A randomised double-blind placebo-controlled study was designed to evaluate the effects of a semisynthetic macrolide antibiotic, clarithromycin, on bronchial hyperresponsiveness to methacholine in patients with a diagnosis of asthma.Adult asthma patients undergoing treatment with budesonide 400 mg b.i.d. and salbutamol 200 mg p.r.n. less than twice weekly were studied. Arm A (16 males/six females, aged 48 ¡ 16 yrs) received clarithromycin 250 mg b.i.d. for 8 weeks, arm B (eight males/12 females, aged 42¡12 yrs) clarithromycin 250 mg t.i.d. and arm C (six males/15 females, aged 41¡16 yrs) placebo dextrose tablets. Bronchial hyperresponsiveness was quantified by measurement of the provocative dose of methacholine causing a 20% fall in forced expiratory volume in one second (PD20).Median (interquartile range) PD20 in the three groups before and after treatment with clarithromycin were: arm A: 0.3 (0.1-1) and 1.3 (0.6-2) mg; arm B: 0.4 (0.1-0.9) and 2 (2-2) mg; and arm C: 0.4 (0.1-0.9) and 0.3 (0.1-0.6) mg, respectively. Serum free cortisol levels were determined and remained unchanged from baseline in the clarithromycin-treated patients.It is concluded that clarithromycin reduces the degree of bronchial hyperresponsiveness in patients with asthma. Asthma is characterised by bronchial hyperresponsiveness (BHR) to nonspecific stimuli such as histamine, methacholine, cold air and exercise. BHR is related to airway inflammation and the degree of BHR indirectly reflects the severity of the disease [1]. Systemic corticosteroids administered on a long-term basis reduce BHR, but their use has been associated with significant side-effects. Modern asthma research is orientated towards the use of inhaled corticosteroids, which also decrease BHR, or alternative drug therapies possessing less toxic immunosuppressive, immunomodulating and antiinflammatory qualities.Macrolides such as troleandomycin and erythromycin have been shown to be effective in the treatment of asthma [2,3]. Their action in the steroid-dependent asthmatic patient is mediated at least in part by decreased corticosteroid metabolism. For example, troleandomycin and clarithromycin decrease methylprednisolone clearance and increase plasma methylprednisolone levels [4,5]. However, clarithromycin does not have a significant effect on prednisolone elimination [5]. Erythromycin and especially the newer macrolides (e.g. roxithromycin, clarithromycin and azithromycin) exert specific anti-inflammatory effects, including inhibition of generation of reactive oxygen species by polymorphonuclear leucocytes [6,7]. In addition, macrolide antibiotics may improve lung function due to their activity against Mycoplasma pneumoniae and Chlamydia pneumoniae, which are involved in asthma exacerbations [8][9][10].As a result of the actions described above, macrolides probably reduce the severity of BHR in adults and children with asthma. Most published data on reduction of BHR refer to erythromycin, roxithromycin or azithromycin [11][12][13]. There are very few data on the ...
Background: Liposomal cisplatin is a new formulation developed to reduce the systemic toxicity of cisplatin while simultaneously improving the targeting of the drug to the primary tumor and to metastases by increasing circulation time in the body fluids and tissues. The primary objectives were to determine nephrotoxicity, gastrointestinal side-effects, peripheral neuropathy and hematological toxicity and secondary objectives were to determine the response rate, time to tumor progression (TTP) and survival.Patients and methods: Two hundred and thirty-six chemotherapy-naive patients with inoperable non-small-cell lung cancer were randomly allocated to receive either 200 mg/m2 of liposomal cisplatin and 135 mg/m2 paclitaxel (arm A) or 75 mg/m2 cisplatin and 135 mg/m2 paclitaxel (arm B), once every 2 weeks on an outpatient basis. Two hundred and twenty-nine patients were assessable for toxicity, response rate and survival. Nine treatment cycles were planned.Results: Arm A patients showed statistically significant lower nephrotoxicity, grade 3 and 4 leucopenia, grade 2 and 3 neuropathy, nausea, vomiting and fatigue. There was no significant difference in median and overall survival and TTP between the two arms; median survival was 9 and 10 months in arms A and B, respectively, and TTP was 6.5 and 6 months in arms A and B, respectively.Conclusions: Liposomal cisplatin in combination with paclitaxel has been shown to be much less toxic than the original cisplatin combined with paclitaxel. Nephrotoxicity in particular was negligible after liposomal cisplatin administration. TTP and survival were similar in both treatment arms.
Genetic polymorphisms of the genes encoding for the xenobiotic metabolizing enzymes result in individual variations in the efficiency of detoxification of environmental carcinogens, and have been extensively associated with variable risk for lung neoplasms in different ethnic and environmental backgrounds. In this study, using PCR-RFLP based assays, we investigated the distribution of genetic polymorphisms in CYP1A1, GSTM1 and GSTT1 genes in Greek lung cancer patients (N=122) and healthy controls (N=178). The frequency of CYP1A1 m1 homozygous genotype was 0.04 in patients and 0.02 in controls (detected in 4.10% of patients and in 1.69% of controls, respectively), that of GSTM1 null genotype was 0.52 in patients and 0.54 in controls, whereas those of GSTT1 null genotype was 0.17 and 0.11, in patients and controls, respectively. The GSTM1 null genotype was more frequent in adenocarcinoma, as well as in lung cancer patients with history of chronic obstructive pulmonary disease (COPD). The GSTT1 null genotype correlated with advanced age of the patients at the time of diagnosis. Three combinations of rare genotypes -in subjects carrying simultaneously deviations from the common genotype in more than one gene -were overrepresented in lung cancer patients, compared to control population, and were furthermore significantly associated with history of heavy tobacco consumption in lung cancer patients. The results imply involvement of specific genotype combinations of CYP1A1, GSTM1 and GSTT1 alleles in the development of lung cancer in heavy smokers. Abstract. Genetic polymorphisms of the genes encoding for the xenobiotic metabolizing enzymes result in individual variations in the efficiency of detoxification of environmental carcinogens, and have been extensively associated with variable risk for lung neoplasms in different ethnic and environmental backgrounds. In this study, using PCR-RFLP based assays, we investigated the distribution of genetic polymorphisms in CYP1A1, GSTM1 and GSTT1 genes in Greek lung cancer patients (N=122) and healthy controls (N=178). The frequency of CYP1A1 m1 homozygous genotype was 0.04 in patients and 0.02 in controls (detected in 4.10% of patients and in 1.69% of controls, respectively), that of GSTM1 null genotype was 0.52 in patients and 0.54 in controls, whereas those of GSTT1 null genotype was 0.17 and 0.11, in patients and controls, respectively. The GSTM1 null genotype was more frequent in adenocarcinoma, as well as in lung cancer patients with history of chronic obstructive pulmonary disease (COPD). The GSTT1 null genotype correlated with advanced age of the patients at the time of diagnosis. Three combinations of rare genotypes -in subjects carrying simultaneously deviations from the common genotype in more than one gene -were over-represented in lung cancer patients, compared to control population, and were furthermore significantly associated with history of heavy tobacco consumption in lung cancer patients. The results imply involvement of specific genotype combinations o...
PCT combined with VRL produces similar (non-significant) response rates, survival and toxicity (except for neutropenia, as noted above) to standard CRP-PCT treatment in untreated advanced-stage NSCLC.
With 69 years being the median age at diagnosis in the United States, management of elderly patients with advanced non-small cell lung cancer (NSCLC) has become a common problem faced by the oncology practitioner. We evaluated a biweekly administration of the combination regimen using docetaxel (Sanofi Aventis, Athens) and gemcitabine (Eli Lilly, Athens) in a phase II study (objective response rate, median survival, median response duration and safety). A total of 198 cycles were administered to 38 patients with advanced NSCLC with a median age of 72 years (range 65-85 years). Patients received docetaxel 80 mg/m(2 )and gemcitabine 1000 mg/m (2 )on days 1 and 14 of a 28-day cycle. Twenty patients achieved a partial response (PR) (20/34, 58.8%), 4 patients had stable disease (SD) (4/34, 11.7%) and 10 (10/34, 29.4%) had progressive disease (PD). The median time to disease progression was 3 months (range 1-11 months) with a mean survival of 7 months (range 1-29 months). Hematological and non-hematological toxic effects were generally mild to moderate and manageable: grade 3 neurotoxicity and grade 3 allergy occurred in 5 patients (13.1%) and 1 patient (2.6%), respectively. Peripheral neuropathy, mostly grades 1 and 2, was reported in 29 patients (76.3%), which was seen more frequently in patients >70 years of age (P=0.048).We conclude that the biweekly administration of a docetaxel/gemcitabine combination with G-CSF support constitutes a tolerable and convenient regimen for the treatment of elderly patients with advanced NSCLC, with efficacy similar to that reported in other regimens. Hence, this two-drug combination appears promising and warrants further evaluation.
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