Certification of polio eradication: process and lessons learned

Since the 1988 World Health Assembly resolution to eradicate poliomyelitis, considerable progress has been made towards interrupting the transmission of wild poliovirus globally. A formal process for the certification of polio eradication was established on the basis of experience gained during smallpox eradication. Independent groups of experts were designated at the global, regional, and country levels to conduct the process. The main requirements for the global certification of the eradication of wild poliovirus are the absence of wild poliovirus, isolated from suspect polio cases, healthy individuals, or environmental samples, in all WHO regions for a period of at least three years in the presence of high-quality, certification-standard surveillance and the containment of all wild poliovirus stocks in laboratories. Three WHO regions--the Region of the Americas (1994), Western Pacific Region (2000), and European Region (2002)--have already been certified free of indigenous wild poliovirus. Eradication and certification activities are progressing well in the three endemic regions (African, Eastern Mediterranean, and South-East Asia). Several challenges remain for the certification of polio eradication: the need for even closer coordination of certification activities between WHO regions, the verification of laboratory containment, the development of an appropriate mechanism to verify the absence of circulating vaccine-derived polioviruses in the future, and the maintenance of polio-free status in certified regions until global certification.     

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.