Lawrence Mayer

In vivo maintenance of synergistic cytarabine:daunorubicin ratios greatly enhances therapeutic efficacy

We demonstrate here that cytarabine and daunorubicin, a standard drug combination used in the treatment of leukaemia, exhibits drug ratio-dependent synergistic antitumor activity in vitro and in vivo. A cytarabine:daunorubicin molar ratio of 5:1 displayed the greatest degree of synergy and minimum antagonism in a panel of 15 tumor cell lines in vitro. Co-encapsulating cytarabine and daunorubicin inside liposomes maintained the synergistic drug ratio in plasma for 24h post-injection. Liposome-encapsulated cytarabine:daunorubicin combinations exhibited drug ratio-dependent in vivo efficacy with the 5:1 molar drug ratio (designated CPX-351) having the greatest therapeutic index, despite using sub-MTD daunorubicin doses. CPX-351 exhibited superior therapeutic activity compared to free-drug cocktails, with high proportions of long-term survivors, consistent with in vivo synergy. The therapeutic advantage of CPX-351 was associated with prolonged maintenance of synergistic drug ratios in bone marrow. These results indicate that in vitro informatics on cytarabine:daunorubicin cytotoxicity can be translated in vivo to optimize the efficacy of anticancer drug combinations by controlling the exposure of drug ratios with drug delivery vehicles.

Surface-associated serum proteins inhibit the uptake of phosphatidylserine and poly(ethylene glycol) liposomes by mouse macrophages.

Serum proteins, acting as opsonins, are believed to contribute significantly to liposome-macrophage cell association and thus regulate liposome uptake by cells of the mononuclear phagocytic system (MPS). We studied the effect of serum protein on binding and uptake of phosphatidylglycerol-, phosphatidylserine-, cardiolipin-, and N,N-dioleyl-N,N-dimethylammonium chloride- (DODAC) containing as well as poly(ethylene glycol)- (PEG) containing liposomes by mouse bone marrow macrophages in vitro. Consistent with the postulated surface-shielding properties of PEG, protein-free uptake of liposomes containing 5 mol% PEG and either 20 mol% anionic phosphatidylserine or 20 mol% cationic DODAC was equivalent to uptake of neutral liposomes. In contrast to previous reports indicating that protein adsorption to liposomes increases uptake by macrophages, the presence of bound serum protein did not increase the uptake of these liposomes by cultured macrophages. Rather, we found that pre-incubating liposomes with serum reduced the uptake of liposomes containing phosphatidylserine. Surprisingly, serum treatment of PEG-containing liposomes also significantly reduced liposome uptake by macrophages. It is postulated that, in the case of phosphatidylserine liposomes, the bound serum protein can provide a non-specific surface-shielding property that reduces the charge-mediated interactions between liposomes and bone marrow macrophage cells. In addition, incubation of PEG-bearing liposomes with serum can result in a change in the properties of the PEG, resulting in a surface that is better protected against interactions with cells.

Modeling residential demand for natural gas as a function of the coldness of the month

Abstract A simple two-parameter model of the monthly demand for natural gas for space heating is developed. First, a simple indicator of the coldness of the month labeled “modified degree days” is presented. Both aggregate monthly demand and monthly demand for a single unit are modeled as a function of this indicator. The model has two parameters, a reference temperature which reflects the internal temperature and free heat contribution and a slope parameter which reflects the thermal behavior of the dwelling. Variation in these two parameters is related to characteristics of the dwelling. Finally, the effect of the onset of the energy crisis on the two parameters is assessed.

Optimizing Liposomal Cisplatin Efficacy through Membrane Composition Manipulations.

The first liposomal formulation of cisplatin to be evaluated clinically was SPI-077. Although the formulation demonstrated enhanced cisplatin tumor accumulation in preclinical models it did not enhance clinical efficacy, possibly due to limited cisplatin release from the formulation localized within the tumor. We have examined a series of liposomal formulations to address the in vivo relationship between cisplatin release rate and formulation efficacy in the P388 murine leukemia model. The base formulation of phosphatidylcholine: phosphatidylglycerol: cholesterol was altered in the C18 and C16 phospholipid content to influence membrane fluidity and thereby impacting drug circulation lifetime and drug retention. Phase transition temperatures (Tm) ranged from 42–55°C. The high Tm formulations demonstrated enhanced drug retention properties accompanied by low antitumor activity while the lowest Tm formulations released the drug too rapidly in the plasma, limiting drug delivery to the tumor which also resulted in low antitumor activity. A formulation composed of DSPC : DPPC : DSPG : Chol; (35 : 35 : 20 : 10) with an intermediate drug release rate and a cisplatin plasma half-life of 8.3 hours showed the greatest antitumor activity. This manuscript highlights the critical role that drug release rates play in the design of an optimized drug delivery vehicle.

Estimation of standardized regression coefficients

Abstract Often in reporting the results of a regression analysis, researchers, particularly in the social sciences, choose to standardize the estimators of the regression coefficients into what are called “beta coefficients.” Most studies in which beta coefficients are reported involve linear models which contain stochastic predictor variables. However, in dealing with regression models in which thep redictor variables are nonstochastic, standardized regression coefficients can be defined which are analogous to those found in the models with stochastic predictor variables. We consider the problem of estimating these parameters. Several estimators are introduced and their properties are discussed. Two data examples are included to demonstrate the empirical behavior of the various estimators.

Estimating the effects of the onset of the energy crisis on residential energy demand

Abstract The onset of the energy crisis as indicated by the start of the Arab oil embargo gave both the private and public sector incentive to reduce the domestic demand for natural gas and oil. Through several mechanisms the residential consumer was encouraged to reduce the demand for energy in the home. We examine a community of almost-identical owner-occupied townhouses to assess the degree to which these mechanisms were effective. The homogeneity of the community removes many sources of variation which would plague an analysis of a random sample of American homes. The demand for natural gas, a fuel which is used only for space heating in our townhouses, was reduced significantly but the demand for electricity was unaffected by the onset of the crisis.

The Development of Liposomes for Enhanced Delivery of Chemotherapeutics to Tumors

Liposomes were first discovered in the 1960s by Bangham, who observed that ordered spherical membranes spontaneously formed when dried lipids were hydrated into aqueous solutions (1). The potential utility of these carrier systems for the delivery of therapeutic agents to disease sites has continually evolved since this initial observation. In order for liposomes to be considered as a viable pharmaceutical-delivery system, many issues needed to be resolved including efficient drug encapsulation, liposome stability, and the production of homogeneous liposome populations. These obstacles were overcome in the 1980s with the development of various liposome-production procedures including extrusion (2), dialysis (3), homogenization (4), and dehydration/rehydration techniques (5). Currently, the most commonly used process is extrusion due to its ease of usage, simplicity, speed, and reproducibility.

Passive and semi-active targeting of bone marrow and leukemia cells using anionic low cholesterol liposomes

Abstract Historically, the use of liposomes to enhance delivery of anticancer agents to cancer cells has focused primarily on solid tumors, which are characterized by rapid angiogenesis resulting in a poorly formed hypervasculature with abnormal vessel walls. The leaky vasculature in combination with poor lymphatic drainage has been demonstrated to lead to the accumulation of liposomes via the enhanced permeation and retention effect. However, only very limited information exists on the disposition of such delivery systems in the bone marrow compartment, the primary site of tumor cell origination and growth for many hematological malignancies. In this review we discuss the biological properties of anionic low-cholesterol liposome formulations and their potential for passively accumulating within the bone marrow and being selectively engulfed by leukemia cells compared to normal bone marrow cells. The therapeutic implications for preferential bone marrow delivery as well as the potential routes for the internalization of drug-encapsulated liposomes into cells in the absence of a targeting ligand are reviewed.

The effect of price on the residential demand for electricity: A statistical study

The statistics of the demand for electricity and the relationship between the price of electricity and the demand are examined through analysis of the monthly consumption statistics of a community of owner-occupied, almost identical townhouses. The average yearly demand for electricity grew from 1971 until 1973 and then decreased by less than 2% a year for the next three years. In spite of price increases, demand for electricity during the heating season (the units are heated by a forced-air natural gas furnace) increased steadily but slightly over the six years of observation. A simple statistical model is used to split the cooling season demand for electricity into air-conditioner demand and the demand for lights and appliances. The non-cooling portion of the demand decreased from 1974 to 1975, but otherwise increased each year from 1971 to 1976. The portion of the demand that we estimate is used for cooling appears to have increased between 1971 and 1974 and then decreased between 1974 and 1976. The evolution of the electricity-rate schedule for this community is considered and then two simple statistical models, which relate demand to price, are estimated. These indicate that, although the marginal price has doubled (in current dollars), these changes in price have had little effect on demand.

The Use of Exploratory Methods in Ecomonic Analysis: Analyzing Residential Energy Demand

Publisher Summary Exploratory data analysis is a set of methods designed to examine and describe the structure of data. The exploratory approach, or mode, involves the use of descriptive techniques and the intuition of the analyst to investigate the structure of data. Unlike the confirmatory approach, or mode, which relies on classical statistical analysis and data to confirm and reformulate theory through the vehicles of parameter estimation and hypothesis testing, the exploratory mode uses data to suggest theory through the vehicle of informal data examination. In some sense, it can be considered a prelude to classical statistical analysis. It is suggested that the exploratory mode is an important supplement to the confirmatory mode for the analysis of economic phenomena in areas, such as residential energy demand, in which the degree of prior belief in the available empirical theory or the quality and comprehensiveness of the available data may not be sufficient to allow adoption of the strong axiomatic structures associated with most classical statistical techniques.