European journal of cancer & clinical oncology最新文献

The prognosis of malignant melanoma (MM) depends on the level of invasion, vertical tumour size, location of the primary, clinical stage, and sex. Whereas MMs are potentially curable in the early stage of disease, the therapeutic possibilities are very limited in advanced and disseminated MM. Most chemotherapeutic agents lack sufficient activity in MM especially with regard to survival. Dacarbazine (DTIC) is the most effective drug in MM with response rates of 20-25% followed by other drugs such as melphalan with 15-20%, hydroxyurea and platin derivates. Multidrug regimens were not shown to be more effective than DTIC alone. Radiotherapy may be relevant in local treatment of metastases. With regard to the poor prognosis and limited therapeutic approaches in advanced and disseminated MM, new strategies are required. In this context immunotherapeutic strategies with biological response modifiers are of interest for adjuvant or palliative approaches. Earlier trials with Bacillus Calmette-Guerin (BCG) +/- DTIC as adjuvant or palliative treatment revealed no effect of BCG on the prognosis. Alpha-interferon (alpha-IFN) was shown to induce remissions in about 15% and gamma-IFN in about 10% of patients. A very interesting new approach is the induction and/or activation of autologous cytotoxic cells by systemic administration of recombinant interleukin-2 (rIL-2) with response rates of 20-25% and the in vivo propagation and transfer of so-called tumour infiltrating lymphocytes. Further trials combining rIL-2 with other cytokines, chemotherapy, tumour vaccination or monoclonals against melanoma cells are required.

Three main types of 5-HT (serotonin) receptor have been recognised. The 5-HT3 receptor is located on neuronal tissues in the peripheral and central nervous systems. Ondansetron is a highly selective and potent antagonist for this receptor type. The severe nausea and vomiting caused by cytotoxic agents and radiotherapy can be reduced by metoclopramide treatment, but extrapyramidal side effects are common due to antagonism of dopamine receptors. Ondansetron has been found to significantly delay the onset of emesis, and reduce the number of retches and vomits in ferrets receiving cisplatin, cyclophosphamide, or radiation, at much lower doses than metoclopramide and without the associated side effects. Experiments to define the site of action of ondansetron suggest that at least part of its antiemetic action is in the area postrema, though a peripheral site of action in the upper gastrointestinal tract is also a possibility.

Ondansetron, a 5-HT3 antagonist proposed for use in the treatment of chemotherapy-induced emesis, was first given to man in 1984 and in the 4 years subsequent to this, the drug was given to more than 220 different healthy volunteers. In pharmacodynamic studies, there was evidence to suggest that ondansetron was gastroprokinetic but reduced transit time through the small bowel. Ondansetron was of no benefit in a model of motion sickness. The pharmacokinetics of ondansetron have been defined in volunteers using intravenous and oral dosage regimens proposed for the clinic. Ondansetron had a terminal plasma half-life of 3.0-3.5 h and plasma clearance (principally metabolic) of the order of 600 ml/min, and there was no evidence of accumulation at steady state. The absolute oral bioavailability of ondansetron was 59%. Metabolic studies showed the drug to be excreted predominantly in urine and faeces, with a metabolite profile in urine similar to that seen in the animal species used for toxicological testing. Ondansetron is both safe and well tolerated at daily doses of up to 64 mg given to volunteers.

Ondansetron injection is an aqueous solution containing ondansetron base as the hydrochloride dihydrate. The pH of the injection was selected to achieve good physical and chemical stability. The shelf life is 3 years when stored below 30 degrees C, protected from light. Ondansetron injection may be diluted for administration by slow intravenous injection or infusion and is compatible with several intravenous infusion fluids. In addition, specific concentrations of cisplatin, 5-fluorouracil, carboplatin, etoposide, ceftazidime, cyclophosphamide and doxorubicin are compatible when administered via a giving set delivering ondansetron by infusion.

High performance liquid chromatography has been found to be an accurate method for determination of ondansetron in plasma. Within a single assay, and between assays, the differences between theoretical and observed means obtained from analysis of spiked samples were low and good precision was obtained. The method has been used to assay several thousand samples from subjects included in pharmacokinetic studies. The pharmacokinetic profile of ondansetron has been established following single and multiple oral dosing and intravenous infusions.

The means by which gram-negative bacilli can resist newer beta-lactam antibiotics are reviewed. A first situation is generated by mutants which produce great amounts of a chromosomal cephalosporinase. These cells are present (frequency: 10(-4) to 10(-7] within bacterial populations such as Enterobacter cloacae, and multiply after selection during therapy by third-generation cephalosporins or monobactams. A second problem arose by 1985, with the sudden development of plasmid-mediated beta-lactamases markedly active against third-generation cephalosporins. Some recent molecules, such as penems, are not affected by the two mechanisms mentioned above but remain exposed to other resistance problems. Notably Pseudomonas aeruginosa strains can develop resistance during therapy by imipenem thanks to specific alterations of the bacterial outer membrane. As a consequence of these resistance difficulties, new interpretations for susceptibility testing and new therapeutic approaches should be considered.

During the last decade, the survival of patients with fever and neutropenia has continued to improve. This is largely a reflection of the increasing repertoire of antimicrobial agents available to treat the fevers and infections that arise in this ever-increasing population of patients. Although it would be optimal if therapeutic decisions could always be made based on the microbial isolates and their sensitivity patterns, this is generally not possible in the cancer patient. Fever remains the predominant manifestation of infection, but the underlying microbial etiology is infrequently delineated. In spite of improved diagnostic tests, clinical acumen along with vigilant and repetitive patient assessment remain the cornerstone for evaluation of the cancer patient who becomes febrile. Indeed, strict adherence to simple principles can have a significant impact on improving the chances for survival of cancer patients who develop fever or infection.

The safety of ondansetron has been reviewed based on experience in its use as an anti-emetic treatment in about 1,400 patients receiving cancer treatment and further experience in about 650 volunteers and patients with other medical conditions. Evidence from animal pharmacology and toxicology had indicated that ondansetron had a wide therapeutic index, no interaction with commonly co-prescribed drugs, and no dependence liability. No end-organ toxicity had been seen. Clinical experience showed that ondansetron is well tolerated; the principal side effects being constipation and headache, which in the context of cancer treatment were not troublesome. Increases in liver function tests were observed, undoubtedly due in many instances to the underlying cancer or metastases and to chemotherapy, and the incidence was similar on ondansetron and metoclopramide. No extrapyramidal side effects were reported.

Infections continue to be common complications of bone marrow transplantation, but recent advances have improved their outcome. Oral chemoprophylaxis with the fluoroquinolones has reduced gram-negative infections during periods of granulocytopenia, while new triazole drugs show promise for improving antifungal prophylaxis. Similarly, recombinant hematopoietic growth factors may reduce infections by shortening the period of post-transplant granulocytopenia. The efficacy of double beta-lactam antibiotic therapy or monotherapy with imipenem has obviated the need to use aminoglycosides in the empiric treatment of febrile patients receiving cyclosporine or other nephrotoxic agents. Treatment of post-transplant interstitial pneumonia associated with cytomegalovirus (CMV) remains problematic, but recent results using the combination of ganciclovir plus intravenous immune globulin have been favorable. In CMV-seronegative patients, CMV infections and pneumonia can be prevented or modified by using CMV-seronegative blood products and intravenous immune globulin. Intravenous immune globulin also has the additional benefits of modifying graft versus host disease and preventing late bacterial infections after marrow engraftment. In CMV-seropositive patients, prophylactic ganciclovir may prevent CMV reactivation and pneumonia and is the subject of an ongoing controlled clinical trial.