Novartis

About: Novartis is a company organization based out in Basel, Switzerland. It is known for research contribution in the topics: Alkyl & Population. The organization has 41930 authors who have published 50566 publications receiving 1978996 citations. The organization is also known as: Novartis International AG.

Preclinical pharmacology of CGP 42'446, a new, potent, heterocyclic bisphosphonate compound.

Abstract: We have investigated the pharmacologic effects of a new bisphosphonate compound, CGP 42′446 [2-(imidazol-1-yl)-1-hydroxyethylidene-1,1-bisphosphonate], on bone metabolism. The compound exhibited potent inhibitory activity on the bone resorption induced by 1,25-dihydroxyvitamin D3 both in vivo in the thyroparathyroidectomized rat (ED50 0.072 μg/kg SC) and in vitro in mouse calvarial cultures (IC50 0.002 μM). A comparison of the in vivo and in vitro inhibitory potencies of a total of nine bisphosphonates revealed an excellent correlation between the two assays (r = 0.97). CGP 42′446 also potently inhibited calvarial bone resorption induced by parathyroid hormone (1–34), parathyroid hormone-related protein (1–34), and recombinant human interleukin-1β. Short-term treatment of growing rats with CGP 42′446 dose-dependently increased the radiographic density of the tibial proximal metaphysis (ED50 1.7 μg/kg SC) as well as increasing the calcium and hydroxyproline content of femoral trabeculae (ED50 values 0.17 and 1.1 μg/kg SC, respectively), but there was no detectable effect on cortical bone. On a molar basis in this range of in vivo screening assays, CGP 42′446 was between 940-fold (thyroparathyroidectomized rat) and 87-fold (rat femoral trabecular calcium content) more potent than pamidronate. It is concluded that CGP 42′446 is a promising new, highly potent bisphosphonate for the suppression of the increased bone resorption associated with various diseases.

Controlled trial of interleukin-2 infusions in patients infected with the human immunodeficiency virus.

Abstract: Background Interleukin-2 is a cytokine that regulates the proliferation and differentiation of lymphocytes. In preliminary studies, intermittent infusions of interleukin-2 led to increases in CD4 counts in patients with human immunodeficiency virus (HIV) infection and more than 200 CD4 cells per cubic millimeter. We conducted a controlled study to evaluate the long-term effects of such therapy on both CD4 counts and the viral burden. Methods Sixty HIV-infected patients with base-line CD4 counts above 200 cells per cubic millimeter were randomly assigned to receive either interleukin-2 plus antiretroviral therapy (31 patients, 1 of whom was lost to follow-up) or antiretroviral therapy alone (29 patients). Interleukin-2 was administered every two months for six cycles of five days each, starting at a dosage of 18 million IU per day. Safety and immunologic and virologic measures were monitored monthly until four months after the last treatment cycle. Results In patients treated with interleukin-2, the mean (...

STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T cell activity in the lung tumor microenvironment

Abstract: STK11/LKB1 is among the most commonly inactivated tumor suppressors in non-small cell lung cancer (NSCLC), especially in tumors harboring KRAS mutations. Many oncogenes promote immune escape, undermining the effectiveness of immunotherapies, but it is unclear whether the inactivation of tumor suppressor genes, such as STK11/LKB1, exerts similar effects. In this study, we investigated the consequences of STK11/LKB1 loss on the immune microenvironment in a mouse model of KRAS-driven NSCLC. Genetic ablation of STK11/LKB1 resulted in accumulation of neutrophils with T-cell-suppressive effects, along with a corresponding increase in the expression of T-cell exhaustion markers and tumor-promoting cytokines. The number of tumor-infiltrating lymphocytes was also reduced in LKB1-deficient mouse and human tumors. Furthermore, STK11/LKB1-inactivating mutations were associated with reduced expression of PD-1 ligand PD-L1 in mouse and patient tumors as well as in tumor-derived cell lines. Consistent with these results, PD-1-targeting antibodies were ineffective against Lkb1-deficient tumors. In contrast, treating Lkb1-deficient mice with an IL6-neutralizing antibody or a neutrophil-depleting antibody yielded therapeutic benefits associated with reduced neutrophil accumulation and proinflammatory cytokine expression. Our findings illustrate how tumor suppressor mutations can modulate the immune milieu of the tumor microenvironment, and they offer specific implications for addressing STK11/LKB1-mutated tumors with PD-1-targeting antibody therapies.

Effects of Vildagliptin on Glucose Control Over 24 Weeks in Patients With Type 2 Diabetes Inadequately Controlled With Metformin

Abstract: OBJECTIVE —We sought to evaluate the efficacy and safety of vildagliptin, a new dipeptidyl peptidase-4 inhibitor, added to metformin during 24 weeks of treatment in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS —This was a double-blind, randomized, multicenter, parallel group study of a 24-week treatment with 50 mg vildagliptin daily ( n = 177), 100 mg vildagliptin daily ( n = 185), or placebo ( n = 182) in patients continuing a stable metformin dose regimen (≥1,500 mg/day) but achieving inadequate glycemic control (A1C 7.5–11%). RESULTS —The between-treatment difference (vildagliptin − placebo) in adjusted mean change (AMΔ) ± SE in A1C from baseline to end point was −0.7 ± 0.1% ( P P P = 0.003) and −1.7 ± 0.3 mmol/l ( P P = 0.022 vs. placebo), 14.8, and 18.2% of patients receiving 50 mg vildagliptin daily, 100 mg vildagliptin daily, or placebo, respectively. One patient in each treatment group experienced one mild hypoglycemic event. CONCLUSIONS —Vildagliptin is well tolerated and produces clinically meaningful, dose-related decreases in A1C and FPG as add-on therapy in patients with type 2 diabetes inadequately controlled by metformin.