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Papers by Lawrence Mayer

Circulation, 2000

Background —Epidemiological studies suggest a decreased risk of coronary heart disease (CHD) in h... more Background —Epidemiological studies suggest a decreased risk of coronary heart disease (CHD) in healthy women taking hormonal replacement therapy (HRT). Whether this effect is shared by oral and transdermal preparations is unknown. Methods and Results —We conducted a population-based case-control study nested in a cohort of women 50 to 74 years of age without cardiovascular disease history in the United Kingdom. Among 164 769 women from the General Practice Research Database (January 1, 1991, to December 31, 1995), we identified 1242 first acute myocardial infarctions (AMI) and confirmed 1013 after medical record review. We randomly selected 5000 age-frequency–matched control subjects. AMI incidence was 1.6 per 1000 person-years; 13% and 17% of cases and control subjects used HRT within 6 months before the index date. Risk factor and comorbidity–adjusted OR of AMI for current-recent HRT users compared with nonusers was 0.72 (95% CI 0.59 to 0.89). The OR was similar within 30 days be...

Archives of Neurology, 2006

Analytical Methods, 2013

A simple and rapid reversed-phase high performance liquid chromatography method, using resonance ... more A simple and rapid reversed-phase high performance liquid chromatography method, using resonance Rayleigh scattering detection, for the determination of neomycin sulfate in serum samples was developed. Separation was performed on a Synergi Hydro-RP column with water solution which contained 0.18% TFA (v/v) as the mobile phase. Separation variables were optimized and discussed. In acid medium, neomycin sulfate could react with trypan red to form ion-association complexes, there is a stoichiometric ratio of 1:1 between the reaction of the neomycin sulfate with trypan red by Job plot analysis and the molar ratio method. Scanning electron microscopy revealed that these aggregates were spherical gathered particles with an average size of 45 nm, which was in agreement with the theoretical results. The analytical parameters were provided by the system, limit of detection (LOD) of 56 ng mL−1 (3σ), linear correlation of 0.9990 and linear range response from 0.48 to 23.52 μg mL−1. The precision of the method was <4%. Herein we demonstrated a novel method for the determination of neomycin sulfate which obtained satisfactory results.

Molecular Interventions, 2007

C ancer chemotherapy treatments typically employ drug combinations in which the dose of each agen... more C ancer chemotherapy treatments typically employ drug combinations in which the dose of each agent is pushed to the brink of unacceptable toxicity; however, emerging evidence indicates that this approach may not be providing optimal effi cacy due to the manner in which drugs interact. Specifi cally, whereas certain ratios of combined drugs can be synergistic, other ratios of the same agents may be antagonistic, implying that the most effi cacious combinations may be those that utilize certain agents at reduced doses. Advances in nano-scale drug delivery vehicles now enable the translation of in vitro information on synergistic drug ratios into improved anticancer combination therapies in which the desired drug ratio can be controlled and maintained following administration in vivo, so that synergistic effects can be exploited. This "ratiometric" approach to combination chemotherapy opens new opportunities to enhance the effectiveness of existing and future treatment regimens across a spectrum of human diseases.

Journal of Liposome Research, 1990

Cancer research, 1997

Conventional methods that are used to overcome multidrug resistance (MDR) often involve the coadm... more Conventional methods that are used to overcome multidrug resistance (MDR) often involve the coadministration of chemosensitizers and anticancer drugs. The cyclosporin analogue SDZ PSC 833 [(3'-keto-Bmt1)-(Val2)-cyclosporin] (PSC 833) has been shown to possess powerful chemosensitization properties in vitro, in addition to being intrinsically nontoxic. However, coadministration of PSC 833 with anticancer drugs, such as daunorubicin, doxorubicin (DOX), and Taxol, have resulted in the exacerbation of anticancer drug toxicity, which is due to altered anticancer drug pharmacokinetics. Here, we hypothesized that optimization of the anticancer drug delivery, using liposomal carriers, may, by avoiding these adverse interactions, offer a significant advantage over nonencapsulated drugs. Toxicity studies were conducted in normal BDF1 mice, with i.v. DOX (free or liposome encapsulated) administration and p.o. PSC 833 in single and multiple dosage regimens over a 15-day study period. p.o. a...

Journal of Neurosurgery, 1995

✓ Anthracyclines entrapped in small-sized, sterically stabilized liposomes have the advantage of ... more ✓ Anthracyclines entrapped in small-sized, sterically stabilized liposomes have the advantage of long circulation time, reduced systemic toxicity, increased uptake into systemic tumors, and gradual release of their payload. To date, there is no information on the behavior of these liposomes in brain tumors. The objective of this study was to compare the biodistribution and clinical efficacy of free doxorubicin (F-DOX) and stealth liposome—encapsulated DOX (SL-DOX) in a secondary brain tumor model. Nine days after tumor inoculation Fischer rats with a right parietal malignant sarcoma received an intravenous dose of 6 mg/kg of either F-DOX or SL-DOX for evaluation of drug biodistribution. For therapeutic trials a single dose of 8 mg/kg was given 6 or 11 days after tumor induction, or alternatively, weekly doses (5 mg/kg) were given on Days 6,13, and 20. Liposome—encapsulated DOX was slowly cleared from plasma with a t1/2 of 35 hours. Free-DOX maximum tumor drug levels reached a mean v...

Cancer Chemotherapy and Pharmacology, 1998

To establish the pharmacodynamic relationships between drug biodistribution and drug toxicity/eca... more To establish the pharmacodynamic relationships between drug biodistribution and drug toxicity/ecacy, a comprehensive preclinical evaluation of sphingomyelin/cholesterol (SM/chol) liposomal vincristine and unencapsulated vincristine in mice was undertaken. Methods: Pharmaceutically acceptable formulations of unencapsulated vincristine and liposomal vincristine at drug/lipid ratios of 0.05 or 0.10 (wt/wt) were evaluated for toxicity, antitumor activity and pharmacokinetics following intravenous administration. Results: Mice given liposomal vincristine at 2 mg/kg vincristine had concentrations of vincristine in blood and plasma at least two orders of magnitude greater then those achieved after an identical dose of unencapsulated drug. One day after administration of the liposomal vincristine, there were at least tenfold greater drug quantities, relative to unencapsulated vincristine, in the axillary lymph nodes, heart, inguinal lymph nodes, kidney, liver, skin, small intestines and spleen. Increased plasma and tissue exposure to vincristine as a result of encapsulation in SM/chol liposomes was not associated with increased drug toxicities. Treatment of the murine P388 ascitic tumor with a single intravenous dose of unencapsulated drug at 2, 3 and 4 mg/kg, initiated 1 day after tumor cell inoculation, resulted in a 33 to 38% increase in lifespan. In contrast, long-term survival rates of 50% or more were achieved in all groups treated with the SM/chol liposomal vincristine formulations at doses of 2, 3 and 4 mg/kg. At the 4 mg/kg dose, eight of ten and nine of ten animals survived past day 60 when treated with SM/chol liposomal vincristine prepared at the 0.05 and 0.1 drug/lipid ratios, respectively. Conclusions: Overall, increased and prolonged plasma concentrations of vincristine achieved by liposomal encapsulation were correlated with dramatically increased antitumor activity in comparison with the unencapsulated drug, but no correlations could be established between pharmacokinetic parameters and toxicity.

Clinical cancer research : an official journal of the American Association for Cancer Research, 2000

Bcl-2 is a key apoptosis-regulating protein that has been implicated in mechanisms of chemoresist... more Bcl-2 is a key apoptosis-regulating protein that has been implicated in mechanisms of chemoresistance for a variety of malignancies by blocking programmed cell death. This study investigated the activity of the Bcl-2 antisense oligodeoxynucleotide (AS ODN) G3139 combined with free doxorubicin (F-DOX) or sterically stabilized liposomal doxorubicin (SL-DOX) to determine the role that drug pharmacodistribution properties may have on antitumor activity using a Bcl-2-expressing human breast solid tumor xenograft model. Administration of G3139 was able to delay the growth of MDA435/LCC6 cells compared with control ODN-treated animals; however, in all of the cases, tumors reestablished after AS ODN treatment. Western blot analyses of Bcl-2 levels of solid tumors showed a sequence-specific down-regulation of the Bcl-2 protein after four daily doses of G3139, which correlated with histological evidence of tumor cell death. Interestingly, the expression of Bcl-2 returned to pretreatment level...

British Journal of Cancer, 1995

This study reports on the development of a liposomal formulation of vincristine with significantl... more This study reports on the development of a liposomal formulation of vincristine with significantly enhanced stability and biological properties. The in vitro and in vivo pharmacokinetic, tumour delivery and efficacy properties of liposomal vincristine formulations based on sphingomyelin (SM) and cholesterol were compared with liposomes composed of distearoylphosphatidylcholine (DSPC) and cholesterol. SM/cholesterol liposomes had significantly greater in vitro stability than did similar DSPC/cholesterol liposomes. SM/ cholesterol liposomes also had significantly improved biological properties compared with DSPC/cholesterol. Specifically, SM/cholesterol liposomes administered intravenously retained 25% of the entrapped vincristine after 72 h in the circulation, compared with 5% retention in DSPC/cholesterol liposomes. The improved retention properties of SM/cholesterol liposomes resulted in plasma vincristine levels 7-fold higher than in DSPC/cholesterol liposomes. The improved circulation lifetime of vincristine in SM/cholesterol liposomes correlated with increased vincristine accumulation in peritoneal ascitic murine P388 tumours and in subcutaneous solid A431 human xenograft tumours. Increased vincristine delivery to tumours was also accompanied by increased anti-tumour efficacy. Treatment with SM/cholesterol liposomal formulations of vincristine resulted in greater than 50% cures in mice bearing ascitic P388 tumours, an activity that could not be achieved with the DSPC/cholesterol formulation. Similarly, treatment of mice with severe combined immunodeficiency (SCID) bearing solid human A431 xenograft tumours with SM/cholesterol vincristine formulations delayed the time required for 100% increase in tumour mass to >40 days, compared with 5 days, 7 days and 14 days for mice receiving no treatment or treatment with free vincristine or DSPC/cholesterol formulations of vincristine respectively.

Cancer research, 1994

Prolonged exposure to vincristine correlates with improved therapeutic activity. In this work, tw... more Prolonged exposure to vincristine correlates with improved therapeutic activity. In this work, two methods are used to increase the circulation longevity of liposomal formulations of vincristine. The first involves incorporation of the ganglioside GM1, which acts to increase the circulation longevity of liposomal carriers, while the second approach relies on a modification of the vincristine encapsulation procedure which enhances drug retention. It is shown that these approaches are synergistic and increase the circulation half-life of vincristine from approximately 1 h to greater than 12 h. This results in a dramatic improvement in the therapeutic activity of liposomal vincristine as measured using a murine P388 lymphocytic leukemia model. At doses above 2 mg/kg, the optimized liposomal vincristine formulation cures greater than 50% of mice bearing the P388 tumor, whereas free vincristine results in no cures.

Cancer research, 1989

The effects of vesicle size, lipid composition, and drug-to-lipid ratio on the biological activit... more The effects of vesicle size, lipid composition, and drug-to-lipid ratio on the biological activity of liposomal doxorubicin in mice have been investigated using a versatile procedure for encapsulating doxorubicin inside liposomes. In this procedure, vesicles exhibiting transmembrane pH gradients (acidic inside) were employed to achieve drug trapping efficiencies in excess of 98%. Drug-to-lipid ratios as high as 0.3:1 (wt:wt) could be obtained in a manner that is relatively independent of lipid composition and vesicle size. Egg phosphatidylcholine (EPC)/cholesterol (55:45; mol/mol) vesicles sized through filters with a 200-nm pore size and loaded employing transmembrane pH gradients to achieve a doxorubicin-to-lipid ratio of 0.3:1 (wt/wt) increased the LD50 of free drug by approximately twofold. Removing cholesterol or decreasing the drug-to-lipid ratio in EPC/cholesterol preparations led to significant decreases in the LD50 of liposomal doxorubicin whereas, the LD50 increased 4- to ...

Journal of Drug Delivery, 2011

Diblock copolymer nanoparticles encapsulating a paclitaxel prodrug, Propac 7, have been used to d... more Diblock copolymer nanoparticles encapsulating a paclitaxel prodrug, Propac 7, have been used to demonstrate the usefulness of a nonmetabolizable radioactive marker, cholesteryl hexadecyl ether (CHE), to evaluate nanoparticle formulation variables. Since CHE did not exchange out of the nanoparticles, the rate of clearance of the CHE could be used as an indicator of nanoparticle stability in vivo. We simultaneously monitored prodrug circulation and carrier circulation in the plasma and the retention of CHE relative to the retention of prodrug in the plasma was used to distinguish prodrug release from nanoparticle plasma clearance. Nanoparticles labelled with CHE were also used to evaluate accumulation of nanoparticles in the tumour. This marker has provided relevant data which we have applied to optimise our nanoparticle formulations.

Journal of Pharmacology and Experimental Therapeutics, 2002

One of the major obstacles in the development of ligandtargeted liposomes is poor liposome circul... more One of the major obstacles in the development of ligandtargeted liposomes is poor liposome circulation longevity as a result of antibody-mediated elimination of these highly immunogenic carriers. Because studies from our laboratory suggest that it is not possible to reduce the immunogenicity of ligandconjugated liposomes by using surface-grafted poly(ethylene glycol) (PEG), we investigated the usefulness of PEG in protecting hapten-conjugated liposomes from elimination by an existing immune response that was previously established against the hapten. Using biotin as a model hapten, a strong biotinspecific antibody response was generated in mice by using bovine serum albumin-biotin. When these animals were challenged with liposomes containing biotin-conjugated lipid (1 or 0.1%), these liposomes were rapidly eliminated. Incorporation of PEG-lipids into these liposomes substantially reduced biotinspecific antibody binding as measured using an in vitro antibody consumption assay. However, depending on the hapten This study was supported by a grant from the Canadian Institute of Health Research.

Journal of Liposome Research, 1995

Vincristine is a potent therapeutic agent with activity against a variety of tumor types. It is a... more Vincristine is a potent therapeutic agent with activity against a variety of tumor types. It is a cell-cycle specific agent which has exhibited enhanced anti-tumor activity when delivered in liposomal form. Vincristine can be encapsulated into large unilamellar vesicles in response to a transmembrane pH gradient with trapping efficiencies approaching 100%. The extent of vincristine encapsulation, and the subsequent retention of the drug within the liposomes, both in vitro and in vivo, are strongly dependent on the lipid composition of the liposome and on the magnitude of the transmembrane pH gradient. Liposomal formulations of vincristine have been optimized for both liposome circulation longevity, drug retention characteristics and in vivo antitumor activity. When compared to free vincristine, these formulations significantly increase the levels of vincristine remaining in the plasma after i.v. administration. These formulations also significantly increase the delivery of vincristine to tumor sites. As a consequence of the improved accumulation of vincristine at tumor sites, liposomal formulations of vincristine exhibit dramatically improved efficacy against a variety of ascitic and solid murine and human tumors than does free vincristine. Liposomal vincristine is expected to be of wide utility in a variety of human malignancies. INTRODUCTION The encapsulation of several antineoplastic drugs within liposomes has effected significant decreases in drug-induced toxic side effects with maintained or increased anti-tumor activity (1-12). That is, liposomal encapsulation increases the therapeutic index of some 523

Journal of Controlled Release, 2013

Pharmacokinetic modeling and simulation is a powerful tool for the prediction of drug concentrati... more Pharmacokinetic modeling and simulation is a powerful tool for the prediction of drug concentrations in the absence of analytical techniques that allow for direct quantification. The present study applied this modeling approach to determine active drug release from a nanoparticle prodrug formulation. A comparative pharmacokinetic study of a nanoscale micellar docetaxel (DTX) prodrug, Procet 8, and commercial DTX formulation, Taxotere, was conducted in bile duct cannulated rats. The nanoscale (~40 nm) size of the Procet 8 formulation resulted in confinement within the plasma space and high prodrug plasma concentrations. Ex vivo prodrug hydrolysis during plasma sample preparation resulted in unacceptable error that precluded direct measurement of DTX concentrations. Pharmacokinetic modeling of Taxotere and Procet 8 plasma concentrations, and their associated biliary metabolites, allowed for prediction of the DTX concentration profile and DTX bioavailability, and thereby evaluation of Procet 8 metabolism.

Journal of Controlled Release, 2012

Drug nanocarrier clearance by the immune system must be minimized to achieve targeted delivery to... more Drug nanocarrier clearance by the immune system must be minimized to achieve targeted delivery to pathological tissues. There is considerable interest in finding in vitro tests that can predict in vivo clearance outcomes. In this work, we produce nanocarriers with dense PEG layers resulting from block copolymer-directed assembly during rapid precipitation. Nanocarriers are formed using block copolymers with hydrophobic blocks of polystyrene (PS), poly-ε-caprolactone (PCL), poly-D,L-lactide (PLA), or poly-lactide-co-glycolide (PLGA), and hydrophilic blocks of polyethylene glycol (PEG) with molecular weights from 1.5 kg/mol to 9 kg/mol. Nanocarriers with paclitaxel prodrugs are evaluated in vivo in Foxn1 nu mice to determine relative rates of clearance. The amount of nanocarrier in circulation after 4 h varies from 10% to 85% of initial dose, depending on the block copolymer. In vitro complement activation assays are conducted in an effort to correlate the protection of the nanocarrier surface from complement binding and activation and in vivo circulation. Guidelines for optimizing block copolymer structure to maximize circulation of nanocarriers formed by rapid precipitation and directed assembly are proposed, relating to the relative size of the hydrophilic and hydrophobic block, the hydrophobicity of the anchoring block, the absolute size of the PEG block, and polymer crystallinity. The in vitro results distinguish between the poorly circulating PEG 5k-PCL 9k and the better circulating nanocarriers, but could not rank the better circulating nanocarriers in order of circulation time. Analysis of PEG surface packing on monodisperse 200 nm latex spheres indicates that the sizes of the hydrophobic PCL, PS, and PLA blocks are correlated with the PEG blob size, and possibly the clearance from circulation. Suggestions for next step in vitro measurements are made.

International Psychogeriatrics, 2013

ABSTRACTBackground:There is a lack of empirical evidence about the impact of regulations on demen... more ABSTRACTBackground:There is a lack of empirical evidence about the impact of regulations on dementia care quality in assisted living (AL). We examined cohort differences in dementia recognition and treatment indicators between two cohorts of AL residents with dementia, evaluated prior to and following a dementia-related policy modification to more adequately assess memory and behavioral problems.Methods:Cross-sectional comparison of two AL resident cohorts was done (Cohort 1 [evaluated 2001–2003] and Cohort 2 [evaluated 2004–2006]) from the Maryland Assisted Living studies. Initial in-person evaluations of residents with dementia (n = 248) were performed from a random sample of 28 AL facilities in Maryland (physician examination, clinical characteristics, and staff and family recognition of dementia included). Adequacy of dementia workup and treatment was rated by an expert consensus panel.Results:Staff recognition of dementia was better in Cohort 1 than in Cohort 2 (77% vs. 63%, p ...

International Journal of Geriatric Psychiatry, 2008

Objective To estimate the frequency and correlates of insomnia and daytime sleepiness among peopl... more Objective To estimate the frequency and correlates of insomnia and daytime sleepiness among people with dementia in AL facilities. Methods Participants were randomly selected from 22 different assisted living facilities in Maryland. A total of 124 dementia participants were included in the analysis. All participants were rated on an 11-item sleep questionnaire regarding insomnia and daytime sleepiness. Results Sleep disturbance was present in 59.2% of people with dementia. Of the total sample, 21.8% had insomnia only (IN); 21.6% had excessive daytime sleepiness only (DS); and 16.8% had both IN and DS. 40.8% had no sleep disturbance. IN and DS scores were not significantly associated with each other (r ¼ 0.07, p ¼ 0.43). Of those in the IN group, the majority had mild and moderate dementia and of those in the DS only group the majority had severe dementia. Those with IN only performed the best and DS only performed the worst on both cognitive measures (the Mini Mental State Examination) (F ¼ 3.26, p ¼ 0.014), and on physical measures (the physical subscale of the psychogeraitric dependency rating scale) (F ¼ 6.09, p < 0.001). There was no significant difference between the groups on the Cornell scale for depression in dementia. Conclusion The frequency of insomnia and daytime sleepiness in dementia subjects in AL is similar to that found in nursing homes. Daytime sleepiness is associated with poorer cognitive and day-today functioning. Effective management of DS may lead to improved functioning in the AL residents. Insomnia is associated with the best outcomes, even better than those with no sleep disturbance. This finding needs to be replicated.