Papain-induced asthma: a man with dyspnea from dawn till dust.

A 52-year-old man, a current smoker (40 pack years) with unremarkable medical history, was referred to the outpatient pneumology clinic because of recent complaints of shortness of breath and wheezing, which were relieved by inhaled bronchodilators. Serial peak expiratory flow (PEF) measurements showed a clear rise in PEF during the weekend and a fall on the evening after the first day of the week. It also showed that evening values were always lower than morning values. During a holiday, a slow but persistent rise in PEF was observed. Such a pattern is highly suggestive for occupational asthma. A detailed description of his job revealed papain exposure. After a positive specific IgE and skin prick test for papain the diagnosis of papain induced asthma was made. When an allergy and serious lung function impairment is proven against products encountered in a work related situation, not improving after maximal preventive measures, the patient is advised to change job.

Higher food intake and appreciation with a new food delivery system in a Belgian hospital. Meals on Wheels, a bedside meal approach: a prospective cohort trial.

AIM: A new system of meal distribution called Meals on Wheels, allowing food ordering at mealtime and providing guidance by trained nutritional assistants, might show benefit in offering nutritional support. This study investigates whether Meals on Wheels improves total food intake per day and yielded improved appreciation of food quality and increased access to food and mealtimes. METHODS: In a prospective cohort trial where control and intervention groups were taken from all patients hospitalized at the respiratory disease department, age, sex, BMI, admission weight, height, reason for admission and discharge weight were noted, as was food intake, supplements, waste per meal and daily total. For food appreciation the questionnaire developed by Naithani et al. was used. The study included 83 patients in the control group and 106 patients in the Meals on Wheels group. RESULTS: Mean total daily food intake was 236 g higher in patients in the Meals on Wheels than in controls. There was higher intake of oral nutritional supplements in the Meals on Wheels group compared to controls, resulting in significantly less oral nutritional supplements wasted. There was also significantly less waste in the Meals on Wheels group. For food access and appreciation, patients appreciated Meals on Wheels more than the old system in terms of choice, hunger, food quality and organization. CONCLUSIONS: Meals on Wheels resulted in higher food intake during each meal, less waste and better use of oral nutritional supplements. Patients appreciated Meals on Wheels more than the old system in terms of choice, hunger, food quality and organization.

Superior sulcus tumor arising in an azygos lobe.

A non-small cell lung cancer presenting as a superior sulcus tumor in an azygos lobe has not yet been reported. We present such a case in a 69-year-old man undergoing complete resection after induction chemoradiotherapy and discuss the specific location of a superior sulcus tumor and the aberrant anatomy of an azygos lobe.

Clinical-benefit response in advanced non-small-cell lung cancer: A multicentre prospective randomised phase III study of single agent gemcitabine versus cisplatin-vindesine.

BACKGROUND: The modest improvement in median survival of advanced non-small-cell lung cancer (NSCLC) by cisplatin-based chemotherapy has led to the current opinion that clinical benefit for the patient is at least as important an end-point as objective response rate (ORR) or survival. Clinical benefit response was the primary end-point of this prospective randomised trial in symptomatic, advanced stage IIIB/IV NSCLC, comparing single agent gemcitabine (GEM) to cisplatin-based chemotherapy. PATIENTS AND METHODS: Patients received either GEM (1000 mg/m2, days 1, 8 and 15) or cisplatin (100 mg/M2, day 1) plus Vindesine (3 mg/m2, days 1 and 15) (PV), both every four weeks. Clinical benefit was measured by a simple metric based on changes in a visual analogue symptom score list, the Karnofsky performance status and the weight. RESULTS: One hundred sixty-nine patients were randomised (84 GEM, 85 PV). Prognostic factors and baseline symptoms were well balanced between the two arms. Most of the the objective responders and about half of the patients with disease stabilisation experienced clinical benefit. Compared to PV, a significantly larger number of GEM-treated patients experienced a clinical benefit (48.1 vs. 28.9%, P = 0.03) that lasted significantly longer (median duration 16 vs. 10 weeks, P = 0.01). No important differences in ORR, time-to-progression or median survival were observed. Grade 3 + 4 toxicity was significantly higher in the PV-group for leukopenia (P = 0.0003), neutropenia (P < 0.0001), nausea/vomiting (P = 0.0006), alopecia (P < 0.0001), and neurotoxicity (P = 0.04). Some severe pulmonary toxicity to GEM was noted. CONCLUSION: Comparison of GEM with cisplatin-based therapy in symptomatic, advanced NSCLC demonstrates that GEM produces significantly a stronger and longer-lasting clinical benefit, probably due to its equal effectiveness in terms of ORR, time-to-progression or survival, combined with significantly less severe therapy-related toxicity.

Fatal asthma attributed to patent foramen ovale.

A 37 year old woman was admitted to the hospital with acute severe asthma, shortly followed by respiratory failure and circulatory arrest. Despite intensive cardio-pulmonary resuscitation, during which extreme arterial hypoxaemia persisted, the patient died. Postmortem examination revealed a patent foramen ovale, with a diameter of 1 cm. A severe right-to-left shunt, initiated by acute pulmonary hypertension, was considered to be the cause of death. Because of the relatively high prevalence of patent foramen ovale in the normal population, we suggest this patency may enhance the risk of fatal outcome of acute severe asthma.

Penetration of netilmicin in the lower respiratory tract after once-daily dosing.

A major criticism of the use of aminoglycosides for the treatment of pneumonia is the poor penetration in infected airways. Once-daily dosing of aminoglycosides results in higher peak plasma concentrations without increasing toxic reactions and with optimization of pharmacodynamic properties. To predict intrapulmonary antimicrobial activity after once-daily dosing of aminoglycosides, it is necessary to determine the respective bronchial and alveolar disposition. We prospectively conducted a pharmacokinetic study of netilmicin following the first intravenous administration of a once-daily dosing schedule in 20 ventilated patients with pneumonia. A bronchoscopic sampling of bronchial secretions and a subsegmental bronchoalveolar lavage (BAL) were performed 60, 90, 120, and 180 min (five patients at each time point) on the first treatment day after intravenous administration over 30 min of 450 mg of netilmicin. The netilmicin concentrations in the alveolar lining fluid (ALF) were calculated using urea as an endogenous marker of dilution. In bronchial secretions, a peak concentration of 2.00 (SEM: 0.26) mg/L or 6 percent of the 30-min plasma concentration was reached at 120 min. In ALF, much higher levels were found. At 120 min, a peak ALF concentration of 14.7 (SEM: 2.22) mg/L or 41 percent of the 30-min plasma concentration was reached. Spearman's rank correlation testing failed to show a correlation between bronchial and ALF concentrations. Higher plasma concentrations of netilmicin after once-daily dosing give rise to ALF concentrations exceeding the minimum inhibitory concentration of susceptible respiratory pathogens involved in nosocomial pneumonia, while bronchial concentrations remain low. Aminoglycoside concentrations in bronchial secretions cannot be used to predict alveolar concentrations. Low diffusibility can no longer be considered as a disadvantage of aminoglycosides for treating pneumonias.

Changes in lymphocyte subpopulations in patients treated with cefodizime for acute lower respiratory tract infections.

The influence of cefodizime (CDZ) on CD4 and CD8 lymphocytes was investigated in patients with lower respiratory tract infection and underlying respiratory diseases. Ten men and one woman were treated with CDZ 1 g i.m. b.i.d. for ten days. The infecting organisms were Haemophilus influenzae (5), Streptococcus pneumoniae (2) and Escherichia coli (1). No adverse events were reported. Nine patients were clinically cured; two required further antibiotic therapy. Leucocyte counts decreased significantly during treatment. Lymphocyte counts and CD4 cells both increased significantly in absolute and relative numbers, while there was a much smaller increase in CD8 cells. This resulted in a significant increase in the CD4/CD8 ratio. These effects of CDZ might be of benefit for immunocompromised patients with bacterial infections.

Pharmacokinetic evaluation of tobramycin in the alveolar lining fluid of the rat after endotracheal administration.

Using bronchoalveolar lavage (BAL) we evaluated the concentration-time profile of tobramycin in the alveolar lining fluid (ALF) of rats after direct endotracheal instillation (1.5 mg/kg) and aerosolization (10 mg/ml for 15 min). Very high and long-persisting concentrations of tobramycin were reached in ALF after both modes of administration. After aerosolization a peak concentration in ALF of 339 +/- 41 micrograms/ml was reached with a slow but progressive decline to 45 +/- 8 micrograms/ml at 6 h. After direct endotracheal instillation significantly higher (p less than 0.01) concentrations in ALF (peak concentration, 2,100 +/- 16 micrograms/ml) were reached and formed a stable plateau until 4 h after administration, progressively declining thereafter (400 +/- 30 micrograms/ml at 6 h). Systemic vascular absorption from the alveoli was minimal, but it was higher after direct endotracheal instillation (peak serum concentration, 1.55 +/- 0.21 micrograms/ml). We conclude that in view of the favorable pharmacokinetic profile and the minimal systemic absorption, endobronchial administration of aminoglycosides may be a valuable alternative to systemic administration, which eventually can reduce systemic toxicity and the need for therapeutic drug monitoring.

The penetration of aminoglycosides into the alveolar lining fluid of rats. The effect of airway inflammation.

The concentration-time profile of gentamicin and tobramycin in the alveolar lining fluid (ALF) of rats was determined after intravenous bolus injection using bronchoalveolar lavage (BAL). BAL can be used for evaluating the penetration of both aminoglycosides into the ALF if highly sensitive detection methods are used, and an endogenous marker (urea) can be applied to avoid the unpredictable dilutional effect of the lavage procedure. The concentration of gentamicin and tobramycin in ALF reached a peak after 5 and 10 min, respectively, and remained high when plasma concentrations were declining, suggesting an accumulation reservoir in the lung acini. The ratio of the AUC of the concentration-time profile in ALF and plasma was 0.67 and 0.45 for gentamicin and tobramycin, respectively. The penetration of both aminoglycosides into the ALF was significantly higher after induction of airway inflammation by inhalation of endotoxin. The ratio of the AUC in ALF and plasma in the endotoxin-exposed animals was 0.76 and 0.55 for gentamicin and tobramycin, respectively. The ratio of the AUC of the concentration-time profile of gentamicin in ALF to that of tobramycin was 1.27 without inflammation and 1.44 after endotoxin exposure. Thus, both with and without inflammation, gentamicin penetrates better into the ALF than does tobramycin.

Pharmacokinetics of antibiotics in the lungs.

This paper reviews current knowledge on the relationship between local penetration or antibiotics and therapeutic efficacy in pulmonary and bronchial infections. The antimicrobial drug concentration at the site of infection is supposedly determinative for the efficacy of the antibiotic treatment but the number of studies in respiratory infections supporting this hypothesis is limited. The mechanisms responsible for the pulmonary deposition or orally or systemically administered antibiotics include passive diffusion, active transport, bulk flow and permeation. The penetration of antimicrobial drugs into the respiratory tract is influenced by both host-related factors, such as inflammation or mechanical injury, and drug-related factors, such as molecular weight. In addition, local bio-inactivation can occur. The final bioactive antibiotic concentration at the site of the respiratory infection is, therefore, the result or a very complex dynamic process. Different sampling and measuring methods have been used for the assessment of antibiotic concentrations at the site of respiratory infections. Concentrations in sputum, bronchial secretions and biopsy specimens have been correlated with serum concentrations and clinical outcome. Bronchoalveolar lavage could be a promising technique for evaluating antibiotic drug concentrations in alveolar lining fluid. For many antibiotics, data concerning penetration and pharmacokinetic behaviour in the respiratory tract are lacking.

Penetration of ampicillin and sulbactam in the lower airways during respiratory infections.

We studied the penetration of ampicillin-sulbactam in the alveolar lining fluid (ALF) of eight patients after intravenous administration of 2,000 mg of ampicillin and 1,000 mg of sulbactam three times daily over 30 min. Bronchoalveolar lavage was performed on day 3, 30 min after the end of the morning drug administration. The mean penetration ratios (i.e., the ratios of the concentrations in ALF versus those in serum) were 53% (standard error, 12%) and 61% (standard error 31%) for ampicillin and sulbactam, respectively. The concentration ratio of ampicillin versus sulbactam in serum was not significantly different from that in ALF. From a pharmacokinetic point of view, ampicillin-sulbactam is a good choice for treatment of infectious exacerbation of chronic obstructive pulmonary disease and community-acquired bacterial pneumonia, since the concentrations of both drugs in ALF exceed the MICs for the respiratory pathogens responsible.

Pharmacokinetics of nisoldipine in renal dysfunction.

The pharmacokinetics of nisoldipine have been studied after oral administration of one 10 mg tablet to 3 groups of patients: Group A (n = 8) with a mean creatinine of 90 ml/min, Group B (n = 8) with a mean creatinine clearance of 12 ml/min and Group C of 12 patients on maintenance haemodialysis. All of them were studied off-dialysis and 7 were also studied on a dialysis day. No significant differences were observed between Groups A, B and C (on an interdialysis day) in AUC (0-7h), tmax, Cmax and plasma protein binding. Unchanged nisoldipine could not be recovered from the urine in any patient. Haemodialysis did not significantly affect AUC, tmax and Cmax, and nisoldipine could not be detected in the dialysate. The results indicate that the dose of nisoldipine need not be changed in patients with renal dysfunction, and that a supplementary dose is not required after haemodialysis. Blood pressure in the uraemics fell more than in the patients with good renal function.

Bronchoalveolar lavage in acute hypersensitivity pneumonitis caused by sulfasalazine.

Sulfasalazine has been reported to induce pulmonary eosinophilia and hypersensitivity with symptoms of dyspnea and fever. We present the results of bronchoalveolar lavage in a patient with acute sulfasalazine-induced hypersensitivity pneumonitis. The lavage specimen showed a significant influx of eosinophils.

The pharmacokinetics of ciprofloxacin in patients with impaired renal function.

Pharmacokinetics of ciprofloxacin after single oral administration of 250 mg were studied in patients with and without renal failure. Ciprofloxacin concentrations were measured by HPLC. The elimination half-life was 8.7 +/- 0.9 h (mean +/- S.E.M.) in six renal failure patients not on haemodialysis, as compared to 4.4 +/- 0.2 h in six patients with normal renal function. The urinary recovery of unchanged ciprofloxacin was 5.3 +/- 1.7% of dose over 24 h in the renal failure patients, as compared to 37.0 +/- 3.7% in the patients with normal renal function. In haemodialysis patients, the half-life was 5.8 +/- 0.9 h on an interdialysis day, and 3.2 +/- 0.4 h during haemodialysis.

Philadelphia-positive T-acute lymphoblastic leukemia.

A case of typical T-acute lymphoblastic leukemia (T-ALL) is reported in which, at diagnosis, 100% of bone marrow metaphases showed a Philadelphia (Ph) translocation, t(9;22). These cells completely disappeared following chemotherapy. The significance of the Ph chromosome in T and B leukemic cells is discussed.