Navitoclax (ABT-263) and bendamustine ± rituximab induce enhanced killing of non-Hodgkin's lymphoma tumours in vivo.

BACKGROUND AND PURPOSE: Bendamustine with or without rituximab provides an effective and more tolerable alternative to the polytherapy cyclophosphamide-doxorubicin-vincristine-prednisolone (CHOP) in the treatment of haematological tumours and is currently approved for the treatment of many haematological malignancies. Navitoclax (ABT-263) is a potent inhibitor of Bcl-2, Bcl-x(L) and Bcl-w, which has demonstrated efficacy in haematological tumours alone and in combination with other agents. This paper describes the in vivo efficacy of combining either bendamustine or bendamustine plus rituximab (BR) with navitoclax in xenograft models of non-Hodgkin's lymphoma EXPERIMENTAL APPROACH: Activity was tested in xenograft models of diffuse large B-cell lymphoma (DoHH-2, SuDHL-4), mantle cell lymphoma (Granta 519) and Burkitt's lymphoma (RAMOS). Activity was also monitored in a systemic model of Granta 519. KEY RESULTS: Navitoclax potentiated bendamustine activity in all cell lines tested. Bendamustine activated p53 in Granta 519 tumours, concurrent with activation of caspase 3. Navitoclax also improved responses to bendamustine-rituximab (BR) in a subset of tumours. CONCLUSIONS AND IMPLICATIONS: Navitoclax in combination with bendamustine and BR is a viable combination strategy for use in the clinic and demonstrated superior efficacy compared with previously reported data for navitoclax plus CHOP and rituximab-CHOP.

Efficacies of ABT-773, a new ketolide, against experimental bacterial infections.

ABT-773 is a novel ketolide effective against antibacterial-resistant respiratory tract pathogens. The pharmacokinetic profile of ABT-773 was studied in rats and consisted of a mean peak concentration in plasma of 1.07 microg/ml and an area under the concentration-time curve (AUC) of 12.03 microg. h/ml when the compound was delivered at a dose of 25 mg/kg of body weight. It concentrated in rat lung tissue, with a lung tissue-to-plasma ratio of 29 based on the AUC. In acute systemic infections in mice, ABT-773 showed efficacy against macrolide-susceptible strains of Staphylococcus aureus, Streptococcus pneumoniae, S. pyogenes, and Listeria monocytogenes. Additionally, ABT-773 improved the survival of mice infected with resistant S. pneumoniae containing either the ermB gene, the mefE gene, or altered penicillin binding protein genes. In a rat lung model of infection, ABT-773 demonstrated 50% effective doses lower than those of comparator macrolides when evaluated against the following strains of S. pneumoniae: a macrolide-lincosamide-streptogramin B-susceptible strain, an ermB strain, and an mefE strain. ABT-773 was also effective against Haemophilus influenzae lung infections in rats. Thus, ABT-773 may prove to be a useful new antibacterial agent for the treatment of respiratory tract infections.

Legal issues affecting medical clearance to resume play after mild brain injury.

Physician care of athletes suffering mild brain trauma involves medical and legal considerations. Physicians must adhere to their primary responsibility to protect their athletes' health by following good medical practice and not allowing nonmedical factors to unduly influence their judgment. Courts recognize the team physician's role as gatekeeper and generally defer to his or her medical judgment in return-to-play decisions.

Relevance of the ferret model of Helicobacter-induced gastritis to evaluation of antibacterial therapies.

OBJECTIVES: The goals of the study were 1) to evaluate the efficacy of clinically relevant antibacterial therapies in the ferret model of Helicobacter-induced gastritis and 2) to compare these results to the efficacy achieved clinically in humans. METHODS: Ferrets were inoculated with H. mustelae, and gastritis was allowed to develop. The double therapy of clarithromycin and omeprazole and the triple therapies of clarithromycin or amoxicillin with metronidazole and omeprazole were administered. Efficacy was evaluated by Helicobacter burden cultured from biopsy samples and by histopathological evaluation of Helicobacter burden and gastric inflammation with pylorus and fundus samples obtained 4 wk after the end of antibacterial therapy. RESULTS: Clarithromycin-based double and triple therapies significantly reduced Helicobacter burden and decreased gastric inflammation. Clarithromycin-based double therapy was more effective than amoxicillin-based triple therapy. Reduction of the length of clarithromycin therapy from 14 to 7 days decreased efficacy. Antibacterial therapies in the ferret did not produce eradication rates comparable to clinical results, even though the serum concentrations of clarithromycin in ferret were in excess of concentrations used in humans. Relapse of Helicobacter infection after the end of therapy occurred in some cases. CONCLUSIONS: Although the ferret model of Helicobacter gastric infection underestimated the clinical efficacy of antibacterial treatments in humans, the model was valuable for comparing the relative efficacy of antibacterial therapies.

Model of Streptococcus pneumoniae meningitis in adult rats.

The purpose of this study was to develop a model of bacterial meningitis in young adult rats for assessing the efficacy of antimicrobial agents. Sixty 200- to 300-g male Sprague Dawley CD rats were inoculated intracisternally with 5.78 log10 CFU of a clinical isolate of Streptococcus pneumoniae in 5% hog gastric mucin. Inoculated rats were assigned to six groups containing 10 animals each. Group-1 rats served as controls and did not receive antibiotics. Rats of groups 2 to 4 received (subcutaneously every 12 h) cefotaxime (25, 6.25, and 1.56 mg/kg of body weight respectively). Rats of groups 5 and 6 received ampicillin (50 and 12.5 mg/kg respectively) and gentamicin (2.0 and 0.5 mg/kg respectively). Five additional Sprague Dawley CD rats were inoculated with only gastric hog mucin and were assigned to group 7. At postinoculation day 4 all animals were euthanized. Cerebral spinal fluid was collected for culturing. Brains were harvested for histologic examination and culturing. Untreated, infected control (group-1) animals were culture-positive for S. pneumoniae in the brain and cerebral spinal fluid. Of the antibiotic regimens evaluated, only cefotaxime (25 mg/kg) eradicated bacteria from the cerebral spinal fluid and brain. Cefotaxime at 25 or 6.25 mg/kg significantly (P < or = 0.05) decreased the bacterial burden of S. pneumoniae, whereas cefotaxime at 1.56 mg/kg and ampicillin/gentamicin combinations did not. There was histopathological evidence of subacute meningitis in infected rats. No meningitis was observed in rats receiving 25 mg of cefotaxime/kg. This model demonstrates the ability to induce bacterial meningitis with S. pneumoniae in adult rats and the ability to clear infection in 90 to 100% of the animals by administration of cefotaxime at dosages of 6.25 and 25 mg/kg given subcutaneously every 12 h.

When Is Disqualification From Sports Justified? Medical Judgment vs Patients' Rights.

An important medicolegal issue is how best to resolve disputes about an athlete's medical eligibility. Team physicians typically recommend against athletic participation when they feel that it will pose an unreasonable risk of injury to an athlete who has an abnormality. But such athletes may cite federal laws designed to protect the disabled and claim a right to participate. The legal framework for resolving sports-participation disputes involving physically impaired athletes is still developing. Recent case law reflects a split decision regarding the legality of excluding athletes whose condition, in the opinion of the team physician, exposes them to an increased risk of significant harm.

Legal considerations in treating the injured athlete.

This article is intended to inform physical therapists about legal considerations impacting the practice of sports physical therapy. Our objective is to generate an awareness of these issues to enhance the quality of physical therapy provided to injured athletes and to minimize potential legal liability. Three areas in which physical therapists who treat injured athletes need to be particularly careful are: 1) providing treatment designed to enable continued play with an injury before it is fully healed, 2) informing an athlete of the potential health risks of continued athletic activity in his or her physical condition, and 3) evaluating and advising an athlete concerning his or her ability to resume athletic activity. Based on the parallels between industrial rehabilitation and sports physical therapy, the authors propose that consensus objective criteria and guidelines should be established to assist therapists in advising referring physicians and athletes whether return to play is appropriate under the circumstances.

HIV-Positive Athletes.

In brief Though the risk of HIV transmission in sports' is slight, physicians who treat active patients can encounter some weighty legal issues. Mandatory testing, exclusion of HIV-positive athletes from competition, and breaching of patient confidentiality are actions that can lead to lawsuits. Knowing the possible consequences can help physicians in setting effective-and legal-prevention policies.