Open, randomized, multi-center phase II study comparing efficacy and tolerability of Erlotinib vs. Carboplatin/Vinorelbin in elderly patients (>70 years of age) with untreated non-small cell lung cancer.

BACKGROUND: Targeting the epidermal-growth-factor-receptor (EGFR) in non-small cell lung cancer (NSCLC) is an established treatment option with less toxicity compared to conventional chemotherapy. This study was undertaken to determine whether Erlotinib is non-inferior compared to chemotherapy as a first-line therapy in unselected elderly patients. MATERIALS AND METHODS: Patients ≥ 70 years with untreated, metastatic NSCLC were randomized to Erlotinib (E), 150 mg/day or Carboplatin (AUC5) plus Vinorelbine (25mg/m(2) on days 1 and 8) every three weeks (CV). Primary endpoint was progression-free survival (PFS). After progression, crossover was strongly recommended. Secondary endpoints were duration of response, 1-year survival, overall survival (OS), response rate (RR), quality of life (FACT-L), assessment of comorbidities by simplified comorbidity score (SCS) and Charlsons' comorbidity score, safety and assessment of molecular markers. RESULTS: Between June 2006 and August 2008 284 pts were randomized to E (144) and CV (140). PFS was significantly inferior with E (median PFS 2.4 versus 4.6 months [HR 1.6, 75% CI 1.22-2.09, p: 0.0005]) as well as RR (7.8% v 28.3%, p: 0.0001). No significant difference in OS appeared (median E: 7.3 months versus CV: 8.4 months, HR: 1.24 [75% CI 0.9-1.71]). In never smokers PFS (median PFS: 3.7 v 4.3 m, E v CV, HR 0.72, 75% CI 0.35-1.48) and OS (median: 16.5 versus 17 months, HR 0.99 [75% CI 0.38-2.57]) were comparable. More skin toxicity and diarrhea was seen with E compared to more myelotoxicity, neurotoxicity and constipation with CV. Less severe adverse events were observed with E (81 v 102, E v CV). CONCLUSION: CV had an increased efficacy compared with E in an unselected population of elderly patients with advanced NSCLC.

[Epidemiology of lung cancer]. / Epidemiologie des Lungenkarzinoms.

In 2005 approximately 45,000 people contracted lung cancer in Germany and at the same time a total of 40,641 patients died from the disease, making lung carcinoma the most frequent cause of tumor death in men. The peak age for the disease is between 70 and 85 years. The main risk factor of inhaling tobacco smoke is responsible for 85% of the cases of lung cancer. There is a direct correlation between the number of cigarettes smoked and the risk of developing lung cancer. Screening programs, e.g., low-dose computed tomography, are currently undergoing clinical assessment worldwide, but at the present time are not yet being comprehensively established.

Influence of age and comorbidities on the chemotherapeutic management of lung cancer.

More than 60% of all patients with cancer are currently older than 65 years. Correspondingly, the peak of lung cancer incidence is reached in the age group between 75 and 80 years. As a consequence to this ageing patient population, three factors become of major importance for the chemotherapeutic management of lung cancer, namely functional status, age-specific phenomenon and the presence of comorbidities. While the functional status is dependent on physiological changes in organ function, ageing-specific phenomena include depression, alterations of mental status, reduced nutritional status and missing social support. Comorbidities frequently have a risk profile comparable to that of lung cancer. Clinical studies with a special focus on elderly patients are still rare. In small-cell lung cancer retrospective analyses have demonstrated that age alone is not a major prognostic factor compared to performance status, tumor stage or gender. Nevertheless elderly patients with lung cancer are still frequently excluded from clinical trials, and receive less optimal or even no chemotherapeutic treatment at all. Studies evaluating less aggressive treatment figured out that single agent therapy with etoposide is inferior compared to combination chemotherapy in patients with small cell lung cancer (SCLC). In elderly patients with non-small cell lung cancer (NSCLC), single agent treatment with vinorelbine plus 'Best Supportive Care' was significantly superior to 'Best Supportive Care (BSC)' alone; with respect to survival and symptom palliation.

Five day moxifloxacin therapy compared with 7 day clarithromycin therapy for the treatment of acute exacerbations of chronic bronchitis.

In this multinational, randomized, double-blind study, the efficacy and safety of a 5 day course of moxifloxacin 400 mg orally od was compared with that of a 7 day course of clarithromycin 500 mg orally bd. in 750 patients with acute exacerbations of chronic bronchitis, characterized by at least two of the symptoms: sputum purulence, increased sputum volume or increased dyspnoea. Seven days after the end of therapy, clinical cure was achieved for 89% (287 of 322) of efficacy-evaluable patients in the moxifloxacin group and 88% (289 of 327) of patients in the clarithromycin group (95% CI, -3.9%, 5.8%). At follow-up (21-28 days post-treatment), the continued clinical cure rates were 89% (256 of 287) for moxifloxacin and 89% (257 of 289) for clarithromycin. A total of 342 pathogenic bacteria were isolated from the sputum of 287 patients. The most common pathogens were Haemophilus influenzae (37%), Streptococcus pneumoniae (31%) and Moraxella catarrhalis (18%). Seven days post-treatment, a successful bacteriological response was obtained for 77% (89 of 115) of patients in the moxifloxacin group and 62% (71 of 114) of patients in the clarithromycin group, indicating superiority of moxifloxacin (95% CI, 3.6%, 26.9%). Both treatments were well tolerated with few adverse events. This study demonstrated that for the treatment of acute exacerbations of chronic bronchitis a 5 day course of moxifloxacin 400 mg od was clinically equivalent and bacteriologically superior to a 7 day course of clarithromycin 500 mg bd.

High-level sensitivity of quantitative pp65 cytomegalovirus (CMV) antigenemia assay for diagnosis of CMV disease in AIDS patients and follow-up.

Cytomegalovirus (CMV) antigenemia was evaluated in 174 patients positive for human immunodeficiency virus. Antigenemia could be detected in 96.7% of patients with CMV disease, 76.9% of patients suffering from a relapse of the disease, and 11.4% of asymptomatic patients with CD4 levels of < 100 cells per microliter. No antigenemia was detected in patients with CD4 levels of 250 to 500 cells per microliter. Specificity and the positive predictive value for CMV disease were increased only if more than 5 positive cells per slide were considered. However, CMV disease may also occur in patients with low-grade antigenemia.

[Intraoperative transesophageal versus preoperative transthoracic contrast echocardiography. A method for detection of patent foramen ovale in neurosurgical patients]. / Intraoperative transösophageale versus präoperative transthorakale Kontrast-Echokardiographie. Eine Methode zum Nachweis eines funktionell offenen Foramen ovale bei neurochirurgischen Patienten.

Preoperative detection of a patent foramen ovale (PFO) may be achieved employing either transthoracic echocardiography (TTE) with the Valsalva manoeuvre in the awake patient or trans-oesophageal echocardiography (TEE) in the anaesthesised patient. Our study was undertaken to validate these methods with regard to their efficacy in identifying patients at risk for paradoxical air embolism (PAE). METHODS. In 67 patients ranging from 28 to 70 years of age, TTE was performed utilising the Valsalva manoeuvre prior to surgery. The patients were informed about all procedures and agreed to take part in the study. After induction of anaesthesia the patients were evaluated with TEE in the supine and sitting positions. At end-inspiration 10 ml agitated gelatine solution (Gelafundin) was injected through a central venous catheter into the right atrium after airway pressure of 20 cm H2O had been maintained for 5 s. The injected bolus was observed throughout the ventilatory cycle, with special attention being given to early expiration and systole. A right-to-left shunt was assumed if five echo targets were observed in the left atrium. RESULTS. The prevalence of PFO detected by TTE/Valsalva was 9%. The diagnosis was confirmed by TEE in 2 patients in the supine and 1 in the sitting position. An echocardiogram in these patients showed bulging of the septum to the left, which was not seen in those patients in whom PFO was detected only by TTE. DISCUSSION. The reason for the lower incidence of PFO detected by TEE during airway pressure 20 cm H2O may have been an insufficient increase of pressure in the right atrium with a negative right-to-left atrial pressure gradient. A standardised ventilation manoeuvre with supra-atmospheric airway pressure of 20 cm H2O is not sufficient. Bulging of the intra-atrial septum from right to left during airway pressure is a possible indication of the efficacy of the manoeuvre, regardless of the influence of the breathing pattern.

Fluoroquinolones: interaction profile during enteral absorption.

Fluoroquinolones are used worldwide in the treatment of severe infections. These drugs, however, can interact with other agents. This paper is a review of drug interactions with different quinolone derivatives at the absorption phase; the review deals mainly with the prototype quinolones, ciprofloxacin and ofloxacin, and also with some of the newer agents. The concomitant agents considered are food, H2-receptor antagonists, anticholinergic drugs and metallic cation-containing compounds. Food (standard breakfast), H2-receptor antagonists and anticholinergic drugs had no major effect on the bioavailability of the quinolones. However, antacids, ferrous sulfate and other metallic cation-containing compounds impaired the bioavailability of the quinolones. This effect is due to chelation between the functional groups of the quinolone molecule and the metallic cations, resulting in insoluble complexes that can be absorbed. The degree of impairment varied between different quinolone derivatives.

Pharmacokinetics of loracarbef and interaction with acetylcysteine.

A study was conducted to evaluate the pharmacokinetics of loracarbef, a new synthetic oral carbacephem antibiotic, following administration of 400 mg in normal male volunteers. The influence of food and possible interaction with acetylcysteine, a commonly used mucolytic agent, was also studied. Twelve healthy volunteers participated in the study and randomly received an oral dose of 400 mg loracarbef in the fasting state, 400 mg loracarbef following a standard breakfast or 400 mg loracarbef together with 200 mg acetylcysteine in granular form. Serum and urine concentrations were determined over 24 h by means of a bioassay. Loracarbef was well tolerated. Four volunteers complained of mild, transient headache. The substance was well absorbed with a mean peak level of 19.21 +/- 3.94 mg/l in the fasting state; it was primarily excreted in active form via the kidneys (urine recovery/24 h: 86-92%). The elimination half-life ranged from 70.3 to 102.0 min. Acetylcysteine had no effect on the absorption of loracarbef. The intake together with food delayed the absorption time, but had no influence on the bioavailability.

Pharmacokinetics and serum bactericidal activities of quinolones in combination with clindamycin, metronidazole, and ornidazole.

To enhance the antimicrobial spectrum of the quinolones against anaerobic organisms and gram-positive bacteria, we investigated in two studies the parenteral combinations of ciprofloxacin (200 mg) and ofloxacin (200 mg) with metronidazole (500 mg) or clindamycin (600 mg) and the oral combinations of enoxacin (400 mg) and fleroxacin (400 mg) with metronidazole (400 mg), clindamycin (300 mg), or ornidazole (500 mg) (only with fleroxacin). The pharmacokinetics and serum bactericidal activities (SBAs) against 5 aerobic and 2 anaerobic species (total, 58 strains) were determined in two groups of 10 healthy volunteers by using a randomized crossover study design. The additions of metronidazole, clindamycin, and ornidazole did not affect the pharmacokinetics of the quinolones. The combination of clindamycin with ciprofloxacin, ofloxacin, and, to a lesser extent, fleroxacin resulted in an increase of the SBA against gram-positive strains (mean peak titers): Staphylococcus aureus, ciprofloxacin alone, 1:5.5; ciprofloxacin-clindamycin, 1:19.9; ofloxacin alone, 1:3.6; ofloxacin-clindamycin, 1:17.5; fleroxacin alone, 1:4.3; fleroxacin-clindamycin, 1:8.1; Streptococcus pneumoniae (fleroxacin and enoxacin were not tested), ciprofloxacin alone, 1:2.0; ciprofloxacin-clindamycin, 1:53; ofloxacin alone, 1:2.6; and ofloxacin-clindamycin, 1:49.2. The high SBA of quinolones against gram-negative bacteria was not affected by the combinations; however, relatively low activities against Pseudomonas aeruginosa were detected. In general, against anaerobic bacteria, low bactericidal activities were determined in both studies (mean peak titers ranged from 1:2.1 to 1:3.1; mean trough titers range from 1:2.0 to 1:2.9). In clinical settings with severe mixed infections, a parenteral therapy consisting of modern quinolones together with clindamycin or imidazole derivatives seems to be active and offers no obvious interactions.

Pharmacokinetics of FCE 22891, a new oral penem.

FCE 22891 is the oral prodrug of FCE 22101, a new broad-spectrum penem. The pharmacokinetics of FCE 22891 after single-dose administration, its absolute bioavailability, and the effect of food intake on its absorption were investigated in three different randomized crossover studies in healthy volunteers. Drug levels in blood and urine were measured by high-pressure liquid chromatography and bioassay. For optimal comparison of the results of all studies, and since there was good agreement of both methods, only the high-pressure liquid chromatography results are included. The pharmacokinetics of the penem were linear, and its bioavailability after oral administration was 42 +/- 11%. Food intake increased the total area under the curve from 0 h to infinity from 11.9 +/- 3.5 to 14.1 +/- 2.4 mg.h/liter. A specific side effect, i.e., bladder complaints, was registered in some volunteers taking FCE 22891 at doses greater than or equal to 1.0 g.

Combination effects of ciprofloxacin, clindamycin, and metronidazole intravenously in volunteers.

Despite the broad antibacterial spectrum of ciprofloxacin, most anaerobic organisms are resistant to the drug, whereas several gram-positive organisms are only moderately susceptible. Thus, in some clinical situations, combined treatment with ciprofloxacin and metronidazole or clindamycin could be useful. Therefore, the pharmacokinetics and serum bactericidal activities of ciprofloxacin in combination with clindamycin or metronidazole were investigated using a randomized crossover study design in 10 healthy volunteers. Ciprofloxacin (200 mg) was administered alone and in combination with clindamycin (600 mg) or metronidazole (500 mg); all drugs were given intravenously over 30 minutes. Serum and urine concentrations of the substances were measured using standard methods (high-performance liquid chromatography or gas chromatography). Blood samples for determination of serum bactericidal activity against five different aerobic and two anaerobic bacterial species (a total of 58 strains) were obtained one hour and six hours after drug infusion. All values were statistically analyzed by use of the Student t test.

Influence of ranitidine, pirenzepine, and aluminum magnesium hydroxide on the bioavailability of various antibiotics, including amoxicillin, cephalexin, doxycycline, and amoxicillin-clavulanic acid.

Two randomized double-blind crossover studies and one randomized crossover study were performed to document possible drug-drug interactions between antacids (aluminum magnesium hydroxide, 10 ml per dose for 10 doses), antimuscarinic drugs (pirenzepine, 50 mg per dose for 4 doses), and H2-blockers (ranitidine, 150 mg per dose for 3 doses) and amoxicillin (1,000 mg), cephalexin (1,000 mg), doxycycline (200 mg), and amoxicillin-clavulanic acid (625 mg). Ten healthy volunteers participated in each study. Concentrations in serum and urine were measured by bioassay, and pharmacokinetic parameters were calculated by the usual open one- or two-compartment models (statistics were determined by the Wilcoxon test). The antacid, pirenzepine, and ranitidine had no influence on the bioavailability of amoxicillin, cephalexin, and amoxicillin-clavulanic acid. Only small differences could be observed in the pharmacokinetic parameters, but they are not of therapeutic importance. However, the antacid caused a significant (P less than 0.01) reduction in the gastrointestinal absorption of doxycycline (area under the concentration-time curve, 38.6 +/- 22.7 mg.h/liter, fasting; 6.0 +/- 3.2 mg.h/liter, with antacid), resulting in subtherapeutic levels of doxycycline.