyssal-plain turbidites can be tectonically transported for long distances as the underlying oceanic basement drifts towards a subduction front. Post-accretionary displacement can occur as a consequence of strike-slip faulting, and the total distance of tectonic dislocation may reach several thousand kilometers. The present-day Aleutian forearc region (North Pacific Ocean) illustrates many of the "problems" which typify subduction zones. Several petrologic suites can be identified, and there are significant variations in detrital modes in both time and space. The Aleutian region serves as a sobering modern analog for accreted rock units such as the Franciscan Complex of California, where intercalations of discrete sandstone suites have been noted. In the absence of paleomagnetic control, interpretations of sediment provenance within ancient subduction complexes probably should be restricted to the generic level.

(Table T3) Granulometry of sediments from ODP Leg 190 sites

We present the results of grain-size analysis performed on hemipelagic sediment from Sites 1173, 1174, 1175, and 1177 at the Nankai Trough. Analyses of the <63-µm fraction were performed with a laser particle counter, and results were converted to equivalent settling diameters by means of an empirical regression with data from pipette analysis. The relations among grain size, porosity, bulk density, void ratio, and moisture content are influenced by the increasing compaction of sediment with depth as well as facies changes. Thus, departures of bulk density and porosity from normal compaction trends cannot be attributed to grain size on the basis of our laboratory results.