Pharmacokinetics of intra-articular betamethasone sodium phosphate and betamethasone acetate and endogenous hydrocortisone suppression in exercising horses.

To the date, no reports exist of the pharmacokinetics (PK) of betamethasone (BTM) sodium phosphate and betamethasone acetate administered intra-articular (IA) into multiple joints in exercising horses. The purpose of the study was to determine the PK of BTM and HYD concentrations in plasma and urine after IA administration of a total of 30 mg BTM. Eight 4 years old Thoroughbred mares were exercised on a treadmill and BTM was administered IA. Plasma and urine BTM and HYD were determined via high performance liquid chromatography spectrometry for 6 weeks. Concentration-time profiles of BTM and HYD in plasma and urine were used to generate PK estimates for non-compartmental analyses and comparisons among times and HYD concentrations. BTM in plasma had greater Tmax (Tmax 0.8 h) vs. urine (Tmax 7.1 h). Urine BTM concentration (ng/mL) and amount (AUClast ; h × ng/mL) were greater than plasma. HYD was suppressed for at least 3 days (<1 ng/mL) for all horses. The time of last quantifiable concentration of BTM (Tlast ; hour) was not significantly different in plasma than urine. Use of highly sensitive HPLC-MS/MS assays enabled early detection and prolonged and consistent determination of BTM in plasma and urine.

Pharmacokinetics of oral ivabradine in healthy cats.

A liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical method for the measurement of the novel heart rate-lowering drug ivabradine and its major metabolite, S-18982, was cross-validated in the plasma of eight healthy cats. Plasma concentrations were then determined after single and repeated oral administration of ivabradine. Individual plasma concentrations versus time from each cat were used in compartmental analysis using the commercially available software WinNonlin. Both ivabradine and S-18982 reached their maximum concentrations of 103.33 and 3.86 ng/mL within 1 h. Following repeated administration, areas under the plasma concentration-time curves for ivabradine and S-18982 did not significantly increase. Two-compartmental and one-compartmental models with first-order input and elimination provided the best fit to the data for ivabradine and S-18982, respectively. Both models were combined to produce a single 4-compartment model characterizing ivabradine and S-18982 pharmacokinetics. The results of this study indicate that repeated oral doses of ivabradine produced plasma drug concentrations suitable for 12-h dosing intervals in healthy cats. Furthermore, the analytical assay and combined ivabradine/S-18982 model provide tools for further evaluation of ivabradine pharmacokinetics and pharmacodynamics in future studies in cats.

An evaluation of the core physical exam in patients with minor peripheral chief complaints.

OBJECTIVE: We sought to determine (1) how often and why emergency medicine resident physicians perform core physical exams in patients with minor peripheral chief complaints (MCCs); and (2) the clinical impact this practice. METHODS: This prospective observational study was conducted at an urban emergency department with a 4 year emergency medicine residency. Charts of all emergency department patients presenting with MCCs in June-September 2003 were reviewed by blinded assistants for documentation of (1) core physical exams; (2) abnormal core physical exam findings; and (3) additional work up, treatment or follow up related to abnormal core physical exam findings. In May-June 2004 all emergency medicine residents were asked how often they perform core physical exams on emergency department patients with MCCs and their motivating factors for this practice. RESULTS: 297 patients met MCC inclusion/exclusion criteria. Among the 591 total cardiac, lung and abdominal exams performed, 8 (1.4%, 95% confidence interval (CI) 0.7% to 2.7%) were abnormal and only 1 (0.1%, 95% CI 0% to 0.1%) finding led to further testing (ECG); none prompted change in treatment or follow up. All 46 eligible emergency medicine residents were evaluated; 72% (33) performed core physical exams in half or more patients with MCCs. Their primary reasons were to screen the underserved emergency department population, the belief that such exams are standard of care, and establishment of physician-patient rapport. CONCLUSIONS: Because they want to screen an underserved population, establish rapport, and meet what they believe is a standard of care, most emergency medicine residents performed core exams on patients with MCCs. Abnormal core physical exam findings are unusual and rarely lead to further testing or change in management.

Non-immunosuppressive FTY720-derivative OSU-2S mediates reactive oxygen species-mediated cytotoxicity in canine B-cell lymphoma.

OSU-2S is a FTY720 (Fingolimod) derivative that lacks immunosuppressive properties but exhibits strong anti-tumour activity in several haematological and solid tumour models. We have recently shown OSU-2S to mediate potent cytotoxicity in human mantle cell lymphoma cell lines and primary cells. We report here the pre-clinical activity of OSU-2S in spontaneous B-cell lymphoma of dogs which shares many characteristics of human lymphoma. OSU-2S mediated apoptosis in canine B-cell lines and primary B-cell lymphoma cells obtained from spontaneous lymphoma bearing dogs. OSU-2S induced reactive oxygen species (ROS) in canine lymphoma cells and inhibition of ROS partially rescued OSU-2S-mediated cell death. These studies provide a rational basis for the use of spontaneous lymphoma in pet dogs as a preclinical large animal model for the development of OSU-2S as small molecule for treating people and dogs with lymphoma.

Influence of OATP1B1 Function on the Disposition of Sorafenib-ß-D-Glucuronide.

The oral multikinase inhibitor sorafenib undergoes extensive UGT1A9-mediated formation of sorafenib-ß-D-glucuronide (SG). Using transporter-deficient mouse models, it was previously established that SG can be extruded into bile by ABCC2 or follow a liver-to-blood shuttling loop via ABCC3-mediated efflux into the systemic circulation, and subsequent uptake in neighboring hepatocytes by OATP1B-type transporters. Here we evaluated the possibility that this unusual process, called hepatocyte hopping, is also operational in humans and can be modulated through pharmacological inhibition. We found that SG transport by OATP1B1 or murine Oatp1b2 was effectively inhibited by rifampin, and that this agent can significantly increase plasma levels of SG in wildtype mice, but not in Oatp1b2-deficient animals. In human subjects receiving sorafenib, rifampin acutely increased the systemic exposure to SG. Our study emphasizes the need to consider hepatic handling of xenobiotic glucuronides in the design of drug-drug interaction studies of agents that undergo extensive phase II conjugation.

Associations of High-Dose Melphalan Pharmacokinetics and Outcomes in the Setting of a Randomized Cryotherapy Trial.

High-dose melphalan followed by autologous stem cell transplantation remains the standard of care for eligible patients with multiple myeloma, but disease response and toxicity, including severe mucositis, varies among patients. Our randomized trial investigated duration of cryotherapy (2 and 6 h) for reduction of mucositis prevalence and severity and explored factors associated with variability in pharmacokinetics and outcomes from melphalan therapy. The results demonstrate that 2-h is at least as effective as 6-h cryotherapy in decreasing severe mucositis. From a population pharmacokinetic model, we identified that fat-free mass, hematocrit, and creatinine clearance were significant covariates, as reported previously. Furthermore, we observed the rs4240803 SLC7A5 polymorphism was significantly associated with pharmacokinetic variability, and pharmacokinetics was associated with both mucositis and neutropenia. However, melphalan exposure was not associated with progression-free or overall survival in our dataset. These findings contribute to ongoing efforts to personalize melphalan dosing in transplant patients.

Tumor antigen ROR1 targeted drug delivery mediated selective leukemic but not normal B-cell cytotoxicity in chronic lymphocytic leukemia.

Selective cytotoxicity to cancer cells without compromising their normal counterparts pose a huge challenge for traditional drug design. Here we developed a tumor antigen-targeted delivery of immunonanoparticle carrying a novel non-immunosuppressive FTY720 derivative OSU-2S with potent cytotoxicity against leukemic B cells. OSU-2S induces activation of protein phosphatase 2A (PP2A), phosphorylation and nuclear translocation of SHP1(S591) and deregulation of multiple cellular processes in chronic lymphocytic leukemia (CLL) resulting in potent cytotoxicity. To preclude OSU-2S-mediated effects on these ubiquitous phosphatases in unintended cells and avoid potential adverse effects, we developed an OSU-2S-targeted delivery of immunonanoparticles (2A2-OSU-2S-ILP), that mediated selective cytotoxicity of CLL but not normal B cells through targeting receptor tyrosine kinase ROR1 expressed in leukemic but not normal B cells. Developing a novel spontaneous CLL mouse model expressing human ROR1 (hROR1) in all leukemic B cells, we demonstrate the therapeutic benefit of enhanced survival with 2A2-OSU-2S-ILP in vivo. The newly developed non-immunosuppressive OSU-2S, its delivery using human CLL directed immunonanoparticles and the novel transgenic (Tg) mouse model of CLL that expresses hROR1 exclusively in leukemic B cell surface are highly innovative and can be applied to CLL and other ROR1+ malignancies including mantle cell lymphoma and acute lymphoblastic leukemia.

Familial segregation of venous thromboembolism.

BACKGROUND: Venous thromboembolism (VTE) is postulated as a complex disease, but the heritability and mode of inheritance are uncertain. OBJECTIVE: To determine if VTE (i) segregates in families; (ii) is attributable to inheritance, shared environment, or both; and (iii) the possible mode of inheritance. PATIENTS AND METHODS: In a family-based study of relatives from 751 probands (60% female) with objectively diagnosed VTE (without cancer), we performed complex segregation analyses corrected for mode of ascertainment, considering age-specific, non-gender- and gender-specific liability classes under Mendelian and non-Mendelian assumptions. We tested 12 models categorized into four model sets: (i) sporadic (assumes no genetic effect); (ii) Mendelian inheritance of a major gene (including dominant, additive, recessive or codominant classes); (iii) mixed model (Mendelian inheritance including the same four classes plus the effect of polygenes); and (iv) non-Mendelian. RESULTS: Among the 16 650 relatives, 753 (48% female) were affected with VTE, of whom 62% were first-degree relatives. The sporadic model was rejected in both non-gender- and gender-specific liability class analyses. Among the remaining gender-specific models, the unrestricted (non-Mendelian) inheritance model was favored with an estimated heritability of 0.52. Among the Mendelian models, the dominant mixed model was preferred, with an estimated heritability and major disease allele frequency of 0.62 and 0.25, respectively, suggesting an effect of several minor genes. CONCLUSION: A multifactorial non-Mendelian inheritance model was favored as the cause for VTE, while a model postulating a purely environmental cause was rejected. VTE is probably a result of multigenic action as well as environmental exposures.

Phenomenology and treatment of psychotic disorders in the psychiatric emergency service.

The emergency evaluation of a psychotic patient calls on all of the skills of the psychiatrist. The immediate control of dangerous behavior takes place at the same time that clinicians evaluate patients for delirium. A screening physical examination, a brief mental status examination, and a high index of suspicion for medical diseases are essential tools in the first few minutes of a patient's stay in the psychiatric emergency service. Drugs of abuse are often part of a patient's presentation. Here, too, the first task is to rule out delirium, particularly from sedative or alcohol withdrawal. As soon as a patient's condition is stabilized, the psychiatrist should review all of the available information, develop a working diagnosis, and initiate definitive treatment of the presumed disorder. With fewer emergency patients being hospitalized and with shorter lengths of hospital stay, these initial decisions acquire increasing significance for patient outcome.

A snapshot of challenges and solutions in cancer drug development and therapy.

Cancer chemotherapy has transitioned from the use of cytotoxic drugs to the era of agents with an apparent selectivity for a cancer-specific target. The past decade has provided evidence that therapy with such agents can be curative in subsets of patients. It is anticipated that incorporation of pharmacological principles for novel therapeutics will result in further refinement of outcome measures as well as the discovery of new treatment modalities for multiple malignant diseases.

Race and ethnicity in cancer therapy: what have we learned?

Racial and ethnic disparities in the pathogenesis of common malignancies and outcomes from treatment remain a major health concern. Factors attributed to these disparities include differences in lifestyle, environment, genetics, and tumor biology. As we strive to personalize cancer therapy, it will be imperative that we understand the relative contributions of each factor so that we may apply this knowledge in choosing the best treatment for each individual, regardless of his or her racial or ethnic heritage.

Erlotinib in African Americans with advanced non-small cell lung cancer: a prospective randomized study with genetic and pharmacokinetic analyses.

Prospective studies on epidermal growth factor receptor (EGFR) inhibitors in African Americans with non-small cell lung cancer (NSCLC) have not previously been performed. In this phase II randomized study, 55 African Americans with NSCLC received 150 mg/day erlotinib or a body weight-adjusted dose with subsequent escalations to the maximum-allowable dose, 200 mg/day, to achieve rash. Erlotinib and OSI-420 exposures were lower than those observed in previous studies, consistent with CYP3A pharmacogenetics implying higher metabolic activity. Tumor genetics showed only two EGFR mutations, EGFR amplification in 17/47 samples, eight KRAS mutations, and five EML4-ALK translocations. Although absence of rash was associated with shorter time to progression (TTP), disease-control rate, TTP, and 1-year survival were not different between the two dose groups, indicating the dose-to-rash strategy failed to increase clinical benefit. Low incidence of toxicity and low erlotinib exposure suggest standardized and maximum-allowable dosing may be suboptimal in African Americans.

Staff training decreases use of seclusion and restraint in an acute psychiatric hospital.

Rates of seclusion and restraint in an urban psychiatric hospital were compared during the 12-month periods before and after implementing the recommendations of a multidisciplinary quality improvement work-group convened to reduce the hospital's use of physical containment. Interventions included a mandatory staff training session on the management of assaultive behavior, weekly discussion items during team meetings for each local ward, and hospital-wide publicity charting the ongoing progress of the effort. Total annual rates of restraint dropped 13.8%. The average duration of restraint per admission decreased 54.6%. Staff injuries were reduced by 18.8% during the study period.

Delayed emergency department presentation in critically ill patients.

OBJECTIVES: To determine the frequency and causes of delayed emergency department presentation in critically ill patients who did not have acute myocardial infarction and to evaluate whether factors such as age, gender, prior medical advice, lack of insurance, or low educational level are associated with delayed presentation. DESIGN: Prospective, descriptive analysis. SETTING: Emergency department and medical intensive care unit of an urban county hospital. PATIENTS: All adult patients admitted from the emergency department to the medical intensive care unit for reasons other than unstable angina, acute myocardial infarction, or stroke over two 9-wk blocks. INTERVENTIONS: Within 72 hrs of intensive care unit admission, patients or their families were interviewed to determine time elapsed between the onset of symptoms and patient emergency department presentation and to elicit reasons for delays in seeking medical treatment. MEASUREMENTS AND MAIN RESULTS: We interviewed 155 of 173 (90%) of eligible patients and found that 58% waited >24 hrs before presenting to the emergency department. The most commonly cited primary reason for delays were beliefs that symptoms were not serious enough for emergency care (31%) and that symptoms would resolve spontaneously (29%). Most (55%) sought medical treatment only at the urging of family members or other advocates. Although variables such as lack of insurance and low educational level were not associated with delayed presentation, male gender and having sought medical advice before presenting to the emergency department were significantly associated with delay (p =.036 for each). CONCLUSIONS: Because of poor understanding of the gravity and natural progression of their symptoms, most critically ill patients waited >24 hrs to present to our emergency department. Education on warning symptom recognition for serious illnesses may be warranted not only for patients themselves but also for family members and caregivers.