Benefit-risk assessment of antileukotrienes in the management of asthma.

Antileukotrienes are a relatively new class of anti-asthma drugs that either block leukotriene synthesis (5-lipoxygenase inhibitors) like zileuton, or antagonise the most relevant of their receptors (the cysteinyl leukotriene 1 receptor [CysLT1]) like montelukast, zafirlukast or pranlukast. Hence, their major effect is an anti-inflammatory one. With the exception of pranlukast, the other antileukotrienes have been studied and marketed in the US and Europe for long enough to establish that they are useful drugs in the management of asthma. Their effects, significantly better than placebo, seem more pronounced in subjective measurements (i.e. symptoms scores or quality-of-life tests) than in objective parameters (i.e. forced expiratory volume in 1 second or peak expiratory flow rate). Also, there is some evidence that these drugs work better in some subsets of patients with certain genetic polymorphisms - probably related to their leukotriene metabolism - or patients with certain asthma characteristics. There are a small number of comparative studies only, and with regard to long-term asthma control differences between the agents have not been evaluated. Nevertheless, their overall effect appears comparable with sodium cromoglycate (cromolyn sodium) or theophylline, but significantly less than low-dose inhaled corticosteroids. Antileukotrienes have been shown to have a degree of corticosteroid-sparing effect, but salmeterol appears to perform better as an add-on drug. Montelukast is probably the most useful antileukotriene for continuous treatment of exercise-induced asthma, performing as well as salmeterol without inducing any tolerance. All antileukotrienes are taken orally; their frequency of administration is quite different ranging from four times daily (zileuton) to once daily (montelukast). Antileukotrienes are well tolerated drugs, even though zileuton intake has been related to transitional liver enzyme elevations in some cases. Also Churg-Strauss syndrome (a systemic vasculitis), has been described in small numbers of patients taking CysLT1 antagonists. It is quite probable that this disease appears as a consequence of an 'unmasking' effect when corticosteroid dosages are reduced in patients with severe asthma once CysLT1 antagonists are introduced, but more data are needed to definitely establish the mechanism behind this effect. Overall, however, the benefits of antileukotrienes in the treatment of asthma greatly outweigh their risks.     

Pharmacokinetics of trofosfamide and its dechloroethylated metabolites

 To contribute to effective and safe outpatient treatment, we investigated the metabolism of trofosfamide (Trofo) after oral administration. We analyzed Trofo metabolism in 15 patients aged from 3 to 73 years who were treated with 150 or 250 mg/m² Trofo in combination with etoposide. Serum samples were collected with 13 patients after oral administration, and Trofo and its dechloroethylated metabolites were quantified by gas chromatography. Urine samples were collected from five patients and analyzed by same method. Ifosfamide (Ifo) was the main metabolite in serum and urine (AUC_Trofo:AUC_Ifo 1:13), whereas cyclophosphamide (Cyclo) was formed in smaller amounts (AUC_Ifo:AUC_Cyclo 18:1). Ifo and Cyclo were further oxidized in the chloroethyl side chains to form 2- and 3-dechloroethylifosfamide in varying quantities. The urinary excretion of Trofo and its dechloroethylated metabolites amounted to about 10% of the total dose. Our results confirm former in vitro observations about the metabolism of Trofo. The main side-chain metabolites Ifo and Cyclo can be further activated by oxidation and formation of their respective phosphoramide mustards. Hence, Trofo is an interesting agent for oral chemotherapy. Received 21 July 1996 / Accepted: 11 November 1996     

Age does not influence early and late tumor-related outcome for bronchogenic carcinoma

BACKGROUND: The influence of age on early and late outcome after surgical resection of bronchogenic carcinoma is unknown. In an attempt to clarify this issue, we reviewed the outcome of 212 consecutive patients with primary lung cancer who had surgical treatment for bronchogenic carcinoma. METHODS: Ninety-two patients were younger than 50 years (group 1), and 120 patients were older than 70 years of age (group 2). Squamous cell carcinoma and adenocarcinoma were the most common histologic types in both groups. According to the new international staging classification, a similar proportion of stage I, II, and III were observed in both groups. RESULTS: Only the rate of pneumonectomy was significantly higher in younger patients (41% versus 22%, p = 0.002). The overall operative mortality rate in group 1 was 2.2% and 2.6% after pneumonectomy. In group 2 the overall mortality rate was 2.5% and 3.8% after pneumonectomy. Advanced age did not affect operative mortality. The adjusted (tumor-related) survival rate at 5 years was 56% in group 1 and 53% in group 2 (p = 0.93). The adjusted survival rate for patients with stage I was 61% in group 1 and 65% in group 2 (p = 0.21), and for stage IIIa 39% in group 1 and 48% in group 2 (p = 0.43). The adjusted 5-year survival rate was 56% in group 1 and 59% in group 2 for squamous cell carcinoma (p = 0.53) and 49% in group 1 and 42% in group 2 for adenocarcinoma (p = 0.76). CONCLUSIONS: Perioperative risk and midterm survival were similar in younger and older patients after surgical resection of bronchogenic carcinoma. We believe that this result is because surgical candidates constitute already a highly selected group of patients. From these data it is not possible to conclude that biologic behavior of lung cancer is more aggressive in younger patients.     

Quercetin promotes degradation of survivin and thereby enhances death-receptor-mediated apoptosis in glioma cells

The flavonoid quercetin has been reported to inhibit the proliferation of cancer cells, whereas it has no effect on nonneoplastic cells. U87-MG, U251, A172, LN229, and U373 malignant glioma cells were treated with quercetin (50-200 microM). Quercetin did not cause cytotoxicity 24 h after treatment. Combining quercetin with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) strongly augmented TRAIL-mediated apoptosis in U87-MG, U251, A172, and LN229 glioma cells; U373 cells could not be sensitized by quercetin to TRAIL-mediated apoptosis. TRAIL-induced apoptosis was enhanced by quercetin-induced reduction of survivin protein levels. Upon treatment with quercetin, the protein level of survivin was strongly suppressed in U87-MG, U251, and A172 but not in U373 glioma cells. Quercetin exposure resulted in proteasomal degradation of survivin. TRAIL-quercetin-induced apoptosis was markedly reduced by overexpression of survivin. In addition, upon treatment with quercetin, downregulation of survivin was also regulated by the Akt pathway. Taken together, the results of the present study suggest that quercetin sensitizes glioma cells to death-receptor-mediated apoptosis by suppression of inhibitor of the apoptosis protein survivin.     

Transitional care for patients with acute stroke—A priority‐setting project

BackgroundThe scope of this priority‐setting process is communication and collaboration in transitional care for patients with acute stroke. Actively involving persons with stroke and their family caregivers is important both in transitional care and when setting priorities for research. Established priority‐setting methods are time‐consuming and require extensive resources. They are therefore not feasible in small‐scale research. This article describes a pragmatic priority‐setting process to identify a prioritized top 10 list of research needs regarding transitional care for patients with acute stroke.MethodsA pragmatic priority‐setting approach inspired by the James Lind Alliance was developed. It involves establishing a user group, identifying the research needs through an online survey, analysing and checking the research needs against systematic reviews, culminating in an online prioritization of the top 10 list.ResultsThe process was completed in 7 months. A total of 122 patients, family caregivers, health personnel and caseworkers submitted 484 research needs, and 19 users prioritized the top 10 list. The list includes the categories ‘patients and caregivers’ needs and health literacy’, ‘health personnel''s common understanding’, ‘information flow between health personnel and patients and caregivers’, ‘available interventions and follow‐up of patients and caregivers’, ‘interaction and collaboration between health personnel and caseworkers across hospital and primary healthcare’ and ‘disabilities after stroke’.ConclusionThis paper outlines a pragmatic approach to identifying and prioritizing users'' research needs that was completed in 7 months. The top 10 list resulting from this priority setting process can guide future research relating to communication and collaboration during the transition from hospital to the community for patients with stroke.Patient and Public ContributionMembers of three stroke organizations participated in the advisory group. They gave feedback on the scope and the process, distributed the surveys and prioritized the top 10 list. Persons with stroke and their caregivers submitted research needs in the survey.     

Gaps and opportunities in the treatment of relapsed-refractory multiple myeloma: Consensus recommendations of the NCI Multiple Myeloma Steering Committee

A wide variety of new therapeutic options for Multiple Myeloma (MM) have recently become available, extending progression-free and overall survival for patients in meaningful ways. However, these treatments are not curative, and patients eventually relapse, necessitating decisions on the appropriate choice of treatment(s) for the next phase of the disease. Additionally, an important subset of MM patients will prove to be refractory to the majority of the available treatments, requiring selection of effective therapies from the remaining options. Immunomodulatory agents (IMiDs), proteasome inhibitors, monoclonal antibodies, and alkylating agents are the major classes of MM therapies, with several options in each class. Patients who are refractory to one agent in a class may be responsive to a related compound or to a drug from a different class. However, rules for selection of alternative treatments in these situations are somewhat empirical and later phase clinical trials to inform those choices are ongoing. To address these issues the NCI Multiple Myeloma Steering Committee formed a relapsed/refractory working group to review optimal treatment choices, timing, and sequencing and provide recommendations. Additional issues considered include the role of salvage autologous stem cell transplantation, risk stratification, targeted approaches for genetic subsets of MM, appropriate clinical trial endpoints, and promising investigational agents. This report summarizes the deliberations of the working group and suggests potential avenues of research to improve the precision, timing, and durability of treatments for Myeloma.Subject terms: Combination drug therapy, Cancer therapeutic resistance, Targeted therapies     

Methämoglobinbildung durch Sulfonamide im System Leberhomogenat,Erythrocyten, NADPH und Sauerstoff

Summary Methaemoglobin formation by sulfonamides in a system containing liver homogenates, NADPH and erythrocytes was compared under standardized conditions.

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Referat der 28. Tagung der Deutschen Pharmakologischen Gesellschaft vom 5.–8. Okt. 1964 in Bad Nauheim. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 250, 286 (1965).