Public sector contraceptive development history, problems, and prospects for the future

The pharmaceutical industry has progressively discounted the development of new contraceptives. The factors that led to this withdrawal now threaten the introduction of new contraceptives. Public sector research organizations have attempted to fill the gap left by industry. In spite of the organizational difficulties imposed on these research groups, a few of them have been successful in developing new products that include: copper IUDs, levonorgestrel-releasing IUDs, subdermal implants, vaginal rings, new methods of sterilization, and new barrier methods. At present, public sector programs are facing increasing difficulty in funding and staffing their development activities. This is due, in part, to the need for increased funds and manpower to complete successful projects, increasing numbers of organizations competing for a relatively limited pool of resources, increased requirements of regulatory agencies, difficulty in obtaining product liability insurance, and overt public and political opposition to the development of family planning methods. If these issues are resolved, organizational changes in the field will need to be examined if products are to be completed and marketed.     

Equilibria,kinetics and mechanism for the degradation of the cytotoxic compound L-NG-nitroarginine

L-N^G-nitroarginine (LNNA), an analog of L-arginine, is a competitive inhibitor of nitric oxide synthase which causes the selective reduction of blood flow to tumor cells. Despite the potential of LNNA to function as an adjuvant in cancer therapies, its poor solubility and stability have hindered the development of an injectable formulation of LNNA that is suitable for human administration. This work, for the first time, details a systematic study on the determination of equilibrium K_a constants and the rate law of LNNA degradation. The four K_a values of LNNA were determined to be 1.03, 1.10?×?10^?2, 2.51?×?10^?10, and 1.33?×?10^?13 M. From the kinetic and equilibrium studies, we have shown that the deprotonated form of LNNA is the main form of LNNA that undergoes degradation in aqueous media at room temperature. The rate law of LNNA degradation was found to be first order with respect to OH^? concentration and first order with respect to LNNA^? concentration. The rate constant at 25?°C and 1?atm was determined to be 0.04453 M^?1min^?1. A base catalyzed mechanism of LNNA degradation was proposed based on the kinetic study. The mechanism was found to be very useful in explaining the discrepancies and changes of the rate law at different pH values. It is thus recommended that LNNA should be formulated as a concentrated solution in acidic conditions for maximum chemical stability during storage and be diluted with a basic solution to near physiological pH just before administration.     

Status and prospects for the development of high-precision dilatometry

Translated from Izmeritel'naya Tekhnika, No. 6, pp. 26–27, June, 1989.     

Coupling atomistics and continuum in solids: status, prospects, and challenges

The recent focus of the scientific community on multiscale computer modeling techniques of nano-engineered materials stems from the desire to develop more realistic methodologies that are capable of accurately describing the varied time and length scales associated with this class of materials. Of importance is the ability to model the atomistic region using the appropriate techniques such as quantum mechanics/molecular dynamics, and the continuum region using homogenized properties. The continuity of atomistic and continuum regions in a solid necessitates a seamless coupling between these two regions. This is carried out using a transition region. In view of the large discrepancy between length and time scales in atomistic and continuum regions, the development of the transition region has been the main concern of the research community. It is the purpose of this review to critically discuss the issues concerning the transition region and the efforts made by the scientific community in treating them. In particular, this review addresses issues concerning the coupling of molecular dynamics to finite element modeling techniques. Three aspects of this review are accordingly considered. The first is concerned with the current state of atomistic–continuum coupling techniques in computational mechanics. The second is concerned with present the research conducted in the Engineering Mechanics and Design Laboratory at the University of Toronto in the field of nano-reinforced interfaces. Finally, we present the limitations of the current techniques and suggestions for improvements.     

Explosive Compaction of powders,principle and prospects

The explosive compaction method consisting of a cylindrical container surrounded by a proper type and amount of explosive is an inexpensive method to achieve high densities close to theoretical density. The explosive's parameters have to be adjusted to the type of the powder to be compacted. The required explosive's pressure is linearly related to the Vickers hardness of the metal powder particles. If higher pressures are applied, an “explosive liquid phase sinter” - process can be achieved, allowing the welding of individual particles. The residual properties of the material are characterized by a high defect structure and by dislocation densities and subgrain sizes comparable to those after heavy plastic deformation. The same is true of compacted ceramic powders. Enhanced sinter reactivity, chemical and catalytic reactivity may be the result of high values of stored energy observed in the ceramic materials, shock wave treated under conditions of explosive compaction. The properties of materials produced by shock-wave synthesis or by shock-wave transformation are also determined by a high-density defect structure.     

In vitro digestion kinetics of excipients for lipid-based drug delivery and introduction of a relative lipolysis half life

Background: Lipid-based drug delivery systems are widely used for enhancing the solubility of poorly water soluble drugs in the gastro-intestinal tract. Following oral intake, lipid systems undergo digestion in the stomach as well as the intestine. Lipolysis is here a complex process at the oil/water interface, influenced by numerous factors.

Purpose: To study the digestibility of nine excipients often used in lipid-based drug delivery systems. In addition, we introduced a mathematical model to describe in vitro lipolysis kinetics. A relative lipolysis half life was defined using the reference excipient medium-chain triglycerides.

Methods: Using pH-stat equipment, the NaOH consumption was determined in an in vitro lipolysis assay.

Results: We identified two classes of excipients. Some additives were partially hydrolysed, whereas other excipients displayed complete lipolysis. For the latter class, a simplified mathematical model provided a good first approximation of initial lipolysis kinetics.

Conclusions: Digestion characterization of excipients is important for the development of lipid-based delivery systems. The applied kinetic model and the concept of a relative lipolysis half life seemed to be promising tools for comparing in vitro lipolysis results.     

CNS disorders--current treatment options and the prospects for advanced therapies

The development of new pharmaceutical products has successfully addressed a multitude of disease states; however, new product development for treating disorders of the central nervous system (CNS) has lagged behind other therapeutic areas. This is due to several factors including the complexity of the diseases and the lack of technologies for delivery through the blood-brain barrier (BBB). This article examines the current state of six major CNS disease states: depression, epilepsy, multiple sclerosis (MS), neurodegenerative diseases (specifically Alzheimer's disease [AD]), neuropathic pain, and schizophrenia. Discussion topics include analysis of the biological mechanisms underlying each disease, currently approved products, and available animal models for development of new therapeutic agents. Analysis of currently approved therapies shows that all products depend on the molecular properties of the drug or prodrug to penetrate the BBB. Novel technologies, capable of enhancing BBB permeation, are also discussed relative to improving CNS therapies for these disease states.     

The renaissance of home hemodialysis: where we are, why we got here, what is happening in the United States and elsewhere

Home hemodialysis has been around since 1964, but its use has declined over the years in most countries, this despite its advantages, particularly improved patient survival and quality of life and significant cost savings. Experience has shown that home hemodialysis can be performed successfully by many more patients than at present. Recently, with the demonstration of even better results with more frequent hemodialysis that is obviously best performed at home and with the development of new, more patient-friendly machines, the use of home hemodialysis is beginning to increase again.     

In vitro digestion kinetics of excipients for lipid-based drug delivery and introduction of a relative lipolysis half life

Background: Lipid-based drug delivery systems are widely used for enhancing the solubility of poorly water soluble drugs in the gastro-intestinal tract. Following oral intake, lipid systems undergo digestion in the stomach as well as the intestine. Lipolysis is here a complex process at the oil/water interface, influenced by numerous factors. Purpose: To study the digestibility of nine excipients often used in lipid-based drug delivery systems. In addition, we introduced a mathematical model to describe in vitro lipolysis kinetics. A relative lipolysis half life was defined using the reference excipient medium-chain triglycerides. Methods: Using pH-stat equipment, the NaOH consumption was determined in an in vitro lipolysis assay. Results: We identified two classes of excipients. Some additives were partially hydrolysed, whereas other excipients displayed complete lipolysis. For the latter class, a simplified mathematical model provided a good first approximation of initial lipolysis kinetics. Conclusions: Digestion characterization of excipients is important for the development of lipid-based delivery systems. The applied kinetic model and the concept of a relative lipolysis half life seemed to be promising tools for comparing in vitro lipolysis results.     

设计,从生活开始

我与设计的缘分,源自我的父亲。 童年时代的游戏大部分是在父亲的雕塑工作室里玩捏泥巴,在丛林中采集来的花草树叶及家中的桌椅板凳全部成为了我摆弄造型的对象;有时去窑炉后面捡废弃的陶瓷碎片,挑出一些有漂亮纹样的瓷片收藏起来……     

Life extension technology for steam pipe systems—II. Development of life prediction methodology

Part II of this paper addresses the development of a fracture mechanics based life prediction methodology of steam pipes which operate at elevated temperatures but in the sub-creep temperature range. Elastic-plastic fracture mechanics concepts were employed to establish the remaining life prediction methodology and inspection criteria of steam pipes. Leak-before-break analyses were utilized to determine the flaw inspection criteria. Both tension and bending type loading conditions were considered in the life prediction analysis. The life assessment technology is concerned with the fatigue crack growth life of circumferential cracks in a pipe. The material properties of the A106B steam pipe steel reported in Part I of this paper were used to predict the fatigue life of steam pipes. The effects of operating parameters (e.g. stress and temperature), pipe size, and material properties on the remaining life and inspection intervals of steam pipes can be quantitatively evaluated.     

Long-term observations of lithosphere deformations by the Baksan laser interferometer in underground conditions

The results of six years of continuous observations of deformations (strains) of the Earth’s crust and of the accompanying metrological parameters carried out using a high-precision long-base laser interferometerdeformograph are presented. The position of the laser interferometer in the Baksan neutrino observatory (North Caucasus) in an underground gallery with forced ventilation reveals the specific features of the behavior of the temperature and atmospheric pressure under these conditions.