Hydrophobic vancomycin derivatives with improved ADME properties: discovery of telavancin (TD-6424)

Novel derivatives of N-decylaminoethylvancomycin (2), containing appended hydrophilic groups were synthesized and their antibacterial activity and ADME properties were evaluated. The compounds were prepared by reacting amines with the C-terminus (C-) of 2 using PyBOP mediated amide formation, or with the resorcinol-like (R-) position of 2 using a Mannich aminomethylation reaction. These analogs retained the antibacterial activity of 2 against methicillin-resistant staphylococci and vancomycin-resistant enterococci. Compounds with a negatively charged auxiliary group also exhibited improved ADME properties relative to 2. In particular, R-phosphonomethylaminomethyl derivative 21 displayed good in vitro antibacterial activity, high urinary recovery and low distribution to liver and kidney tissues. Based on these results, 21 was advanced into development as TD-6424, and is currently in human clinical trials. The generic name telavancin has recently been approved for compound 21.     

Rational design of potent and selective VLA-4 inhibitors and their utility in the treatment of asthma

Asthma, a chronic inflammatory disease of the airways, is a significant burden on our healthcare system. There is high unmet need for treatments directed towards the underlying causes of the disease. The cell surface integrin VLA-4 (very late antigen-4; alpha4beta1; CD49d/CD29) plays an important role in the trafficking of white blood cells to sites of inflammation and represents an exciting target for the development of novel anti-inflammatory drugs for the treatment of asthma. Here, we review our efforts to use rational design to identify potent, selective inhibitors of VLA-4. We describe the discovery of a series of potent VLA-4 inhibitors through the addition of a novel N-terminal organic cap to a tetrapeptide VLA-4 binding motif 4-((N'-2-methylphenyl)uriedo)phenylacetyl-Leu-Asp-Val-Pro ; Kd = 70 pM), and rationalize their structure-activity relationships using 3D-QSAR. Also, we show our rational peptidomimetic design strategy using "template hopping" from the gpIIb/IIIa integrin antagonist field, and also a novel virtual screening strategy. Two series have been developed, one that has high selectivity for the activated over the non-activated state of the receptor, and the other which is non-selective inhibiting both activated and non-activated VLA-4. Both series are highly selective for VLA-4 versus against other integrin family members. These inhibitors show promise in the treatment of asthma, based upon efficacy in a sheep model of asthma, where they inhibit both the early and late-phase responses to asthma and also block hypersensitivity.     

Low-dose weekly paclitaxel for recurrent or refractory aggressive non-Hodgkin lymphoma

BACKGROUND: Many patients with recurrent, intermediate or high-grade non-Hodgkin lymphoma (NHL) may not respond to or are not candidates for aggressive salvage chemotherapy. Effective, less toxic regimens are needed. Although high-dose taxanes have not been reported to be very effective for the treatment of lymphoma, different delivery rates may allow for different mechanisms of action to be manifest and result in a different toxicity profile and response rate. The current study tested this hypothesis by using low-dose, weekly paclitaxel in patients with recurrent or refractory NHL. METHODS: Adults age > 18 years with refractory or recurrent, aggressive NHL who were not considered curable with standard high-dose therapy received paclitaxel at a dose of 80 mg/m2 weekly for 5 weeks for 2 cycles. RESULTS: Thirty-four patients with refractory NHL and 4 patients with recurrent disease were treated. Approximately 45% of the patients had achieved a prior disease remission. The median number of prior regimens received was 3, 74% of the patients had an International Prognostic Index of > or = 3 at the time of study entry, and 29% had failed high-dose therapy with autologous hematopoietic support. Only one patient encountered severe toxicity (sepsis). Myelosuppression was reported to occur in approximately 20% of patients. A total of 10 patients (26%) achieved a complete disease response and 4 patients (11%) achieved a partial response. CONCLUSIONS: In the current study, low-dose, weekly paclitaxel therapy was found to provide a well tolerated and less toxic approach to the treatment of refractory NHL, with encouraging responses noted in heavily pretreated patients. However, evaluation in patients with an earlier stage of disease is warranted.     

A single treatment of yttrium-90-labeled CHX-A"-C6.5 diabody inhibits the growth of established human tumor xenografts in immunodeficient mice

Antitumor diabody molecules are noncovalent single-chain Fv dimers that recapitulate the divalent binding properties of native IgG antibodies. Diabodies are capable of substantial accumulation in tumor xenografts expressing relevant antigens in immunodeficient mouse models. With a Mr of approximately 55,000, diabodies are rapidly cleared from the circulation, resulting in tumor-to-blood ratios that significantly exceed those achieved early after the administration of monoclonal antibodies. We have evaluated the therapeutic potential of the beta-emitting isotope yttrium-90 (t1/2, 64 hours) conjugated to the C6.5K-A diabody that specifically targets the HER2/neu human tumor-associated antigen. We have found that a single intravenous dose of 150 microCi (200 microg) 90Y-CHX-A"-C6.5K-A diabody substantially inhibits the growth rates of established MDA-361/DYT2 human breast tumor xenografts in athymic nude mice. In contrast, 300 microCi (300 microg) 90Y-CHX-A"-C6.5K-A diabody resulted in only a minor delay in the growth of SK-OV-3 human ovarian cancer xenografts. The maximum tolerated dose was also dependent on the tumor xenograft model used. These studies indicate that genetically engineered antitumor diabody molecules can be used as effective vehicles for radioimmunotherapy.     

Optimizing risk stratification in cardiac rehabilitation with inclusion of a comorbidity index

PURPOSE: The risk stratification criteria of the American Association of Cardiovascular and Pulmonary Rehabilitation include guidelines to be used in stratifying cardiac rehabilitation (CR) patients for risk of disease progression (long term) and clinical events (short term). Noncardiac comorbidities are not included as indicators in these criteria. This study was designed to ascertain the prevalence of noncardiac comorbidities among CR patients, and to assess their relation to the current risk stratification algorithm for clinical events. METHODS: Patients were stratified into high-, intermediate-, and low-risk groups according to the American Association of Cardiovascular and Pulmonary Rehabilitation risk stratification criteria for clinical events (ARSE) at program entry. Within each risk group, age, gender, race, and noncardiac comorbidities were ascertained. Comorbidities were summarized in a comorbidity index (CMI). The relation between clinical events and risk status by ARSE and CMI was evaluated by logistic regression. RESULTS: Among 490 patients (age, 60 +/- 12 years; 35% women; 30% nonwhite) enrolled in CR with ischemic heart disease, the number of comorbidities ranged from 0 to 7 (median, 2; 75th percentile, 3). The patients categorized in the three ARSE groups differed significantly in age and comorbidities. Although ARSE tended to identify patients with a greater comorbidity burden, 38% of the patients with a comorbidity index exceeding the 75th percentile were not classified in the highest ARSE group. Clinical events increased across ARSE and CMI risk strata. Both ARSE and CMI were independent predictors of events in an age-, gender-, and race-adjusted logistic regression analysis (ARSE odds ratio [OR], 1.56; 95% confidence interval [CI], 1.14-2.12; CMI OR, 1.23, 95% CI, 1.03a-1.47). Events were predicted best when both classifications were combined. Exploratory gender-specific analyses suggested that ARSE performed better among men than among women, whereas CMI was a more important predictor among women. CONCLUSIONS: To appreciate more fully the overall complexity of disease among CR patients, ARSE should be supplemented not only with the inclusion of cardiac risk factors, as suggested in the current guidelines, but also with an assessment of noncardiac comorbidities.     

Markers to define ischemia: Are they ready for prime time use in patients with acute coronary syndromes?

Optimal treatment of patients who present with chest pain is predicated on accurate identification of those patients with a cardiac etiology of their discomfort. Serial troponins and electrocardiograms are very sensitive for the detection of myocardial infarction but they are insensitive for the detection of ischemia. There are many analytes that are being actively evaluated for routine use to facilitate the identification of patients with myocardial ischemia. At present, only one assay is US Food and Drug Administration-approved for the exclusion of ischemia; many other analytes are under clinical evaluation and are briefly reviewed. At present, none of these analytes are yet appropriate for routine clinical use.     

Electronic reporting of pelvic inflammatory disease from an emergency department

BACKGROUND AND OBJECTIVES: Pelvic inflammatory disease (PID) is a clinically diagnosed condition that is preventable and underreported. We developed an electronic emergency department (ED) PID reporting system by using an automatic and secure system to send computerized clinician PID diagnoses to the state health department. GOAL: The goal of this study was to assess if electronic transmission of ED PID data could enhance the completeness and timeliness of PID surveillance. STUDY DESIGN: We conducted a retrospective chart review. METHODS: To validate electronic ED diagnoses, we reviewed charts of 157 women with 7 clinicians' diagnoses compatible with PID. We determined which women met the Centers for Disease Control and Prevention (CDC) PID surveillance case definition and determined the positive predictive values of electronic ED diagnoses of PID. We compared completeness of electronic PID reporting with state sexually transmitted disease surveillance. RESULTS: Three diagnoses were appropriate for electronic PID surveillance. Information on women with these diagnoses is sent daily to the health department with no extra effort needed from ED clinicians. Less than 10% of women who met the CDC PID case definition were reported within 6 months through conventional methods. CONCLUSIONS: Electronic ED surveillance will improve completeness and timeliness of PID reporting.     

Systemic thromboembolism in children. Data from the 1-800-NO-CLOTS Consultation Service

Thromboembolism (TE) has recently been recognized as a clinical entity in children. Determining the clinical characteristics of pediatric TE is an important first step in dealing with this new disorder. The paper summarizes 1776 consecutive children with systemic TE referred to 1-800-NO-CLOTS telephone consultation service. 1-800-NO-CLOTS is a free consultation service for clinicians managing pediatric TE. Patient information was collected immediately using standardized forms. In children with systemic TE, infants under one year of age (47%) including neonates (26%) represented the largest distinct pediatric age group. Age-related differences were seen in TE locations, associated conditions, and risk factors. However, venous TE was the most frequent manifestation (74%). Neonates and children with cardiac disorders were more likely to have an arterial TE than a venous TE Beyond the neonatal period, venous TE associated with a central line is more likely to occur than arterial TE. Children with ALL were 5.7 times more likely to have a venous TE than an arterial TE. TE were infrequent in otherwise healthy children with 90% of children having at least one risk factor. Central catheters were the single most common risk factor associated with TE, present in 2/3 of children. Ultrasound was most frequently employed for diagnosis of TE. Finally, there was marked heterogeneity in treatment of children with TE. In children, neonates form the largest single group with TE. TE usually occur only in the presence of one or more risk factors with catheters being the single most important factor.