The Novartis view on emerging drugs and novel targets for the treatment of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a debilitating lung disease characterized by airflow limitation and chronic inflammation in the lungs. The mainstay of drug therapy for COPD is represented by long-acting bronchodilators, an important aspect of Novartis' development program. Novel once-daily dosing bronchodilators, such as the long-acting muscarinic antagonist (LAMA) glycopyrronium and the LAMA/long-acting ß2-agonist (LABA) fixed-dose combination QVA149, have been shown to provide significant benefits to patients with COPD in terms of improvement in lung function, exercise tolerance, health-related quality of life, symptoms and reduction in the rate of exacerbations. Despite the benefits provided by these new treatment options, prevention of disease progression and control of exacerbations in certain patient phenotypes remain key challenges in the treatment of COPD. In order to address these needs and gain new insights into the complexity of COPD, Novartis is, in addition to bronchodilator-only therapies, developing LABA/inhaled corticosteroids (ICS) combinations to target inflammation, such as QMF149, as well as non-steroid based anti-inflammatory agents against key novel targets. These commitments are central to the Novartis' final goal of improving the standard of care in respiratory medicine and offering a better quality of life to patients with COPD.

Evening dosing is associated with higher plasma concentrations of pranlukast, a leukotriene receptor antagonist, in healthy male volunteers.

AIMS: To study the magnitude of differences in the pharmacokinetics of pranlukast, after morning and evening administration. METHODS: Pranlukast (300 mg) was administered to 12 healthy male volunteers on two separate occasions, either in the morning or evening. Both doses were given 30 min after a standard high fat content meal. Blood samples were collected up to 18 h postdose. Plasma was assayed by high performance liquid chromatography. Standard pharmacokinetic and statistical analyses were performed. RESULTS: Statistically significant (P < 0.05) increases were noted in AUC(o,t) (56%) and tmax (2.5 h) after evening administration. Cmax was 14% higher after evening dosing (95% C.I. 0.71-1.84). CONCLUSIONS: Pranlukast bioavailability is apparently increased after evening dosing as compared with morning administration. Higher night-time and early morning plasma concentrations may confer additional therapeutic benefit at a time when asthmatics are at greatest risk of developing bronchospasm.

Resection margins in carcinoma of the head of the pancreas. Implications for radiation therapy.

A retrospective review of the pathology and clinical course of 72 patients undergoing resection of carcinoma of the head of the pancreas was undertaken to identify the frequency of tumor involvement at standard surgical transection margins (stomach, duodenum, pancreas, and bile duct) as well as the peripancreatic soft tissue margin and the potential clinical significance of these findings. Of 72 patients undergoing resection, 37 patients (51%) were found to have tumor extension to the surgical margins. The most commonly involved margin was peripancreatic soft tissue (27 patients) followed by pancreatic transection line (14 patients) and bile duct transection line (4 patients). For 37 patients with tumor present at a resection margin, there were no survivors beyond 41 months. No difference in survival or local control was seen between 14 patients receiving postoperative radiation therapy and 5-fluorouracil (5-FU) compared with 23 patients not receiving additional treatment. In contrast, the 5-year actuarial survival and local control of 35 patients undergoing resection without tumor invasion to a resection margin was 22% and 43%, respectively. The 5-year survival and local control of 16 patients receiving adjuvant radiation therapy and 5-FU was 29% and 42%, respectively, whereas these figures were 18% and 31% for 19 patients not receiving adjuvant therapy (p > 0.10). Because residual local tumor after resection is common, preoperative radiation therapy may be beneficial in this disease. It should minimize the risk of dissemination during operative manipulation and facilitate a curative resection by promoting tumor regression. Because local failure rates approach 60% after resection and adjuvant therapy even in cases having clear resection margins, intraoperative radiation therapy to the tumor bed at the time of resection also might be considered. Protocols evaluating the feasibility and efficacy of preoperative radiation therapy and resection with intraoperative radiation therapy for patients with pancreatic cancer are underway.

Bacterial infection is not necessary for lethal necrotizing pancreatitis in mice.

Sepsis is the most common cause of late death in pancreatitis. The presence of early bacterial infection has been correlated with the severity of the disease. A choline-deficient ethionine-supplemented (CDE) diet given to young female mice produces severe necrotizing pancreatitis that has morphologic and biochemical similarities to the human disease. We therefore searched for bacterial pancreatic infection in female CD-1 mice given the CDE diet. The mortality rate was 47.5% in mice fed the CDE diet. All of these mice had severe pancreatitis with inflammation, edema, and necrosis on histologic examination. Bacterial infection was present in 1/12 pancreatica among nonsurvivors and in 1/32 pancreatica in surviving animals (p not significant). Histologic examination showed edema to be more pronounced in surviving mice, although the overall severity of morphologic changes was not significantly different between survivors and nonsurvivors. We conclude that bacterial infection is not a determinant of the severity or lethality of experimental pancreatitis induced by the CDE diet.

Prevention of postoperative pericardial adhesions. An animal study.

Following heart operations, adhesions uniformly form between the epicardium and surrounding structures such as the pericardium, mediastinal fat, pleura, and sternum. These adhesions make reoperations both difficult and hazardous. Three groups of 15 dogs each were studied to assess the effectiveness of pharmacologic manipulation in reducing the adhesions. In the control group, adhesions were created by allowing epicardial/pericardial surfaces to dry, and then adding cotton fibers and blood before closing the pericardium. In the methylprednisolone group, 500 mg of methylprednisolone was given intravenously at the time of operation, followed by 0.3 mg/kg orally three times a day for one week. In the ibuprofen group, 12.5 mg/kg of ibuprofen was given intravenously at operation and then orally three times in one day, followed by 5 mg/kg orally three times a day for six days. Dogs were killed at three to four weeks and the adhesions between pericardium and epicardium were graded. In the control group, none were adhesion-free and none had filmy adhesions; three dogs had dense patchy adhesions and 12 had dense diffuse adhesions. In the methylprednisolone group, 14 dogs had no adhesions; one had filmy adhesions; and none had dense patchy or dense diffuse adhesions. In the ibuprofen group, none were adhesion-free; one dog had filmy adhesions; four had dense patchy adhesions; and ten had dense diffuse adhesions. The near-total elimination of pericardial/epicardial adhesions utilizing methylprednisolone, if also achievable in humans, would markedly reduce the difficulty and increase the safety of cardiac reoperations.