Combination therapy enhances the inhibition of tumor growth with the fully human anti-type 1 insulin-like growth factor receptor monoclonal antibody CP-751,871.

PURPOSE: The insulin-like growth factor (IGF) signaling pathway is implicated in cellular mitogenesis, angiogenesis, tumor cell survival, and tumorigenesis. Inhibition of this pathway results in decreased cell growth, inhibition of tumor formation in animal models, and increased apoptosis in cells treated with cytotoxic chemotherapy. We generated and characterized a human monoclonal antibody that targeted the IGF receptor. EXPERIMENTAL DESIGN: By use of XenoMouse technology, we generated CP-751,871, a fully human IgG2 antibody with high affinity (K(d) = 1.5 nmol/L) for human IGF-1R and evaluated its biological, pharmacologic, and antitumor properties. RESULTS: This antibody blocks binding of IGF-1 to its receptor (IC(50) 1.8 nmol/L), IGF-1-induced receptor autophosphorylation (IC(50) 0.42 nmol/L) and induced the down-regulation of IGF-1R in vitro and in tumor xenografts. The extent of IGF-1R down-regulation in vivo was proportional to CP-751,871 concentrations in the serum of tumor-bearing mice. Pharmacokinetic profiles in cynomolgus monkeys indicated a close to linear increase of exposure following i.v. dosing of antibody in the range of 3 to 100 mg/kg. CP-751,871 showed significant antitumor activity both as a single agent and in combination with Adriamycin, 5-fluorouracil, or tamoxifen in multiple tumor models. A biomarker assay was developed to establish the relationship between circulating antibody concentrations and down-regulation of IGF-1R in peripheral blood cells. The concentration of CP-751,871 required to down-regulate 50% of IGF-1R on peripheral blood cells was 0.3 nmol/L. CONCLUSION: These data suggest that inhibition of the IGF cascade by use of this monoclonal antibody may be of clinical benefit in the treatment of human cancers.

The biological and biochemical effects of CP-654577, a selective erbB2 kinase inhibitor, on human breast cancer cells.

Aberrant expression or activity of epidermal growth factor receptor (EGFr) or the closely related p185(erbB2) can promote cell proliferation and survival and thereby contribute to tumorigenesis. Specific antibodies and low molecular-weight tyrosine kinase inhibitors of both proteins are in clinical trials for cancer treatment. CP-654577 is a potent inhibitor selective for p185(erbB2), relative to EGFr tyrosine kinase, and selectively reduces erbB2 autophosphorylation in intact cells. Treatment of SKBr3 human breast cancer cells with CP-654577 reduces the levels of the activated form of mitogen-activated protein kinase, increases the levels of cyclin-dependent kinase inhibitor p27(kip1) and reduces expression of cyclins D and E. These biochemical changes result in a reduced level of phosphorylated retinoblastoma protein and an inhibition of cell-cycle progression at G(1). Apoptosis is triggered in both SKBr3 and another high erbB2-expressing cell line, BT474, by exposure to 1 micro M CP-654577, but this effect is not observed in MCF7 cells that express low erbB2. Levels of activated Akt, an important positive regulator of cell survival, are reduced within 2 h of exposure to 250 nM CP-654577, and this may contribute to the increased apoptosis. These biochemical effects are distinct from those produced by Tarceva, a selective EGFr inhibitor. The antitumor activity of CP-654577 was investigated in athymic mice bearing s.c. tumors from Fischer rat embryo fibroblasts transfected with erbB2. CP-654577 produced a dose-dependent reduction of p185(erbB2) autophosphorylation and inhibited the growth of these tumors. CP-654577 warrants further evaluation in tumors with high expression of p185(erbB2) and may differ from selective EGFr inhibitors or nonselective dual EGFr/erbB2 inhibitors in efficacy and therapeutic index.

Prospective randomized trial of heliox-driven continuous nebulizers in the treatment of asthma in the emergency department.

The purpose of this study was to evaluate the efficacy of heliox-driven continuous nebulizers in the management of moderate to severe asthma exacerbations in the Emergency Department (ED). The trial was a prospective, randomized, double-blind, controlled trial in a university Emergency Department (volume 65,000 patients/year) of patients 18-55 years of age with acute asthma exacerbations. Patients were placed on continuous nebulizers driven by 70:30 heliox or air with 30% O(2). Respiratory rate, peak expiratory flow rate (PEFR), forced expiratory volume at 1 s (FEV1), and Borg dyspnea scale were measured at 0 and 2 h. Disposition and patient satisfaction were also assessed. A total of 36 patients completed the study (18 heliox, 18 air). There was no difference between groups in baseline variables. There was significant interval improvement within both groups at 2 h in PEFR, FEV1, Borg, and respiratory rate. There was no significant difference between heliox 70:30 and air/oxygen in PEFR [mean between-group improvement difference 17 liters/min, 95% confidence interval (CI) -20-51], FEV1 (0.03 liters/sec, 95% CI -0.22-0.30), or respiratory rate (mean between-group improvement difference 0.5, 95% CI -2.7-3.8). There was a significant improvement in the patients' perceived dyspnea as measured by the Borg dyspnea scale at 2 h in the heliox group (1.6, 95% CI 0.3-3.0). In this trial of patients with moderate-severe asthma exacerbation, heliox-driven continuous nebulizers failed to demonstrate an improvement in respiratory rate, oxygen saturation, PEFR, or FEV1 at 2 h. However, there was a significant improvement in the patients' perceived dyspnea on heliox over air/oxygen measured by the Borg dyspnea scale.

Heparin-induced thrombocytopenia--recognition and treatment.

Heparin, an important agent for the prophylaxis and treatment of venous and arterial thromboembolism, also can cause heparin-induced thrombocytopenia (HIT). This medication-induced immune-mediated syndrome is characterized by thrombocytopenia and life- or limb-threatening thrombotic events. The initial presentation of HIT is a decrease in platelet count with or without thrombosis. Heparin-induced thrombocytopenia frequently is overlooked in hospital settings, and it must be distinguished from other causes of thrombocytopenia. New therapies include the use of direct thrombin inhibitors argatroban and hirudin.

Sex differences in analgesia: a randomized trial of mu versus kappa opioid agonists.

OBJECTIVES: We sought to evaluate whether there is a sex difference in the analgesic response to mu versus kappa opioids in the management of acute moderate to severe pain of injury in the emergency department. METHODS: The study was a randomized, double-blind, clinical trial comparing the prototypical mu-receptor agonist, morphine sulfate, to the prototypical kappa agonist, butorphanol. The primary endpoints were degree of relief by visual analog scores at 30 and 60 minutes. Statistical analysis was performed using Mann-Whitney Utest for nonparametric analysis and repeated-measures analysis of variance. RESULTS: Ninety-four patients were entered in the study, with 49 (52%) males and 45 (48%) females. Forty-six received morphine sulfate and 48 received butorphanol. There was no difference in demographics in the two groups. At 60 minutes, females had significantly lower visual analog scores with butorphanol compared with morphine (P = 0.046). At 60 minutes, there was a trend for a difference in response of males versus females to morphine, with males responding better than females (P = 0.06). CONCLUSION: Females had better pain scores with butorphanol than morphine at 60 minutes.

Warmed versus room temperature saline for laceration irrigation: a randomized clinical trial.

BACKGROUND: Patient comfort is an important part of laceration repair. METHODS: The study was a randomized single-blind cross-over trial in which each participant received 250 ml warmed and 250 ml room temperature saline irrigation in simple linear wounds after a local anesthetic was instilled. The solutions and the order of irrigation (warmed first versus second) were separately randomized with a washout period between. Investigators obtaining scores were blinded. Participants determined preferred solution, whether the solution was soothing, and which caused the most discomfort. Participants rated the pain of irrigation using separate Visual Analog Scale scores. RESULTS: Thirty-eight patients were enrolled in the study. Significantly more preferred warmed to room temperature solutions (difference, 34%; 95% confidence interval, 5.7-63). A Wilcoxon signed-rank test for paired data showed no order effect (P = 0.49) or difference in pain measured according to the Visual Analog Scale (P = 0.082). CONCLUSION: Warmed saline was more comfortable and soothing than room temperature saline as a wound irrigant among patients with linear lacerations.

Repeat EMS transports among elderly emergency department patients.

OBJECTIVES: Previous studies of repeat care of the elderly have focused on trauma cases only. The purposes of this study were to identify repeat transports of elderly patients to the authors' emergency department (ED) by emergency medical services (EMS), to identify demographics, and to compare chief complaints. METHODS: A population-based, retrospective cohort study was conducted. Data for this study were obtained from computerized registration files in an urban, university-affiliated ED with an annual census of approximately 60,000 visits. Patients were included if they were 65 years of age or older and they were transported by EMS in 1997. The repeater group included patients who had one or more EMS transports within the following 12 months. The comparison group was composed of all patients with no further EMS transport within the 12 months after the index visit. Demographics extracted from the database were gender, chief complaint, total number of visits, and time since previous visits. Repeats were characterized by frequency (number of visits in 12 months after the index visit), type (visit for same vs different complaint), and rate (time to the first return visit). Repeaters were defined as more than one visit within a 12-month period. Repeaters were subdivided as follows: "immediate" (within 72 hours), "short-term" (within 2 months), and "long-term" (within 12 months). Chi-square and 95% confidence intervals (95% CIs) were used. A p-value < 0.05 was considered statistically significant. RESULTS: There were 365 (23%) repeaters and 1,212 (77%) nonrepeaters. Repeaters accounted for 811 (40%) of the total of 2,023 elderly patients transported by EMS. Fifty-seven percent of all elderly patients transported by EMS were female, with no significant difference between the repeaters and nonrepeaters. There were significantly fewer transports for a chief complaint of trauma among the repeaters than among the nonrepeaters (14% vs 26%, diff = 12, 95% CI = 9-15%). Among the 365 repeaters, 186 (51%) had two transports, 92 (15%) had three transports, 36 (10%) had four transports, and 51 (14%) had five or more transports. Of the return transports by repeaters, 40 (12%) were "immediate," 191 (52%) were "short-term," and 134 (36%) were "long-term." CONCLUSION: Repeaters accounted for 18% of elderly ED patients transported by EMS and 40% of elderly transports to the authors' ED. There were significantly fewer trauma transports in the repeater group. One-half of the repeaters returned only once in a 12-month period and a third of these occurred more than three months apart. It is important to understand the characteristics of elderly EMS repeaters in order to use this opportunity for intervention.

Evaluation of self-collected samples in contrast to practitioner-collected samples for detection of Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis by polymerase chain reaction among women living in remote areas.

BACKGROUND: Self-collected samples have been shown to be an acceptable and sensitive method for the detection by polymerase chain reaction (PCR) of sexually transmitted infections (STIs) among women. GOAL The goal of the study was to compare self-collected sampling methods to conventional practitioner endocervical sampling for the PCR detection of Chlamydia trachomatis and Neisseria gonorrhoeae to compare two self-collected sampling methods for the detection of T vaginalis by PCR. STUDY DESIGN: Women (n = 318) from urban and remote areas of central Australia participated in the study when attending their health clinic for a check-up. They each provided a FVU sample, self-collected vaginal swab specimen, and tampon specimen. This was followed by a clinical examination by a practitioner, with collection of endocervical and high vaginal swabs for testing by conventional microscopy and culture for N gonorrhoeae and T vaginalis, respectively. The FVU, self-collected vaginal swab, tampon, and endocervical swab specimens were tested by Roche Cobas Amplicor for C trachomatis and N gonorrhoeae. The self-collected vaginal swab and tampon specimens were also tested by an in-house PCR method for the detection of T vaginalis. RESULTS: In toto, C trachomatis was detected by PCR in 11.5%, N gonorrhoeae in 11.8%, and T vaginalis in 24.6%. Molecular diagnostics for N gonorrhoeae and T vaginalis were significantly more sensitive than traditional assays with microscopy and culture. For the detection of C trachomatis by PCR, tampons were the most sensitive (100.0%) and urine the least sensitive (72.7%) specimens ( = 0.01). For the detection of by PCR, the self-collected tampon was the most sensitive specimen, followed by the endocervical swab, self-collected swab, and urine specimen, with sensitivities of 97.2%, 92.6%, 71.9%, and 31.2%, respectively. For detection of N gonorrhoeae, statistically significant differences were detected for urine versus tampon ( < 0.0001), endocervical swab ( < 0.001), and self-collected swab ( = 0.01) and for self-collected swab versus tampon ( = 0.01). Subsequent data collection showed that sensitivity of urine PCR for detection of N gonorrhoeae improved with freezing of urine specimens and shorter transport time. Tampons were also more sensitive than self-collected swabs for detection of T vaginalis (sensitivity of 100% versus 87.7%). CONCLUSION: Self-collected specimens offer women in remote communities an acceptable and sensitive alternative method of testing for STIs. The low sensitivity of N gonorrhoeae PCR of urine specimens may reflect poor transport and storage conditions, which we have shown can be improved by freezing urine specimens and reducing transport delays.