Inhibition of the mechanistic target of rapamycin (mTOR) protein kinase extends life span and ameliorates aging-related pathologies including declining immune function in model organisms. The objective of this phase 2a randomized, placebo-controlled clinical trial was to determine whether low-dose mTOR inhibitor therapy enhanced immune function and decreased infection rates in 264 elderly subjects given the study drugs for 6 weeks. A low-dose combination of a catalytic (BEZ235) plus an allosteric (RAD001) mTOR inhibitor that selectively inhibits target of rapamycin complex 1 (TORC1) downstream of mTOR was safe and was associated with a significant ( = 0.001) decrease in the rate of infections reported by elderly subjects for a year after study drug initiation. In addition, we observed an up-regulation of antiviral gene expression and an improvement in the response to influenza vaccination in this treatment group. Thus, selective TORC1 inhibition has the potential to improve immune function and reduce infections in the elderly.

A large unmet medical need exists for safer antithrombotic drugs because all currently approved anticoagulant agents interfere with hemostasis, leading to an increased risk of bleeding. Genetic and pharmacologic evidence in humans and animals suggests that reducing factor XI (FXI) levels has the potential to effectively prevent and treat thrombosis with a minimal risk of bleeding. We generated a fully human antibody (MAA868) that binds the catalytic domain of both FXI (zymogen) and activated FXI. Our structural studies show that MAA868 traps FXI and activated FXI in an inactive, zymogen-like conformation, explaining its equally high binding affinity for both forms of the enzyme. This binding mode allows the enzyme to be neutralized before entering the coagulation process, revealing a particularly attractive anticoagulant profile of the antibody. MAA868 exhibited favorable anticoagulant activity in mice with a dose-dependent protection from carotid occlusion in a ferric chloride–induced thrombosis model. MAA868 also caused robust and sustained anticoagulant activity in cynomolgus monkeys as assessed by activated partial thromboplastin time without any evidence of bleeding. Based on these preclinical findings, we conducted a first-in-human study in healthy subjects and showed that single subcutaneous doses of MAA868 were safe and well tolerated. MAA868 resulted in dose- and time-dependent robust and sustained prolongation of activated partial thromboplastin time and FXI suppression for up to 4 weeks or longer, supporting further clinical investigation as a potential once-monthly subcutaneous anticoagulant therapy.

Pain has both physical and emotional components. Physical noxious stimuli activate peripheral sensory neurons that, in turn, relay signals to the spinal and supraspinal nuclei. Subsequently, these signals activate areas within the brain associated with pain. Despite considerable knowledge in this area, analgesics may provide pain complete relief in only one out of five patients. Failure to manage pain may be due to a lack of understanding of the neurobiological processing of pain. Factors such as anticipation, anxiety and pain history play roles in the perception of pain. Non-neuronal cells such as those of the immune system influence perception and modulation of pain by the nervous system. In post-dental surgery patients, the severity of the pain and the relief following administration of anti-inflammatory analgesics has been linked to the time course of inflammatory mediators. Similarly, the relief of post-operative pain after abdominal surgery is also associated with a reduction in expression of pro-inflammatory mediators. Administration of anti-cytokines to sciatica patients and subsequent pain relief further emphasizes the role of pro-inflammatory mediators in modulation of pain. Increased expression of inflammatory mediators may also alter response to analgesia. For example, rheumatoid patients with temporal mandibular joint disease with increased expression of interleukins prior to treatment demonstrate inadequate pain relief after administration of anti-TNF-?. In addition, pain or its trauma impairs absorption of oral analgesics causing therapeutic failure. Improved analgesic pharmacotherapy may require a better understanding of the involvement of the inflammatory pathways.

1 In¯ammation may in¯uence response to pharmacotherapy. 2 We investigated the eect of in¯ammation on response to sotalol, a b-adrenergic receptor and potassium channel antagonist. Racemic sotalol (40 mg kg 71) was administered to healthy, acutely (interferona 2a-induced) and chronically (Mycobacterium butyricum-induced adjuvant arthritis) in¯amed male Sprague-Dawley rats (n=4 ± 6/group). Another group of interferon-treated rats received 3 mg kg 71 of anti-TNF antibody in¯iximab. Electrocardiogram (ECG) recorded and plasma sotalol concentration monitored for 6 h. The study was repeated in acutely in¯amed rats following administration of stereochemically pure individual sotalol enantiomers [40 mg kg 71 S (potassium channel blocker) or 20 mg kg 71 R (b-adrenergic/potassium channel blocker)]. 3 Chronic arthritis was readily evident. Acute arthritis was associated with elevated segmented neutrophils and increased plasma nitrite and tumour necrosis factor (TNF) concentrations. Sotalol aected ECG in all rats. In both in¯amed groups, however, response to sotalol in prolongation of QT interval (potassium channel sensitivity) was reduced. The eect of PR interval (b-adrenergic activity) was also reduced following administration of the racemate and R-enantiomer. No signi®cant dierences in pharmacokinetics were observed between control and in¯amed rats. 4 In¯iximab reduced nitrite and TNF concentrations and reversed the eect of acute in¯ammation on both PR and QT intervals. 5 The reduced electrocardiographic responses to sotalol is likely due to the in¯uence of in¯ammation on the action of the drug on both b-adrenergic and potassium channel receptors secondary to over-expression of pro-in¯ammatory cytokines and/or nitric oxide. 6 Our observation may have therapeutic consequences in all conditions where in¯ammatory mediators are increased.

Typically, colonic absorption of a drug is mandatory for a sustained release formulation to hold the drug’s plasma level for more than 12 or 24 h above the minimum therapeutic plasma concentration (efficacy). According to Drugs@FDA, only 7.4% of the oral drugs are extended release forms probably showing colonic absorption. Therefore an early determination of a drug’s colonic absorption using the IntelliCap® in animals or humans will provide the mandatory information to initiate or stop a SR form development. Diltiazem (60 mg) is used in the oral swallowable IntelliCap® and the marketed SR form from Mylan (coated beads). A human study with 14 healthy volunteers compared the Mylan formulation with the IntelliCap® device that releases the drug identical to the in-vitro dissolution of the Mylan product. The plasma profiles of IntelliCap® and Mylan formulation are highly similar. The mean AUC (bioequivalence fulfilled) and mean Cmax of IntelliCap® shows only a difference of +15% and −12%, respectively. But the PK profile of the Mylan formulation shows a broader peak around Cmax. About 81.8% diltiazem was absorbed in the colon (IntelliCap®) comparable to former publications. The Mylan is a SR diffusion coated beads form whereas the IntelliCap® is a monolithic capsule. The beads are transported in the gut and spread which results in a longer Tmax and a broader Cmax peak. The IntelliCap® device can quantitatively measure the colonic absorption of a drug in excellent accordance to a standard oral SR dosage form.