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.

The effect of routine use of computer-generated preventive reminders in a clinical practice.

Computer-generated reminders for patients and physicians can increase provision of preventive services. On July 1, 1989, the Department of Family Medicine at the Medical University of South Carolina extended a computerized prevention reminder system to all physicians and adult patients in the department's clinical practice. The prevention program consisted of computer-generated physician reminders for any deficiencies in five preventive services at the time of patient visits, a personalized patient reminder letter sent just before a patient's birthday, and educational interventions. We defined adherence using a population-based approach, that is, the percentage of all eligible patients who had received the preventive services within the recommended period of time. The data revealed that the percentage of patients who received preventive services either increased or remained stable during the 12-month study period, which ended July 1, 1990. Adherence was greater for women, for older patients, and for those with Medicare/Medicaid and HMO insurance. We noted higher rates of adherence for all five preventive services, compared with baseline rates of adherence recorded on July 1, 1988. A population-based approach to prevention allows physicians to become more active in providing preventive care to patients. Computer-based reminder and tracking systems can integrate population-based prevention into practice.

Analysis of tricyclic antidepressants in human plasma by GLC--chemical-ionization mass spectrometry with selected ion monitoring.

A method is described for the analysis of amitriptyline, doxepin, imipramine, nortriptyline, desmethyldoxepin, desipramine, and protriptyline in human plasma utlizing GLC-chemical-ionization mass spectrometry with selected ion monitoring. The assay is highly specific and is quantitative to at least 1 ng/ml with a standard error typically less than 5%. Representative concentrations of the parent compounds and their monodemethylated metabolites, as meeasured in plasma samples from patients under treatment with tertiary amine tricyclic antidepressants, are given.

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.

Rapid analysis of naphthalene and its metabolites in biological systems: determination by high-performance liquid chromatography/fluorescence detection and by plasma desorption/chemical ionization mass spectrometry.

A rapid procedure for the determination of naphthalene and its metabolites in bile of rainbow trout and mice is described. The integrated analytical techniques combine high-performance liquid chromatography/ultraviolet fluorescence detection and plasma desorption/chemical ionization mass spectrometry for identification and quantitation. After separation by reverse-phase liquid chromatography, naphthalene and its metabolites are detected and quantitated by ultraviolet fluorescence spectrometry. Identification of two metabolites is confirmed by mass spectrometry. A direct insertion probe tip for a conventional chemical ionization mass spectrometer was modified to obtain spectra of thermally labile compounds. A spectrum of less than 100 ng of naphthyl glucuronide, a labile glucuronic acid conjugate of 1-naphthol, was obtained with this system.

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.)

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.

Family practice educators' perceptions of computer-based patient records.

BACKGROUND: Despite the National Institute of Medicine's endorsement of computer-based patient records (CPRs), the majority of family practice residency programs continue to use paper records. This study examined the perceptions of family medicine educators about CPRs to understand their limited use of computerized patient record systems. METHODS: A survey was mailed to the directors of 247 family practice residency programs; 199 were completed and returned (response rate 81%). Respondents were asked to identify their concerns about CPRs, what they perceived as the advantages and disadvantages of CPRs compared with paper records, and the likelihood that their program will implement a CPR within the next year and within the next 5 years. RESULTS: The perceived benefits of CPR were greater efficiency, accuracy, and quality in patient care. However, many respondents were concerned about cost, mechanical breakdowns, conversion hardships, training needs, and physicians' attitudes. Despite these objections, the majority of respondents reported it is ¿somewhat¿ or ¿very¿ likely that their program will implement a CPR system within the next 5 years. CONCLUSIONS: Although the surveyed family medicine educators believed that CPRs offer significant benefits, they also perceived several disadvantages of converting from paper to computer-based patient records. Widespread use of CPRs among family practice programs in the near future depends on the extent to which vendors and others heighten awareness and knowledge about the benefits of CPRs and address concerns about cost, mechanical breakdowns, and transition difficulties.

Factors associated with the frequency of after-hours in-person patient consultations.

In this study, 901 after-hours calls to 26 second- and third-year family practice residents in a university based program were audited to determine patient and physician characteristics associated with after-hours rates of in-person consultation. In-person consultation frequency averaged 25.5%, but ranged from 9% to 53% among physicians (P = .02). Male patients were seen more frequently than female patients (P = .008) Younger patients were seen more frequently than older patients (P = .01). Calls for trauma, obstetrics, and respiratory complaints were more likely to result in in-person consultations than were calls for other problems (P less than .00001). Categorical modeling analysis, used for adjustment, confirmed differences in consultation frequencies both among physicians and due to the nature of the caller's complaint. Neither the time of the call, the patient's race, nor the physician's sex, marital status, level of training, distance lived from the family practice center, or personality type as measured by the Myers-Briggs Type Indicator were associated with the frequency of consultation. Additional research is needed to determine the factors responsible for physician differences in after-hours in-person consultation frequency.

Implementation and evaluation of a computer-based preventive services system.

BACKGROUND AND OBJECTIVES: Insufficient attention has been paid to the role that modern information systems can play in improving the delivery of and education about preventive services in family medicine training and practice sites. From September 1990-September 1993, the Department of Family Medicine at the Medical University of South Carolina conducted a demonstration project designed to develop, implement, and evaluate a comprehensive, computer-based preventive services delivery and educational system, based on the recommendations in the US Preventive Services Task Force (USPSTF) Report. METHODS: A computer-based patient record (CPR) system was implemented. The system had sophisticated preventive services tracking and reminder, physician, and patient education features. Twenty-nine basic USPSTF recommendations were incorporated in the system. An extensive physician education series was also implemented. A multi-method evaluation system, including patient exit surveys, physician interviews, and practice audits was used to evaluate and design improvements to the CPR and education systems. RESULTS: Although the system initially had no effect on patient perceptions about the frequency of preventive services delivery, there was reasonable concordance between patient desires and physician behavior for the discussion of preventive services (Kappa = .5 to .6). Physician acceptance of the system was good--in 1992, 30% of physicians used the preventive services reminders in most of their patient visits, and in 1993, 88% of physicians reported more frequent use. Practice audits from February 1992-July 1993 showed increased adherence with all seven counseling services, 10 of 15 screening services, and one of five immunization services. CONCLUSIONS: A CPR-based preventive services system coupled with an adaptable physician education about and delivery of preventive services. an ideal solution to improving the education about and delivery of preventive services.

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.

Compliance with five health promotion recommendations in a university-based family practice.

Although numerous recommendations are available to guide the primary care physician's provision of preventive health services, a minority of Americans receive recommended care. This study assessed the extent to which patients in a large, university-based family medicine program were receiving five well-accepted health promotion services. These services included fecal occult blood testing, Papanicolaou smears, mammography, serum cholesterol measurements, and tetanus immunization. Demographic factors associated with receipt of these services were assessed. A minority of active patients received the five health promotion services in the recommended interval: fecal occult blood testing 13%, Papanicolaou smear 41%, mammography 16%, cholesterol measurements 20%, and tetanus immunization 19%. The patient's physician practice group, type of medical insurance, physician visit frequency, and increasing age were associated with compliance with the five studied health promotion services.

Computer-generated physician and patient reminders. Tools to improve population adherence to selected preventive services.

Despite an emerging consensus on appropriate preventive services, a minority of patients receive them. A study was undertaken to assess the impact of computer-generated reminders to adult patients, their physicians, or both patients and physicians on adherence to five recommended preventive services: cholesterol measurements, fecal occult blood testing, mammography, Papanicolaou smears, and tetanus immunization. During the academic year 1988-1989, all 7397 adult patients and their 49 physicians in a university family medicine clinical practice were randomized by practice group into one of four study groups: control, physician reminders, patient reminders, and both physician and patient reminders. Adherence was defined in community-oriented terms: the percentage of patients within each group who had received the preventive service in the recommended interval. During the study period, adherence to four of the five preventive services increased significantly, with the largest increases in the physician and patient reminder group: cholesterol measurements increased from 19.5% to 38.1%, fecal occult blood testing 9.3% to 27.0%, mammography 11.4% to 27.1%, and tetanus immunization 23.4% to 35.4% (for each increase, P less than .0001, McNemar's chi-square test). In general, increases were greater in blacks and in patients with any form of insurance coverage. Computer-based physician and patient reminder systems have great promise of improving adherence to preventive services in primary care settings.

Barriers to adherence to preventive services reminder letters: the patient's perspective.

BACKGROUND: Despite an emerging consensus as to which preventive services are appropriate, a minority of patients receive them. Although adherence to recommendations for some interventions has increased, research studies have shown that adherence rates can be further improved through a better understanding of patient attitudes and motivations regarding preventive services. METHODS: Using components of the Patient Path Model, this study examined the response to patient reminder letters for cholesterol screening sent to 1077 adult patients between August and October 1990. The research strategy incorporated both quantitative and qualitative methods, including a telephone survey and focus group interviews of nonresponders to the reminder letter. RESULTS: Three hundred seven patients were surveyed by telephone to ascertain their reasons for nonresponse. One hundred fifty-four (50.2%) did not recall receiving the reminder letter, 84 (27.4%) recalled receiving the letter but did not recall its content, and 69 (22.5%) recalled both receiving the letter and its content. No consistent reason for nonadherence emerged among the 69 nonresponders who recalled the reminder. Twenty-seven of the nonresponders who did not recall receiving the cholesterol reminder participated in the focus groups. The participants stressed the importance of distinguishing the reminder letter from a bill, conveying a personally relevant message, and addressing logistical barriers to preventive services. CONCLUSIONS: Careful attention to the format and content of patient reminder letters is necessary to improve adherence to preventive services recommendations.

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.

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.