Scope and limitations of the co-drug approach to topical drug delivery.

Many currently available drugs show unfavourable physicochemical properties for delivery into or across the skin and temporary chemical modulation of the penetrant is one option to achieve improved delivery properties. Pro-drugs are chemical derivatives of an active drug which is covalently bonded to an inactive pro-moiety in order to overcome pharmaceutical and pharmacokinetic barriers. A pro-drug relies upon conversion within the body to release the parent active drug (and pro-moiety) to elicit its pharmacological effect. The main drawback of this approach is that the pro-moiety is essentially an unwanted ballast which, when released, can lead to adverse effects. The term 'co-drug' refers to two or more therapeutic compounds active against the same disease bonded via a covalent chemical linkage and it is this approach which is reviewed for the first time in the current article. For topically applied co-drugs, each moiety is liberated in situ, either chemically or enzymatically, once the stratum corneum barrier has been overcome by the co-drug. Advantages include synergistic modulation of the disease process, enhancement of drug delivery and pharmacokinetic properties and the potential to enhance stability by masking of labile functional groups. The amount of published work on co-drugs is limited but the available data suggest the co-drug concept could provide a significant therapeutic improvement in dermatological diseases. However, the applicability of the co-drug approach is subject to strict limitations pertaining mainly to the availability of compatible moieties and physicochemical properties of the overall molecule.

A collaborative clerkship with a focus on rural community health.

The Deans' Rural Primary Care Clerkship was developed through the collaborative efforts of South Carolina's two medical schools. The clerkship provides students an innovative learning experience in rural community medicine through the unique combination of learning opportunities with community-oriented primary care, continuous quality improvement, interdisciplinary health care teams, and cultural competency. Much of students' learning addresses current directives for population health training. The positive experience students are having in these rural, underserved South Carolina communities will help them better understand the rewards and challenges of rural, community-responsive health care.

Insurance status and length of stay for involuntarily hospitalized patients.

General and private psychiatric hospitals are becoming increasingly common as sites for involuntary hospitalization. Unlike the public facilities that these settings are supplanting, these hospitals must pay strict attention to issues associated with reimbursement, insurance status, and managed care. This article examines the effects of insurance status on length of stay for involuntarily hospitalized patients in general and private hospitals in Massachusetts. Using a two-stage sampling procedure, data on episodes of involuntary hospitalization were gathered and assessed using multiple regression. The primary effect was found between patients with Medicare, who had the longest stays, and individuals who were uninsured, who had the shortest. The data raise concerns that warrant closer scrutiny on the part of administrators and clinicians.

Long-stay patients in state psychiatric hospitals at the end of the 20th century.

OBJECTIVES: The purpose of this study was to assess the characteristics of long-stay patients in contemporary state psychiatric hospitals and to identify factors representing possible barriers to alternative placements for these patients. METHODS: All patients in inpatient units of the Massachusetts Department of Mental Health who had been hospitalized for at least three years as of April 1, 1999, were assessed by their treatment teams with a standardized data collection instrument. Domains assessed included medical problems, need for nursing care, psychiatric diagnosis, and history of problematic behaviors. RESULTS: The 330 individuals identified as long-stay patients had an array of medical problems and nursing care needs that likely would have been manageable in other long-term-care settings. A total of 276 patients had at least one significant medical problem. However, some patients exhibited behavioral problems that might have complicated such placements, especially when behavioral problems co-occurred with the need for medical supervision. A total of 228 patients had exhibited a significant problematic behavior in the previous 30 days. CONCLUSIONS: Although the number of long-stay patients in state psychiatric hospitals declined dramatically during the second half of the 20th century, a small group of patients still requires care in this setting. State psychiatric hospitals continue to occupy a significant niche in the mental health system.

A rural service-learning model for health administration education.

Service learning for students in the health professions can best be described as an educational methodology based on the collaboration between an academic discipline and a community agency to link student learning with community-based service. This paper describes a service-learning model in rural and medically underserved communities used in a master in health administration program in a rural Southern state. It presents the process, components, outcomes, and challenges. Over the past five years, 56 students completed 116 experiences involving internships, field projects, or special projects in rural and medically underserved communities. A total of 27 percent of our graduates who completed rural and medically underserved experiences accepted job positions in rural health care entities. Strategies utilized by this rural service-learning model include interdisciplinary team training, partnerships among rural and medically underserved community health care entities and academic institutions, faculty-preceptor retreats, and involvement in local community initiatives. These experiences prepare future health administrators to contribute in a meaningful way toward building an effective rural health care delivery system.

Resistance-modifying agents. 9. Synthesis and biological properties of benzimidazole inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase.

The nuclear enzyme poly(ADP-ribose) polymerase (PARP) facilitates the repair of DNA strand breaks and is implicated in the resistance of cancer cells to certain DNA-damaging agents. Inhibitors of PARP have clinical potential as resistance-modifying agents capable of potentiating radiotherapy and the cytotoxicity of some forms of cancer chemotherapy. The preclinical development of 2-aryl-1H-benzimidazole-4-carboxamides as resistance-modifying agents in cancer chemotherapy is described. 1H-Benzimidazole-4-carboxamides, particularly 2-aryl derivatives, are identified as a class of potent PARP inhibitors. Derivatives of 2-phenyl-1H-benzimidazole-4-carboxamide (23, K(i) = 15 nM), in which the phenyl ring contains substituents, have been synthesized. Many of these derivatives exhibit K(i) values for PARP inhibition < 10 nM, with 2-(4-hydroxymethylphenyl)-1H-benzimidazole-4-carboxamide (78, K(i) = 1.6 nM) being one of the most potent. Insight into structure-activity relationships (SAR) for 2-aryl-1H-benzimidazole-4-carboxamides has been enhanced by studying the complex formed between 2-(3-methoxyphenyl)-1H-benzimidazole-4-carboxamide (44, K(i) = 6 nM) and the catalytic domain of chicken PARP. Important hydrogen-bonding and hydrophobic interactions with the protein have been identified for this inhibitor. 2-(4-Hydroxyphenyl)-1H-benzimidazole-4-carboxamide (45, K(i) = 6 nM) potentiates the cytotoxicity of both temozolomide and topotecan against A2780 cells in vitro (by 2.8- and 2.9-fold, respectively).

Job satisfaction and professional development of health information administration faculty.

To provide seamless care for patients while the health care industry undergoes changes, an integrated health information system must be developed. This effort affects the roles and responsibilities of practitioners and educators in health information administration (HIA). The changes may affect job satisfaction of HIA educators as they prepare entry-level practitioners for emerging roles. A national survey of HIA faculty's job satisfaction used the JDI/JIG scales and a researcher-developed instrument. The survey asked what job, institutional, and individual factors were significantly related to overall job satisfaction, whether there is a relationship between organizational fit and overall job satisfaction, and whether HIA faculty were pursuing terminal degrees, and what incentives and impediments they found to do so. Response rate was 78%. These faculty were very satisfied with their jobs. Work, pay, supervision, and co-workers were significantly related to overall job satisfaction, with work and supervision accounting for 47% of the variance. Doctorally prepared faculty valued research more than did others, and tended to be in institutions perceived to value research. Although 79% reported that their institutions encouraged them to pursue advanced degrees, only 23.6% were pursuing doctorates. These findings may be useful in recruiting HIA practitioners into academia as well as for accreditation purposes.

Impact of an electronic medical record system on community-based primary care practices.

BACKGROUND: Although primary care physicians are increasingly interested in adopting electronic medical record (EMR) systems, few use such systems in practice. This study explores the organizational impact of an EMR system on community-based practices that have overcome the initial barriers and are experienced EMR users. METHODS: Five primary care practices that are members of a national research network participated in this study. Using qualitative methods, including semistructured interviews and observations, we assessed the impact of an EMR system on the work lives of various user groups. RESULTS: Physicians and staff indicated that the EMR system has changed not only how they manage patient records but also how they communicate with each other, provide patient care services, and perform job responsibilities. The EMR is also perceived by its users to have an impact on practice costs. Although in most practices physicians and staff were unaware of actual expenses and cost savings associated with the EMR, those in practices that have eliminated duplicate paper-based systems believe they have realized cost savings. CONCLUSIONS: Several important themes emerged. The organizational context in which the system is implemented is important. Effective leadership, the presence of a system champion, availability of technical training and support, and adequate resources are essential elements to the success of the EMR.

Potentiation of temozolomide and topotecan growth inhibition and cytotoxicity by novel poly(adenosine diphosphoribose) polymerase inhibitors in a panel of human tumor cell lines.

Potent poly(ADP-ribose) polymerase (PARP) inhibitors have been developed that potentiate the cytotoxicity of ionizing radiation and anticancer drugs. The biological effects of two novel PARP inhibitors, NU1025 (8-hydroxy-2-methylquinazolin-4-[3H]one, Ki = 48 nM) and NU1085 [2-(4-hydroxyphenyl)benzamidazole-4-carboxamide, Ki = 6 nM], in combination with temozolomide (TM) or topotecan (TP) have been studied in 12 human tumor cell lines (lung, colon, ovary, and breast cancer). Cells were treated with increasing concentrations of TM or TP +/- NU1025 (50, 200 microM) or NU1085 (10 microM) for 72 h. The potentiation of growth inhibition by NU1025 and NU1085 varied between the cell lines from 1.5- to 4-fold for TM and 1- to 5-fold for TP and was unaffected by p53 status. Clonogenic assays undertaken in two of the cell lines confirmed that the potentiation of growth inhibition reflected the potentiation of cytotoxicity. NU1025 (50 microM) was about as effective as 10 microM NU1085 at potentiating growth inhibition and cytotoxicity, consistent with the relative potencies of the two molecules as PARP inhibitors. Potentiation of cytotoxicity was obtained at concentrations of NU1025 and NU1085 that were not toxic per se; however, NU1085 alone was 3-fold more cytotoxic (LC50 values ranged from 83 to 94 microM) than NU1025 alone (LC50 > 900 microM). These data demonstrate that PARP inhibitors are effective resistance-modifying agents in human tumor cell lines and have provided a comprehensive assessment protocol for the selection of optimum combinations of anticancer drugs, PARP inhibitors, and cell lines for in vivo studies.

Inhibition of cyclin-dependent kinases, GSK-3beta and CK1 by hymenialdisine, a marine sponge constituent.

BACKGROUND: Over 2000 protein kinases regulate cellular functions. Screening for inhibitors of some of these kinases has already yielded some potent and selective compounds with promising potential for the treatment of human diseases. RESULTS: The marine sponge constituent hymenialdisine is a potent inhibitor of cyclin-dependent kinases, glycogen synthase kinase-3beta and casein kinase 1. Hymenialdisine competes with ATP for binding to these kinases. A CDK2-hymenialdisine complex crystal structure shows that three hydrogen bonds link hymenialdisine to the Glu81 and Leu83 residues of CDK2, as observed with other inhibitors. Hymenialdisine inhibits CDK5/p35 in vivo as demonstrated by the lack of phosphorylation/down-regulation of Pak1 kinase in E18 rat cortical neurons, and also inhibits GSK-3 in vivo as shown by the inhibition of MAP-1B phosphorylation. Hymenialdisine also blocks the in vivo phosphorylation of the microtubule-binding protein tau at sites that are hyperphosphorylated by GSK-3 and CDK5/p35 in Alzheimer's disease (cross-reacting with Alzheimer's-specific AT100 antibodies). CONCLUSIONS: The natural product hymenialdisine is a new kinase inhibitor with promising potential applications for treating neurodegenerative disorders.

Students add value to learning organizations: the Medical University of South Carolina experience.

Students bring fresh ideas, knowledge, and perspective to health care organizations. As students learn how to apply the principles and methods of continuous improvement, they help improve both the quality of health care and the organization's way of improving quality.

The outcomes movement and the role of health information managers.

The resounding demand that health care organizations demonstrate their effectiveness in providing quality patient services is being voiced by federal and state governments, managed care organizations, the Joint Commission on Accreditation of Healthcare Organizations, and businesses and insurers purchasing and paying for health care services. The outcomes movement arose in response to these demands and is intended to provide a means for increasing medical effectiveness and reducing costs. The article presents an overview of the outcomes movement and discusses the use of outcomes data, the challenges and issues associated with outcomes assessment, and how health information managers can play a role in facilitating outcomes assessment. It suggests areas of professional development that health information managers may wish to explore.

Facilitating linkage through universal patient identifiers: a difficult endeavor.

The article discusses the creation and use of universal patient identifiers to facilitate the linkage of patient records from all the components of the health care delivery system. The benefits and disadvantages of using a national health identifier that uses the Social Security number are discussed. A number of universal patient identifier proposals are presented to illustrate the complexity of the issue. The article concludes with a discussion of what health information managers can currently do in their own facilities to facilitate access to integrated information.

The impact of technology on the confidentiality of health information.

The article discusses the changes in health care delivery and the advances in computer technology that have resulted in benefits to patient care but also have raised concerns for protecting the confidentiality of health information. Numerous techniques for safeguarding computer information are also presented.

A patent lawyer's perspective.

The principles of patent law are first briefly explained. Particular patent problems which arise from the preparation of new drugs in novel chiral forms are then discussed and illustrated by reference to legal decisions.

High toxin content in the dinoflagellate Gonyaulax excavata in nature.

Measurements of toxin content in motile cells of the marine dinoflagellate Gonyaulax excavata were made during its annual blooms in the Bay of Fundy in 1980 through 1983. Plankton organisms were collected with a 20 micron mesh net, filtered to remove zooplankton, centrifuged and extracted by boiling in 0.1 N HCl. Toxin content was measured by mouse bioassay. The plankton material was dominated by G. excavata, with Scrippsiella trochoidea sometimes co-dominating. Before extraction, G. excavata cells were counted microscopically. Toxin values ranged from 2.7 X 10(-6) to 1.1 X 10(-3) micrograms saxitoxin (STX) equivalents per G. excavata cell. The mean of 32 determinations was 2.1 X 10(-4) micrograms STX equivalents per cell (+/- 0.5 X 10(-4) S.E.), which is four times greater than the maximum toxin content recorded for seven strains of G. excavata from the Bay of Fundy when grown in culture. Results show that G. excavata motile cells can contain high levels of toxins in nature and strongly suggest their toxin content in nature can be much greater than under normal laboratory culture conditions. This implies that toxin level data derived from Gonyaulax cultures should be interpreted with caution. Calculations suggest the toxins are major constituents of wild G. excavata cells, accounting on average for about 4% of the total dry weight.

Heterotrophic growth of the filamentous blue-green alga Plectonema boryanum.

Plectonema boryanum can grow in the dark with ribose, sucrose, mannitol, maltose, glucose, or fructose. Cell doubling times with 10 mM substrate are the following: 5 days with ribose, 6 days with sucrose or mannitol, 10 days with maltose, 12 days with glucose, and 13 days with fructose; with ribose plus 0.1% casamino acids it is 2.5 days. Dark-grown cells appear mophologically similar to light-grown cells. Cells grown in the dark for several years remain pigmented and resume photoautotrophic growth when placed in the light. Dim light (85 lux) increases the growth rate with ribose and with ribose plus casamino acids to nearly twice that of the dark rate. In the moderate light, growth takes place with ribose even in the presence of 1 times 10-5 MDCMU.