Evaluation of the safety of daily administration of capromorelin in cats.

Capromorelin is a ghrelin receptor agonist that is FDA approved for appetite stimulation in dogs. The objective of this study was to evaluate the safety of daily oral administration of capromorelin to cats over a range of doses and for an extended period. Two randomized, controlled studies were conducted: in Study 1, cats (n = 6 per group) received placebo or capromorelin at a dose of 9, 15, 30 or 60 mg/kg once daily for 14 days; and in Study 2, cats received capromorelin at 6 mg/kg (n = 8) or placebo (n = 4) once daily for 91 days. Cats were evaluated using clinical observations and clinical pathology test results for both studies, with the addition of postmortem examination in Study 1 and measurements of growth hormone and insulin-like growth factor 1 in Study 2. Abnormal clinical observations were limited to emesis, hypersalivation, lethargy/depression, head shaking and lip smacking, which occurred more frequently in the capromorelin-treated groups than in the placebo group. There were no clinically relevant differences in clinical pathology test results between the capromorelin and placebo groups in either study.

A Prospective, Randomized, Masked, Placebo-Controlled Clinical Study of Capromorelin in Dogs with Reduced Appetite.

BACKGROUND: Reduced appetite is a common clinical sign in dogs. This study evaluated the effectiveness and safety of capromorelin oral solution, (ENTYCE® , Aratana Therapeutics, Leawood, KS) a new drug that is a ghrelin receptor agonist, for stimulation of appetite in dogs with reduced appetite. HYPOTHESIS/OBJECTIVES: Capromorelin will increase appetite, as measured by the owner's evaluation, over 4 days. An additional objective was to evaluate the safety of capromorelin at the labeled dose. ANIMALS: A total of 244 client-owned dogs reported by owners to be inappetent for at least 2 days were enrolled, with 177 cases in the effectiveness analysis. METHODS: In this prospective, randomized, masked, placebo-controlled study, dogs were treated daily with capromorelin (3 mg/kg) oral solution (n = 121) or placebo oral solution (n = 56). Owners completed an evaluation of appetite at days 0 and 3 ± 1. Success was defined as improvement in appetite at day 3. Safety was evaluated by physical examination, clinical pathology, and monitoring adverse events and owner observations. RESULTS: Capromorelin treatment improved appetite compared to placebo (68.6% and 44.6% treatment successes with 95% CI 59.7, 76.3 and 32.2, 57.8, respectively, P = .008). Mean body weight in capromorelin-treated dogs increased compared to placebo-treated dogs (1.8% with 95% CI 1.3, 2.3, and 0.1% with 95% CI 0.9, 1.1, respectively, P < .001). Adverse reactions occurring in >5% of either group were diarrhea and vomiting. CONCLUSIONS AND CLINICAL IMPORTANCE: Capromorelin oral solution is an effective treatment for stimulation of appetite in dogs and represents the first ghrelin receptor agonist shown to be effective for this indication.

A Prospective, Randomized, Masked, Placebo-Controlled Multisite Clinical Study of Grapiprant, an EP4 Prostaglandin Receptor Antagonist (PRA), in Dogs with Osteoarthritis.

BACKGROUND: This study evaluated the effectiveness and safety of grapiprant for treatment of pain in dogs with osteoarthritis (OA). HYPOTHESIS/OBJECTIVES: Grapiprant will relieve pain as measured by the owner's and veterinarian's evaluation of pain in dogs with OA. Another objective was evaluation of the safety of grapiprant. ANIMALS: Two hundred and eighty-five client-owned dogs with OA were enrolled and treated with grapiprant or placebo with 262 cases (N = 131 in each group) evaluable for the effectiveness analysis. METHODS: In this prospective, randomized, masked, placebo-controlled study dogs were treated daily with grapiprant (2 mg/kg) per OS or placebo. Owners completed an evaluation using the Canine Brief Pain Inventory (CBPI) on days 0, 7, 14, 21, and 28. Success was defined as improvement in the CBPI. Veterinary assessments were made on screening and days 14 and 28. Safety was evaluated by physical examination, evaluation of clinical pathology results, and owner observations. RESULTS: Grapiprant treatment improved pain compared to placebo on day 28 (48.1 and 31.3% treatment successes respectively; P = .0315). The pain interference score (PIS) and pain severity score (PSS) improved in the grapiprant group compared to placebo (P = .0029 and 0.0022, respectively). Veterinary assessments were significantly better in the grapiprant-treated dogs (P = .0086). Grapiprant generally was well tolerated, but a higher percentage of treated dogs (17.02%) had occasional vomiting as compared to the placebo group (6.25%). CONCLUSIONS AND CLINICAL IMPORTANCE: Grapiprant is an effective treatment for alleviation of pain in dogs with OA, and represents a modality of treatment that may be better tolerated than current options.

Carprofen pharmacokinetics in plasma and in control and inflamed canine tissue fluid using in vivo ultrafiltration.

Measurement of unbound drug concentrations at their sites of action is necessary for accurate PK/PD modeling. The objective of this study was to determine the unbound concentration of carprofen in canine interstitial fluid (ISF) using in vivo ultrafiltration and to compare pharmacokinetic parameters of free carprofen concentrations between inflamed and control tissue sites. We hypothesized that active concentrations of carprofen would exhibit different dispositions in ISF between inflamed vs. normal tissues. Bilateral ultrafiltration probes were placed subcutaneously in six healthy Beagle dogs 12 h prior to induction of inflammation. Two milliliters of either 2% carrageenan or saline control was injected subcutaneously at each probe site, 12 h prior to intravenous carprofen (4 mg/kg) administration. Plasma and ISF samples were collected at regular intervals for 72 h, and carprofen concentrations were determined using HPLC. Prostaglandin E2 (PGE2 ) concentrations were quantified in ISF using ELISA. Unbound carprofen concentrations were higher in ISF compared with predicted unbound plasma drug concentrations. Concentrations were not significantly higher in inflamed ISF compared with control ISF. Compartmental modeling was used to generate pharmacokinetic parameter estimates, which were not significantly different between sites. Terminal half-life (T½) was longer in the ISF compared with plasma. PGE2 in ISF decreased following administration of carprofen. In vivo ultrafiltration is a reliable method to determine unbound carprofen in ISF, and that disposition of unbound drug into tissue is much higher than predicted from unbound drug concentration in plasma. However, concentrations and pharmacokinetic parameter estimates are not significantly different in inflamed vs. un-inflamed tissues.

Mold-sensitivity in children with moderate-severe asthma is associated with HLA-DR and HLA-DQ.

BACKGROUND: Several epidemiologic studies in the United States and Europe have linked Alternaria sensitivity to both persistence and severity of asthma. In this study, we examined T cell responses and HLA class II alleles in children with moderate-severe asthma. METHODS: Ninety-six children with moderate-severe asthma were compared to 90 children with mild asthma. HLA class II genotyping was performed to determine HLA allelic frequencies. Th1/Th2 Alternaria-specific T cell cytokine responses were determined by the use of Alternaria-stimulated cultures. HLA class II restriction was examined by inhibition of Alternaria-stimulated lymphoproliferative responses with blocking anti-HLA class II monoclonal antibodies. RESULTS: Children with moderate-severe asthma had significantly increased sensitivities to Aspergillus fumigatus; sensitivities to Alternaria were similar in both moderate-severe and mild asthmatics. The frequency of HLA-DRB1*13 alleles were increased in mold-sensitive moderate-severe asthmatic children. HLA-DRB1*03 tended to be increased in mold-sensitive moderate-severe asthmatics. The frequency of HLA-DQB1*03 alleles was significantly decreased in mold and Alternaria-sensitive moderate-severe asthma. HLA class II blocking monoclonal antibodies demonstrated HLA-DR restriction. Alternaria-stimulated IL-5 and IL-13 synthesis was significantly increased in moderate-severe asthmatics. IL-5 and IL-13 synthesis was significantly increased in Alternaria-stimulated lymphocyte cultures of HLA-DQB1*03- asthmatics compared to HLA-DQB1*03+ asthmatics. CONCLUSIONS: In children with Alternaria-sensitive moderate-severe asthma, there was increased Th2 sensitivity to Alternaria stimulation. This was associated with HLA-DR restriction and with increased frequency of HLA-DRB1*13 and HLA-DRB1*03. There was decreased frequency of HLA-DQB1*03 in Alternaria-sensitive moderate-severe asthma, suggesting HLA-DQB1*03 may be protective of the development of Alternaria-sensitive severe asthma.

Ethnically mismatched cord blood transplants in African Americans: the Saint Louis Cord Blood Bank experience.

BACKGROUND: For ethnic minority patients where a suitably matched BM or peripheral blood donor is frequently unavailable, cord blood offers an opportunity for hematopoietic stem cell transplantation. Focused recruitment of ethnic minorities for cord blood donation has been proposed as the preferred strategy to improve access for minority recipients to cord blood for transplantation. The aim of this study was to evaluate cord blood characteristics for Caucasian and African American donors and the success of ethnically mismatched UC blood transplantation in African American recipients. METHODS: Retrospective data analysis was performed comparing the characteristics of 556 cord blood units from African American and Caucasian donors. The outcomes of 18 African American ethnically mismatched transplant recipients were compared with a paired sample of 18 ethnically matched Caucasian recipients. RESULTS: The fraction of collected units meeting acceptability criteria from African Americans was significantly lower compared with Caucasians (P = <0.0001). Additionally, African Americans had a significantly lower post-processing total nucleated cell count (TNC) compared with Caucasians (P=0.007) but there were no other significant differences in conventionally measured product characteristics. In the transplant analysis, there was no difference in overall survival at 1 year (P=0.85) or time to neutrophil engraftment (P=0.92) between the two patient populations. DISCUSSION: At comparable levels of TNC dose and HLA matching, the use of ethnically mismatched UC blood units as a source for allogeneic unrelated transplant can result in successful transplant outcomes for African American patients.

The multimedia computer for low-literacy patient education: a pilot project of cancer risk perceptions.

OBJECTIVE: Inadequate reading literacy is a major barrier to better educating patients. Despite its high prevalence, practical solutions for detecting and overcoming low literacy in a busy clinical setting remain elusive. In exploring the potential role for the multimedia computer in improving office-based patient education, we compared the accuracy of information captured from audio-computer interviewing of patients with that obtained from subsequent verbal questioning. SETTING: Adult medicine clinic, urban community health center PATIENTS: Convenience sample of patients awaiting clinic appointments (n = 59). Exclusion criteria included obvious psychoneurologic impairment or primary language other than English. INTERVENTION: A multimedia computer presentation that used audio-computer interviewing with localized imagery and voices to elicit responses to 4 questions on prior computer use and cancer risk perceptions. MEASUREMENTS AND MAIN RESULTS: Three patients refused or were unable to interact with the computer at all, and 3 patients required restarting the presentation from the beginning but ultimately completed the computerized survey. Of the 51 evaluable patients (72.5% African-American, 66.7% female, mean age 47.5 [+/- 18.1]), the mean time in the computer presentation was significantly longer with older age and with no prior computer use but did not differ by gender or race. Despite a high proportion of no prior computer use (60.8%), there was a high rate of agreement (88.7% overall) between audio-computer interviewing and subsequent verbal questioning. CONCLUSIONS: Audio-computer interviewing is feasible in this urban community health center. The computer offers a partial solution for overcoming literacy barriers inherent in written patient education materials and provides an efficient means of data collection that can be used to better target patients' educational needs.

Cognitive-affective stress response: effects of individual stress propensity on physiological and psychological indicators of strain.

The purpose of this study was to define further the role of individual stress propensity in physiological arousal and subsequent subjective stress and strain by measuring stress-induced reactivity in a laboratory setting. Individual predisposition to stress is conceptualized as a latent construct, cognitive-affective stress propensity, that is manifested as multiple trait indicators, e.g., negative affectivity, anger-irritability, and negative self-esteem. For 80 undergraduates experimental treatments were two stressors, time pressure and performance feedback. Physiological arousal indices included skin temperature, blood volume, and electromyographic activity. Results provide some support for the hypotheses that this propensity moderates the relationships between stressor and physiological arousal and between physiological arousal and subjective stress and strain.

The computer-based lecture.

Advancing computer technology, cost-containment pressures, and desire to make innovative improvements in medical education argue for moving learning resources to the computer. A reasonable target for such a strategy is the traditional clinical lecture. The purpose of the lecture, the advantages and disadvantages of "live" versus computer-based lectures, and the technical options in computerizing the lecture deserve attention in developing a cost-effective, complementary learning strategy that preserves the teacher-learner relationship. Based on a literature review of the traditional clinical lecture, we build on the strengths of the lecture format and discuss strategies for converting the lecture to a computer-based learning presentation.

Surfactant protein A enhances alveolar macrophage phagocytosis of apoptotic neutrophils.

Surfactant protein A (SP-A) is an innate immune molecule that binds foreign organisms that invade the lungs and targets them for phagocytic clearance by the resident pulmonary phagocyte, the alveolar macrophage (AM). We hypothesized that SP-A binds to and enhances macrophage uptake of other nonself particles, specifically apoptotic polymorphonuclear neutrophils (PMNs). PMNs are recruited into the lungs during inflammation, but as inflammation is resolved, PMNs undergo apoptosis and are phagocytosed by AMs. We determined that SP-A increases AM phagocytosis of apoptotic PMNs 280 +/- 62% above the no protein control value. The increase is dose dependent, and heat-treated SP-A still enhanced uptake, whereas deglycosylated SP-A had significantly diminished ability to enhance phagocytosis. Surfactant protein D also increased phagocytosis of apoptotic PMNs by approximately 125%. However, other proteins that are structurally homologous to SP-A, mannose-binding lectin and complement protein 1q, did not. SP-A enhances phagocytosis via an opsonization-dependent mechanism and binds apoptotic PMNs approximately 4-fold more than viable PMNs. Also, binding of SP-A to apoptotic PMNs does not appear to involve SP-A's lectin domain. These data suggest that the pulmonary collectins SP-A and SP-D facilitate the resolution of inflammation by accelerating apoptotic PMN clearance.

Caregivers' unmet needs for support in caring for functionally impaired elderly persons: a community sample.

Few estimates have been made of the extent to which the needs of caregivers are met. In addition to the inadequate capacity of services, many caregivers lack adequate financial resources, social resources, or other means to access them. Caregivers who provide services to minority or poor elderly may be particularly needy since their care receivers tend to be less healthy and are less likely to use institutional facilities. To address this issue, the authors studied a community sample of 124 caregivers who identified correlates of their perceived unmet caregiver needs and their use of supportive services available for their caregiving. Results indicated that 51.8 percent of women and 67.4 percent of men reported needs for one or more community services that were not met. It was concluded that caregivers who are poor or who required financial assistance are at the highest risk for needing assistance while providing caregiving services. Community services may more effectively target potential needs of caregivers through routine screenings.

Factors influencing use of the prostate-specific antigen screening test in primary care.

OBJECTIVE: To evaluate the use of the prostate-specific antigen (PSA) test and digital rectal examination (DRE) in prostate cancer screening by primary care physicians. STUDY DESIGN: Physician survey and retrospective medical record review. METHODS: We randomly selected and reviewed the medical records of 3 cross-sectional samples of male patients and surveyed their primary care physicians at 1-year intervals. All the physicians practiced in Colorado. The study spanned 3 years, including late 1992, when the American Cancer Society recommended the use of PSA in a prostate cancer screening guideline. RESULTS: We reviewed the medical records of 4772 male patients and surveyed 109 primary care physicians. We found that PSA testing for men aged 50 or older increased significantly from 1992 to 1994, from 24% in 1992 to 35% in 1993 and 40% in 1994 (overall odds ratio, 2.94; P < .05). Over the same time period, the DRE rate remained relatively unchanged (39% in 1992, 41% in 1993, and 36% in 1994). Overall PSA use was positively associated with patient age greater than 59 years, patient non-smoking status, physician "readiness to change cancer screening behavior," private insurance status, and nonsolo practice. Before the release of a prostate cancer screening guideline, participating physicians cited the American Cancer Society as the organization that most influenced their practice with respect to cancer screening. The magnitude of the reported influence of the American Cancer Society was correlated with the subsequent use of PSA in 1994 by primary care physicians after adjustment for change in DRE and baseline PSA rates, although the association did not reach statistical significance in multivariable regression models. CONCLUSIONS: Primary care physicians in Colorado significantly increased their use of the PSA test from 1992 to 1994, during which time the American Cancer Society issued a guideline recommending the use of PSA for prostate cancer screening. The reported influence of the American Cancer Society on cancer screening practices correlated with the subsequent increase in PSA testing.

Urinary symptoms as a predictor for participation in prostate cancer screening among African American men.

BACKGROUND: There are minimal data on the influence of urinary symptoms and participation in prostate cancer screening in African American men. METHODS: This correlational study examined the influence of urinary symptoms on 1) participation in a free prostate cancer screening program and 2) abnormal screening results. The 1,402 African American men in the South Carolina Prostate Cancer Project (SCPCP), mean age of 50 years, completed a survey that included self-reported urinary symptoms, participated in a prostate cancer educational program, and received a free prostate cancer screening consisting of a digital rectal examination (DRE) and prostate-specific antigen (PSA) from their personal physician. RESULTS: One in 5 men reported the presence of urinary symptoms. Over 60% of the 1,402 men participated in the free CaP screening. Among the 852 men who participated in the free prostate cancer screening, 73 (8.6%) had abnormal screening results as classified by abnormal DRE and/or PSA >4.0 ng/ml. Urinary symptoms were significant predictors, both of participation in screening (OR = 1.30, CI = 1.00, 1.70) and of obtaining an abnormal screening result (OR = 1.78, CI = 1.17, 2.72). CONCLUSIONS: Prostate cancer health education needs to include the fact that prostate cancer, in its early stages, has no urinary symptoms.

Physician and patient predictors of health maintenance visits.

BACKGROUND: Because of a strong association between health maintenance visits (HMVs) and cancer screening, knowledge of the predictors of an HMV have implications for screening. OBJECTIVE: To examine the association of an HMV with patient, physician, and practice characteristics in the primary care setting. DESIGN: A statewide study of cancer screening was conducted in Colorado to determine concordance with the National Cancer Institute's guidelines for screening for breast, cervical, prostate, and skin cancer. Medical records form patients were randomly chosen from primary care practices. Predictors of an HMV were determined by fitting a logistic model to baseline data, adjusting for the cluster sampling of patients within practices. SETTING: Nonacademic primary care practices in Colorado. PARTICIPANTS: A total of 5746 patients aged 42 to 74 years from 132 primary care practices. MAIN OUTCOME MEASURE: Whether a patient had an HMV in the previous year. RESULTS: Of all patients, 31% had an HMV in the previous year. Patient characteristics associated with having HMVs included nonsmoking status, odds ratio (OR) (95% confidence interval [CI]) of 1.27 (1.11-1.46), age, and sex. Women aged 50 to 69 years were significantly more likely to have an HMV than men aged 50 to 69 years (OR, 1.30; 95% CI, 1.10-1.54). Among adults aged 70 years and older, there were no significant sex differences in receiving HMVs. Physician and practice characteristics associated with providing HMVs included practice size (> or = 3 full-time physicians) (OR, 1.34; 95% CI, 1.01-1.77), physician contemplation of changing approaches to cancer screening (OR, 1.33; 95% CI, 1.04-1.70), and physician female sex (OR, 1.33; 95% CI, 1.04-1.70). Physician age and specialty (general internist or family physician) were not associated with the level of health maintenance delivery. CONCLUSION: Certain subgroups, such as smokers, patients in smaller practices, and physicians not yet considering changing their approach to cancer screening, could be targeted in future intervention studies designed to provide preventive services in primary care settings.

Carcinoma of the bladder in renal transplant patients. A case report and collective review of cases.

Bladder malignancy in the renal transplant recipient is an infrequent occurrence. The 11 previously reported cases reflect an aggressive tumor growth with invasion, requiring partial or complete cystectomy with or without conduit diversion. We report an additional case in a 40-yr-old woman with a living related renal transplant, who experienced rapid progression of her tumor over 3 wk from initial hematuria to a pelvic mass involving the anterior bladder. Her allograft ureter and native ureters, as well as her left iliac vein, became obstructed with tumor in another 2 wk. Biopsy showed poorly differentiated, invasive transitional carcinoma. Attempted resection was abandoned because of finding tumor involvement in most of the pelvis. Chemotherapy was not attempted. She died 2 wk after her attempted resection from tumor burden. Our report presents a collective review of these previously reported 11 cases plus our case. These bladder tumors demonstrate a rapid progression of invasive disease and respond poorly to chemotherapy. There is a possible association of bladder tumors with cyclophosphamide immunosuppression. An aggressive surgical approach should be followed, especially since these tumors present in a younger age group.

Clinic-based interventions to promote breast and cervical cancer screening.

BACKGROUND: Breast and cervical cancer continue to claim the lives of women. Early detection modalities for these cancers are available; however, utilization rates are far from optimal. Studies have documented the motivating effect that physician recommendations have on compliance with preventive health behaviors. The goal of this study was to develop and implement strategies to improve the use of cervical and breast cancer screening among African-American women age 40 and older who resided in low-income housing communities. METHODS: Baseline surveys among clinic providers and a random sample of women in the target population indicated areas to be included in intervention material. Community health center-based strategies included educational interventions for providers and patients, follow-up interventions for abnormal screening tests, and the implementation of a computer tracking system. Pap smear and mammogram utilization rates at the health center were tracked throughout the project period to assess the effect of the clinic-based interventions. RESULTS: Both Pap smear and mammography rates increased over time. Fifteen cases of breast cancer and 1 case of invasive cervical cancer have been detected. Compliance rates for follow-up for cervical dysplasia have increased from 50 to 90%. CONCLUSIONS: These results suggest that clinic-based interventions can improve the use of breast and cervical cancer screening and follow-up among low-income women.

Does withdrawal of antihypertensive medication increase the risk of cardiovascular events? Trial of Nonpharmacologic Interventions in the Elderly (TONE) Cooperative Research Group.

The Fifth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure recommends that attempts to discontinue antihypertensive drug therapy be considered after blood pressure (BP) has been controlled for 1 year. However, discontinuation of drug therapy could unmask underlying conditions and precipitate clinical cardiovascular events. The Trial of Nonpharmacologic Interventions in the Elderly (TONE) was a clinical trial of the efficacy of weight loss and/or sodium reduction in controlling BP after withdrawal of drug therapy in patients with a BP< 145/85 mm Hg on 1 antihypertensive medication. Of 975 participants, 886 entered the drug withdrawal phase of the trial and 774 were successfully withdrawn from their medications. Thirty-three events (stroke, transient ischemic attack, myocardial infarction, arrhythmia, congestive heart failure, angina, other) occurred between randomization and the onset of drug withdrawal (median time 3.6 months), 57 events occurred either during or after drug withdrawal (14.0 months), and 36 events occurred after resumption of antihypertensive therapy (15.9 months). Event rates per 100 person-years were 5.5, 5.5, and 6.8 for the 3 time periods (p=0.84) in the nonoverweight group and 7.2, 5.2, and 5.6 (p=0.08) in the overweight group. The study shows that antihypertensive medication can be safely withdrawn in older persons without clinical evidence of cardiovascular disease who do not have diastolic pressure > or = 150/90 mm Hg at withdrawal, providing that good BP control can be maintained with nonpharmacologic therapy.

Physicians in training as quality managers: survival strategy for academic health centers.

Being responsible for medical education places academic health centers at a disadvantage in competing for managed care contracts. Although many suggestions have been made for changing medical education to produce physicians who are better prepared for the managed care environment, few studies have shown how physicians in training can actually contribute to the competitiveness of an academic health center. We present three examples of engaging trainees in projects with a population-based perspective that demonstrate how quality improvement for the academic health center can be operationalized and even led by physicians in training. In addition to gaining experience in a managed care skill that is increasingly important for future employment, physicians in training can simultaneously improve the quality of care delivered through the academic health center.