Emerging therapeutic opportunities for integrin inhibitors.

Integrins are cell adhesion and signalling proteins crucial to a wide range of biological functions. Effective marketed treatments have successfully targeted integrins αIIbß3, α4ß7/α4ß1 and αLß2 for cardiovascular diseases, inflammatory bowel disease/multiple sclerosis and dry eye disease, respectively. Yet, clinical development of others, notably within the RGD-binding subfamily of αv integrins, including αvß3, have faced significant challenges in the fields of cancer, ophthalmology and osteoporosis. New inhibitors of the related integrins αvß6 and αvß1 have recently come to the fore and are being investigated clinically for the treatment of fibrotic diseases, including idiopathic pulmonary fibrosis and nonalcoholic steatohepatitis. The design of integrin drugs may now be at a turning point, with opportunities to learn from previous clinical trials, to explore new modalities and to incorporate new findings in pharmacological and structural biology. This Review intertwines research from biological, clinical and medicinal chemistry disciplines to discuss historical and current RGD-binding integrin drug discovery, with an emphasis on small-molecule inhibitors of the αv integrins.

The rising incidence of idiopathic pulmonary fibrosis in the U.K.

BACKGROUND: Previous studies have shown that the incidence of idiopathic pulmonary fibrosis (IPF) is rising in the U.K. and U.S.A. Death registrations and primary care data were used to determine the current trends in IPF incidence in the U.K. Because routine clinical data sets were used, the term IPF clinical syndrome (IPF-CS) is used to describe individuals in this study. METHODS: Age- and stratum-specific death registration rates between 1968 and 2008 were calculated and these were applied to the 2008 population to generate annual standardised expected number of deaths. Annual mortality rate ratios were calculated using Poisson regression. Computerised primary care records were used to determine incidence rates of IPF-CS between 2000 and 2008 stratified by age, sex and geographical region, and survival rates between calendar periods were compared. RESULTS: Annual death certificate recording of IPF-CS rose sixfold across the study period from 0.92 per 100,000 in the 1968-1972 calendar periods to 5.10 per 100,000 in the 2006-2008 calendar period, and were higher in men and the older age groups. The incidence of IPF-CS in primary care increased by 35% from 2000 to 2008, with an overall incidence rate of 7.44 per 100,000 person-years (95% CI 7.12 to 7.77). Incidence was higher in men, the older population and in Northwest England. CONCLUSIONS: The incidence of IPF-CS in primary care and registered deaths from this cause in the U.K. continues to rise in the 21st century. The current findings suggest that there are >5000 new cases diagnosed each year in the U.K.

Medication prescribing and monitoring errors in primary care: a report from the Practice Partner Research Network.

INTRODUCTION: Medication errors have been associated with poor patient outcomes and pose significant public health consequences. Establishing medication safety quality indicators is crucial to capturing the pervasiveness of preventable errors and is a fundamental first step in the process of improvement. In this article, a study is presented in which a set of medication prescribing and monitoring quality indicators were developed, and adherence to them was assessed among a group of US primary care practices. METHODS: Twenty Practice Partner Research Network practices in 14 US states with 94 clinicians and 52,246 active adult patients participated in the study. All practices use a common electronic medical record with dosing, interaction and monitoring decision support features. A consensus development process was used to select indicators in the categories of inappropriate treatment, dosing, drug-drug and drug-disease interactions, and monitoring of potential adverse events. Data extracted electronically from practices' electronic medical record were used to assess practice-level adherence with the indicator set as of 1 July 2008. RESULTS: Thirty medication safety indicators were selected. Across all practices, inappropriate treatment, dosing, drug-drug and drug-disease interactions were avoided in 75%, 84%, 98% and 86% of eligible patients, respectively; monitoring of preventable adverse drug events occurred in 75% of patients. There was wide variability in practice adherence with the indicators. DISCUSSION: The consensus development process was successful in selecting a broad set of primary care medication safety quality indicators. Although aggregate adherence was relatively high in this group of practices, opportunities exist to improve potential errors in treatment selection, dosing and monitoring.

Pulmonary gene therapy. Realistic hope for the future, or false dawn in the promised land?

Pulmonary gene therapy offers the hope of treatment for conditions such as cystic fibrosis, lung cancer, pulmonary fibrosis and acute respiratory distress syndrome for which current therapy is inadequate. Although initial clinical trials in cystic fibrosis and non-small cell lung cancer have shown promise the results have not been as good as might have been anticipated. However, clinical improvement has been demonstrated in conditions such as haemophilia [82], cardiovascular disease [83], head and neck cancer [84] and X-linked severe combined immunodeficiency disease [85]. The lack of success of pulmonary gene therapy is due, in part on the physical barriers to transfection perfected by the lung to prevent toxicity from inhaled particles, and partly due to the poor transfection efficiency of non-viral systems, and the immunogenicity of viral systems, of gene transfer. The LID vector goes some way to addressing the problems associated with current gene delivery strategies. With continued improvements in the properties of both viral and non-viral gene delivery systems leading to improved transfection efficiency with reduced toxicity, as well as the development of strategies aimed at reducing the physical barriers to pulmonary transfection, and targeting gene delivery systems to the site of injury, it is likely that pulmonary gene therapy will be used successfully to ameliorate a number of devastating pulmonary conditions.

Formation of LID vector complexes in water alters physicochemical properties and enhances pulmonary gene expression in vivo.

There is currently an urgent need to develop efficient gene-delivery systems for the lung that are free of inflammatory effects. The LID vector is a synthetic gene delivery system, comprised of lipofectin (L), an integrin-targeting peptide (I) and DNA (D) that has previously been shown to have high transfection efficiency in the lung. We have assessed the effect of alternative methods of complex preparation on structural features of the complex, levels and duration of reporter gene expression and the host response to the LID vector. We have demonstrated that making the complex in water affects the structure of the LID complexes making them smaller and more stable with a more cationic surface charge than complexes prepared in phosphate-buffered saline (PBS). When the LID vector was constituted in water and instilled intratracheally into the lungs of mice there was a 10-fold increase in luciferase activity compared with preparation in PBS. Furthermore, luciferase activity was still evident 1 week following vector instillation. This enhancement may be because of altered complex structure, although effects of the hypotonic vector solution on the lung cannot be excluded. The inflammatory effects of instilling the LID vector in water were minimal, even after three administrations of the LID vector, with only mild alterations in cytokine and broncho-alveolar lavage fluid (BALF) cell profiles. These results demonstrate that the LID vector can generate high, and prolonged, levels of gene expression in the lung from small quantities of DNA and that careful attention to synthetic polyplex structure may be important to optimize efficiency of gene expression in vivo.

Cyclooxygenase-2 deficiency results in a loss of the anti-proliferative response to transforming growth factor-beta in human fibrotic lung fibroblasts and promotes bleomycin-induced pulmonary fibrosis in mice.

Prostaglandin E(2) (PGE(2)) inhibits fibroblast proliferation and collagen production. Its synthesis by fibroblasts is induced by profibrotic mediators including transforming growth factor (TGF)-beta(1). However, in patients with pulmonary fibrosis, PGE(2) levels are decreased. In this study we examined the effect of TGF-beta(1) on PGE(2) synthesis, proliferation, collagen production, and cyclooxygenase (COX) mRNA levels in fibroblasts derived from fibrotic and nonfibrotic human lung. In addition, we examined the effect of bleomycin-induced pulmonary fibrosis in COX-2-deficient mice. We demonstrate that basal and TGF-beta(1)-induced PGE(2) synthesis is limited in fibroblasts from fibrotic lung. Functionally, this correlates with a loss of the anti-proliferative response to TGF-beta(1). This failure to induce PGE(2) synthesis is because of an inability to up-regulate COX-2 mRNA levels in these fibroblasts. Furthermore, mice deficient in COX-2 exhibit an enhanced response to bleomycin. We conclude that a decreased capacity to up-regulate COX-2 expression and COX-2-derived PGE(2) synthesis in the presence of increasing levels of profibrotic mediators such as TGF-beta(1) may lead to unopposed fibroblast proliferation and collagen synthesis and contribute to the pathogenesis of pulmonary fibrosis.

System supports for chronic illness care and their relationship to clinical outcomes.

The Chronic Care Model proposes that organizational system changes improve the quality of chronic care. This cross-sectional study explores the relationship between system supports for chronic care and clinical outcomes for two major chronic illnesses: diabetes and cardiovascular disease. Nine community-based primary care practices from the Practice Partner Research Network (PPRNet) are studied using practice group interviews and clinical data from the PPRNet database. As overall system support increases, providers' achievement of recommended care and desirable patient outcomes improves (r = .828, p = .006). Enhanced systems for provider decision support had the strongest positive correlation with clinical outcomes (r = .907, p = .001).

Antibiotics and return visits for respiratory illness: a comparison of pooled versus hierarchical statistical methods.

BACKGROUND: Antibiotic prescribing for respiratory illness has been associated with small reductions in return visits in an analysis of a large practice-based network. In this study, we apply hierarchical analytical methods that account for the clustering of patients by practices to identify whether antibiotic prescribing by primary care physicians reduces subsequent visits for 6 acute respiratory illnesses-upper respiratory infection, pharyngitis, bronchitis, otitis media, sinusitis, and cough. METHODS: The study data came from 318 family physicians and internists in 45 practices in the Practice Partner Research Network from January 1995 through December 1996, with 255,564 active patients. Patients treated with antibiotics were compared with those who were not on the frequency of revisit within the next 14 days. A simple pooling model and 3 hierarchical statistical models (fixed-effects, random-effects, and Bayesian) were used to compare the odds-ratios for return visits. RESULTS: Statistically significant results were found only for bronchitis and sinusitis by the hierarchical models, but the simple pooling model produced statistically significant results for all study conditions. CONCLUSION: We conclude that antibiotics may reduce return visits for patients with bronchitis and sinusitis, but not for patients with other respiratory illness (upper respiratory infection, pharyngitis, otitis media, or cough). Studies of large clinical databases should use methods of analysis that account for the grouping of patients by practice to avoid false positive associations (type I errors.)

Preventive services in the primary care practices of the Practice Partner Research Network.

Despite the emphasis of primary care on preventive services over the past decade, and the reminder systems that are available to promote the provision of these services, many patients still do not receive needed services. This study describes the preventive services that the primary care practices of the Practice Partner Research Network (PPRNet) monitors, and documents adherence to them. Preventive services monitored in PPRNet practices and the levels of adherence to them vary by practice and service. The lower-than-desired levels of adherence offer opportunities for improvement interventions.

An integrin-targeted non-viral vector for pulmonary gene therapy.

Gene therapy offers potential for the treatment of severe respiratory diseases. However, the vectors which are currently available have drawbacks limiting their therapeutic application. Here we report on an integrin-targeted, non-viral gene delivery system for pulmonary gene transfer. We demonstrate that this vector can deliver the lacZ reporter gene to the lung, transfecting bronchial epithelium and parenchymal cells with similar efficiency to an adenoviral vector and with greater efficiency than a cationic liposome. In addition, vector administration can be repeated leading to further gene expression without inducing inflammation. The advantages of this novel gene delivery system provide considerable potential for targeted gene therapy in vivo. Gene Therapy (2000) 7, 393-400.

Quality of care for chronic illness in primary care: opportunity for improvement in process and outcome measures.

OBJECTIVE: To describe adherence to a number of quality indicators and clinical outcomes for asthma, diabetes mellitus, hypertension, coronary heart disease, atrial fibrillation, and cerebrovascular disease in the primary care practices of the Practice Partner Research Network (PPRNet). STUDY DESIGN: Cross-sectional epidemiologic design. PATIENTS AND METHODS: PPRNet is a national research network of ambulatory, mostly primary care practices that use the Practice Partner Patient Records electronic medical records. Participating practices send anonymous clinical data on patients to the PPRNet data center monthly. Standard database management and statistical software are used to compile practice reports. These reports include measures of adherence to process and outcome measures for chronic illnesses, the subject of this report. RESULTS: Forty-eight PPRNet practices provided data for the first quarter of 1998. A total of 336,401 patients were active in these practices during this quarter. At least 2000 active patients had each of the conditions studied. Wide variation in guideline adherence among PPRNet practices was present for each of the performance measures. Better performance was present for physical examination measures and laboratory monitoring than for treatment interventions. Overall performance was excellent for blood pressure monitoring, poor for lipid monitoring in patients with CHD, and intermediate for glycosylated hemoglobin monitoring in patients with diabetes mellitus. CONCLUSION: The findings of this study are comparable to others in documenting that most clinical practice guidelines for chronic illness are not followed for a majority of patients and that large majorities do not reach desired clinical outcomes.

Medication cost information in a computer-based patient record system. Impact on prescribing in a family medicine clinical practice.

BACKGROUND: Medications account for 8% of national health care expenditures, and prescription drugs are a focus of cost containment measures. Physicians have limited knowledge about drug costs, and no method of providing this information has demonstrated sustained cost reductions. OBJECTIVE: To determine the impact of cost information in a computer-based patient record system on prescribing by family physicians. METHODS: A yearlong, controlled clinical trial was conducted at the Family Medicine Center, Medical University of South Carolina, Charleston, a group practice staffed by attending physicians and residents. Prescription cost information was included in the computer-based patient record system used at the center. During a 6-month period, cost information was not displayed; during the subsequent 6-month intervention period, costs were displayed at the time of prescribing. An intention-to-treat analysis was used to compare prescription costs between the control and intervention periods for all medications prescribed, and stratified analyses for several medication and physician factors were performed. RESULTS: A total of 22,883 prescriptions were written during the 1-year study period. The mean +/- SD cost per prescription in the control period was $21.83 +/- $27.00 (range, $0.01-$510.00), and in the intervention period was $22.03 +/- $28.12 (range, $0.01-$435.96) (P = .61, Student t test). Increases in mean prescription cost and proportion of total costs were identified in 4 medication classes: antibiotics, cardiovascular agents, headache therapies, and antithrombotic agents. Decreases in mean prescription cost and proportion of total costs were identified in 5 medication classes: nonsteroidal anti-inflammatory drugs, histamine type 2-receptor antagonists and proton pump inhibitors, ophthalmic preparations, vaginal preparations, and otic preparations. CONCLUSIONS: In this setting, the provision of real-time computerized drug cost information did not affect overall prescription drug costs to patients, although differences in individual medication classes were observed. The negative results of this study may reflect confounding due to the use of historical controls, suboptimal timing of the intervention in the prescribing process, susceptibility bias at the study site, or the insensitivity of prescribing habits to cost information.

Treatment of recurrent otitis media after a previous treatment failure. Which antibiotics work best?

BACKGROUND: Recurrent infection after an episode of otitis media is common in pediatric patients. If a patient experienced primary treatment failure in a preceding episode, physicians often feel pressured to prescribe a broad-spectrum, second-line agent for the next episode rather than a first-line drug. The purpose of our study was to determine whether using a second-line drug resulted in fewer treatment failures in a recurrent otitis episode following an episode of apparent resistance. METHODS: The Practice Partner Research Network database, a national research network of practices that use the same electronic medical record, was reviewed to identify all primary episodes of otitis media over a 2-year period (N = 7807). From this, 1416 pediatric patients with presumed treatment failures were identified. The subset of those with a second otitis media episode more than 90 days after the index episode (N = 343) was selected for study. Of this group, 236 (69%) received first-line antibiotics (amoxicillin, ampicillin, penicillin, or sulfamethoxazole-trimethoprim) and the remaining 107 received a broader-spectrum, second-line antibiotic. The primary outcome was the need for an additional antibiotic for otitis media within the next 45 days. RESULTS: Patients receiving first- and second-line antibiotics did not differ in sex or age. However, those receiving second-line antibiotics had a shorter duration between episodes (231 vs 280 days, P = .007). Failure rates for first- and second-line antibiotics in recurrent episodes were not significantly different (13% vs 19%, P = .20). Because the duration between episodes could have affected failure rates, we stratified the time between episodes into short, intermediate, and long duration. Second-line antibiotics were not superior to first-line drugs in any stratum. CONCLUSIONS: For a new otitis media episode in a patient with a previous treatment failure, first-line drugs (amoxicillin, ampicillin, penicillin, or sulfamethoxazole-trimethoprim) are just as effective as broader-spectrum, more expensive, second-line antibiotics.

Resorcylic acid lactones: naturally occurring potent and selective inhibitors of MEK.

A resorcylic acid lactone, L-783,277, isolated from a Phoma sp. (ATCC 74403) which came from the fruitbody of Helvella acetabulum, is a potent and specific inhibitor of MEK (Map kinase kinase). L-783,277 inhibits MEK with an IC50 value of 4 nM. It weakly inhibits Lck and is inactive against Raf, PKA and PKC. L-783,277 is an irreversible inhibitor of MEK and is competitive with respect to ATP. L-783,290, the trans-isomer of L-783,277, was isolated from the same culture and evaluated together with several semi-synthetic resorcylic acid lactone analogs. A preliminary structure-activity relationship is presented. Several independent cell-based assays have been carried out to study the biological activities of these resorcylic acid lactone compounds and a brief result summary from these studies is presented.

Clavaric acid: a triterpenoid inhibitor of farnesyl-protein transferase from Clavariadelphus truncatus.

Farnesyl-protein transferase (FPTase) catalyses the specific transfer of farnesyl to Ras-peptides that is essential for oncogenic activity in oncogene-mediated tumors. Specific inhibition of FPTase activity has been shown to reduce tumor development in nude mice challenged with oncogenic forms of ras, thereby establishing FPTase as a viable therapeutic target. Our continued efforts to discover inhibitors of FPTase has led to the discovery of a triterpenoidal inhibitor, clavaric acid (1). This compound inhibits rHFPTase with an IC50 value of 1.3 microM. Structure elucidation, structure modifications, and biological activity of clavaric acid are herein described.

Electronic medical records as tools for quality improvement in ambulatory practice: theory and a case study.

Information management is critical in today's health care environment. Traditional paper-based medical records are inadequate information management tools. Electronic medical records (EMRs) overcome many problems with paper records and are ideally suited to help physicians increase productivity and improve the quality of care they provide. The Department of Family Medicine at the Medical University of South Carolina uses the Practice Partner Patient Record EMR system. Department members have developed a quality improvement model based on this EMR system. The model has been used to improve care for acute bronchitis, diabetes mellitus, tobacco abuse, asthma, and postmenopausal osteoporosis.

The computer-based patient record as a CQI tool in a family medicine center.

BACKGROUND: In 1994 the Department of Family Medicine (DFM) at the Medical University of South Carolina (MUSC) developed an innovative infrastructure for continuous quality improvement (CQI) which capitalized on its existing computer-based patient record (CPR) system. CQI PROGRAM: The CPR is a key element in all components of the DFM patient care CQI activities. Computerized record reviews, online queries, and special reports provide the background information needed to establish CQI projects and, in some cases, diagnose the cause. Any data entered into the CPR, including progress notes text, is searchable for use by the quality improvement teams. The most compelling aspect of DFM's CPR-based CQI system is the use of quality control charts that are regularly generated by the research division from CPR data. These charts allow the CQI teams to determine whether any changes in the process measurements are due to chance causes or are caused by specific interventions introduced to improve the process. ONGOING IMPROVEMENT PROJECTS: Four ongoing improvement projects that rely on CPR data and use electronically created control charts are discussed--optimizing the treatment of acute bronchitis, improving adherence to practice guidelines for patients with adult onset diabetes mellitus, improving the recognition and treatment of tobacco abuse, and improving blood pressure control in patients with hypertension. Each improvement project has a unique set of goals and objectives, against which the project's success is measured. CONCLUSION: A CPR system can be used to provide fast, organized access to large amounts of patient information to support structured quality improvement activities.