Summary
This report describes bone safety and histomorphometric data across different dose levels and dosing frequencies of risedronate. Normal bone structure and histomorphometric data were ...observed, with ongoing bone remodeling and mineralization regardless of dose. These data are reassuring and do not suggest compromised bone remodeling during treatment with established risedronate regimens.
Introduction
The efficacy and bone safety of risedronate 5 mg daily were established in pivotal phase III randomized, placebo-controlled clinical studies. Histomorphometric analysis of paired biopsies demonstrated bone safety as reflected by presence of fluorescent tetracycline double-labels in all evaluable biopsies. This report describes bone safety and histomorphometric data across studies of various dose regimens of risedronate.
Methods
Bridging studies, with bone mineral density as the primary endpoint, demonstrated non-inferiority of risedronate 35 mg and 50 mg once a week, risedronate 150 mg once a month, and a risedronate 75-mg dose on two consecutive days a month versus risedronate 5 mg daily. The low oral bioavailability and known dosing limitations due to food interactions of bisphosphonates have led to development of an oral delayed-release dose form of risedronate 35 mg to be taken weekly, before or after breakfast. Bone biopsies were collected at 24 months in studies involving these risedronate dosing regimens; bone safety and histomorphometric data were evaluated.
Results
Qualitative bone histology showed normal mineralization of newly formed bone without evidence of pathological findings, such as osteomalacia, bone marrow dyscrasia, or bone marrow fibrosis. Importantly, ongoing bone remodeling, based on fluorochrome labeling, was observed in all patients regardless of dose and exposure. Key histomorphometric variables were comparable to those observed with the risedronate 5 mg daily dose and were within the range seen in healthy pre- and post-menopausal women.
Conclusions
Overall, the results are reassuring with respect to bone safety and histomorphometric data, and do not suggest oversuppression of bone remodeling during treatment with these established risedronate regimens.
Nucleic acid-based technologies are an emerging research focus area for pharmacological and biological studies because they are biocompatible and can be designed to produce a variety of scaffolds at ...the nanometer scale. The use of nucleic acids (ribonucleic acid (RNA) and/or deoxyribonucleic acid (DNA)) as building materials in programming the assemblies and their further functionalization has recently established a new exciting field of RNA and DNA nanotechnology, which have both already produced a variety of different functional nanostructures and nanodevices. It is evident that the resultant architectures require detailed structural and functional characterization and that a variety of technical approaches must be employed to promote the development of the emerging fields. Small-angle X-ray and neutron scattering (SAS) are structural characterization techniques that are well placed to determine the conformation of nucleic acid nanoparticles (NANPs) under varying solution conditions, thus allowing for the optimization of their design. SAS experiments provide information on the overall shapes and particle dimensions of macromolecules and are ideal for following conformational changes of the molecular ensemble as it behaves in solution. In addition, the inherent differences in the neutron scattering of nucleic acids, lipids, and proteins, as well as the different neutron scattering properties of the isotopes of hydrogen, combined with the ability to uniformly label biological macromolecules with deuterium, allow one to characterize the conformations and relative dispositions of the individual components within an assembly of biomolecules. This article will review the application of SAS methods and provide a summary of their successful utilization in the emerging field of NANP technology to date, as well as share our vision on its use in complementing a broad suite of structural characterization tools with some simulated results that have never been shared before.
Farmer organization and collective action are often seen as key factors in enhancing farmers’ access to markets. Often, too little attention is directed at (a) the most appropriate types of ...organization; (b) whether organization makes less or more sense in the case of producers of an undifferentiated commodity or a higher value product; (c) whether the public or private sector is best placed to support farmer organizations; and (d) the conditions necessary for ensuring their economic viability. Research in Mexico and Central America explored these issues for commodity maize and high value vegetables, respectively. The benefits of farmer organization are more evident in the vegetable sector, characterized by high transaction costs associated with market access. However, horticultural farmer organizations in Honduras and El Salvador include less than 5% of total horticultural producers. This is possibly due to farmer organizations’ limited business skills and non-replicable organizational models. There is less incentive for maize farmers to organize to access output markets as the transaction costs are relatively low. The benefits of maize farmer organization are clearer when it comes to accessing inputs such as credit, seed and fertilizer. Farmer organization is a critical factor in making markets work for the poor, but the role and timing of public and private investment in these organizations is poorly understood.
Structure–activity relationship studies of the novel 2-3-di and trifluoromethyl-5-alkylamino pyrazo-1-lyl-5-methanesulfonyl (SO
2Me)/5-sulfamoyl (SO
2NH
2)-pyridine derivatives for canine COX enzymes ...led to
2e as the lead with desired in vitro activity, selectivity for canine and feline COX-2 enzyme and in vivo efficacy.
Structure–activity relationship (SAR) studies of the novel 2-3-di and trifluoromethyl-5-alkylamino pyrazo-1-yl-5-methanesulfonyl (SO
2Me)/sulfamoyl (SO
2NH
2)-pyridine derivatives for canine COX enzymes are described. The studies led to the identification of
2e as lead with potent in vitro activity, selectivity, and in vivo activity in dogs and cats.
The oximes pralidoxime (2-PAM), its dimethanesulphonate salt derivative P2S, and obidoxime (toxogonin) are currently licensed and fielded for the treatment of chemical warfare (CW) organophosphorous ...(OP) nerve agent poisoning. While they are effective against several of the identified threat CW OP agents, they have little efficacy against others such as soman (GD) and cyclosarin (CF). In addition, they are also significantly less effective than other investigational oximes against the nerve agent known as Russian VX (RVX). Among the oximes currently being investigated, two in particular, HI-6 (asoxime) and MMB-4 (ICD-039, methoxime) have been proposed as replacement therapies for the currently licensed oximes. HI-6 has been safely used in individuals to treat OP insecticide poisoning, as well as in human volunteers, although its efficacy against OP nerve agent poisoning in humans cannot be demonstrated due to ethical considerations. It is currently available for use in defined military settings in Canada, Sweden and the Czech Republic, and is also under development in a number of other countries. The oxime MMB-4 has not yet been studied clinically, but is fielded by the Czech Republic, and is being developed by the United States armed services as a replacement for the currently fielded 2-PAM. This review compares the effectiveness of HI-6 and MMB-4 against nerve agent threats where comparisons can be made. HI-6 has been demonstrated to be generally a superior reactivator of nerve agent inhibited enzyme, particularly with human and non-human primate derived enzyme, and has also shown better protective effects against the lethality of most OP agents in a variety of species. Both compounds appear to be clearly superior to the available oximes, obidoxime and 2-PAM.
Efforts to achieve groundwater sustainability in California's San Joaquin Valley will entail substantial pumping reductions, and much irrigated cropland may become newly fallowed. Winter crops grown ...under water-limited conditions could offer an alternative to fallowing, but their viability may be limited by variable rainfall and high crop failure rates.
The first objective of this study was to evaluate how small (100–200 mm), targeted irrigation events impact crop establishment, forage and grain yields, and the resulting economic and agronomic water productivity of winter wheat at 4 sites in the San Joaquin Valley. Additionally, we assessed the probability of producing economically viable forage yields across the region based on historical precipitation totals combined with 0, 100, or 200 mm of supplemental irrigation.
We used APSIM to run 20-yr simulations of winter wheat establishment and productivity under historical weather conditions at four groundwater dependent sites in California's San Joaquin Valley. For each site, we simulated wheat productivity (biomass and grain) under three irrigation scenarios (no irrigation, 100 mm, or 200 mm) and three sowing dates (mid-October, mid-November, and mid-December). We applied model outputs to calculations of economic and agronomic water productivity, and used the modeled relationship between soft dough biomass yield and total water input (precipitation plus irrigation) to determine the likelihood of a successful wheat crop in any given year across the region.
We found that two 100 mm applications of irrigation applied at times of critical soil water depletion decreased crop failure rates from 45% of years to 0% of years at the driest site. Economic water productivity was highest when wheat was harvested for forage at the soft dough stage, and agronomic water productivity of soft dough forage was highest with supplemental irrigation and early planting. Given the precipitation requirements to achieve economically viable soft dough-stage forage yields, the addition of 100 mm of irrigation in a single event expanded the potential cropping area to 11% (126,356 ha) of groundwater dependent cropland in the region, while 200 mm of irrigation expanded the potential cropping area to 100% (1,109,888 ha) of cropland.
These results suggest that small, targeted supplemental irrigation events could greatly expand the scope for water-limited winter forage production in the San Joaquin Valley. Such an approach could serve as an alternative to land fallowing in areas transitioning away from irrigated summer crops where appropriate technological and policy mechanisms are in place.
Display omitted
•Winter cereals are a viable alternative to fallowing for meeting sustainable groundwater use targets.•A cropping systems model was used to explore the potential for dryland, minimally irrigated wheat in the San Joaquin Valley.•Small, targeted irrigations improved winter wheat viability across the study region.•Non-irrigated wheat establishment was improved by late planting.•When water-limited, forage harvest resulted in higher water productivity than grain.
Quantitative structure−activity relationships have been found among macrolide antibacterial agents in their potencies against the bacterial pathogen Pasteurella multocida both in vitro and in mouse ...infections. To obtain these relationships we measured, among other things, the pK a's and log P's of 15 known macrolides of diverse structures. Among these compounds, in vitro potency log(1/MIC) is a function of log P, log D, and CMR (R = 0.86). In vivo potency is a function of the higher pK a, the HPLC chromatographic capacity factor log k‘, log(1/MIC) and pNF (R = 0.93). pNF is defined as the negative logarithm of the fraction of neutral drug molecules present in aqueous solution at pH 7.4. The same physical properties were determined for 14 macrolides not used in developing the original QSAR models. Using the in vivo model, we calculated the mouse protection potency ranges for these new compounds. Ten estimates agreed with those observed, three were lower by a half-order of magnitude, and one was calculated to be active in the range of 15−50 mg/kg, but in fact was not active at 50 mg/kg, the highest level tested. When these new compounds were combined with the original 15, and the QSAR's updated, the new equations for the in vitro and in vivo potencies were essentially the same as those originally found. Hence, the physical properties indicated above are major determinants of macrolide antibacterial potencies.
Objective
Despite the absolute requirement of Delta/Notch signaling to activate lateral inhibition during early blood vessel development, many mechanisms remain unclear about how this system is ...regulated. Our objective was to determine the involvement of Epsin 15 Homology Domain Containing 2 (EHD2) in delta‐like ligand 4 (Dll4) endocytosis during Notch activation.
Approach and Results
Using both in vivo and in vitro models, we demonstrate that EHD2 is a novel modulator of Notch activation in endothelial cells through controlling endocytosis of Dll4. In vitro, EHD2 localized to plasma membrane‐bound Dll4 and caveolae. Chemical disruption of caveolae complexes resulted in EHD2 failing to organize around Dll4 as well as loss of Dll4 internalization. Reduced Dll4 internalization blunted Notch activation in endothelial cells. In vivo, EHD2 is primarily expressed in the vasculature, colocalizing with junctional marker VE‐cadherin and Dll4. Knockout of EHD2 in zebrafish produced a significant increase in dysmorphic sprouts in zebrafish intersomitic vessels during development and a reduction in downstream Notch signaling.
Conclusions
Overall, we demonstrate that EHD2 is necessary for Dll4 transcytosis and downstream Notch activation.
Anesthetized pigs were injected i.m. with 500
mg HI-6 dichloride (HI-6 2Cl) (1-4-(aminocarbonyl)-pyridiniomethoxymethyl-2(hydroxyimino)methylpyridinium dichloride; CAS 34433-31-3)) or the molar ...equivalent of HI-6 dimethanesulphonate (HI-6 DMS) 633
mg. Plasma HI-6 concentrations were measured by HPLC (1, 3, 5, 10, 15, 30, 60
min and every 30
min until 4
h or 6
h following the i.v. or i.m. dose respectively) while a variety of physiological responses were continuously examined. HI-6 (500
mg 2Cl or 633
mg DMS) resulted in an identical pharmacokinetic profile unaffected by atropine co-administration. Neither HI-6 salt resulted in clinically significant changes in cardiovascular or respiratory function. HI-6 DMS (1899
mg i.v.) resulted in plasma HI-6 concentrations about 10 times higher than measured following i.m. 500
mg 2Cl or 633
mg DMS and resulted in small transitory effect on mean arterial pressure. Atropine plus HI-6 DMS (1–9
mg/kg or 127–172
mg/kg i.m.) protected up to 100% of guinea pigs exposed to 5
×
LD
50 of GF (cyclohexyl methyl phosphonoflouridate) or soman (pinacolyl methylphosphonofluoridate) (GD) respectively. The results suggest that the two HI-6 salts have a similar pharmacokinetic profile while HI-6 DMS appears extremely safe and effective against nerve agents and may be as suitable for human use.
PDF
