Amitriptyline, a tricyclic antidepressant, has been used in the clinic to treat a number of disorders, in particular major depression and neuropathic pain. In the 1970s the ability of tricyclic antidepressants to inhibit acid sphingomyelinase (ASM) was discovered. The enzyme ASM catalyzes the hydrolysis of sphingomyelin to ceramide. ASM and ceramide were shown to play a crucial role in a wide range of diseases, including cancer, cystic fibrosis, diabetes, Alzheimer's disease, and major depression, as well as viral (e.g., measles virus) and bacterial (e.g., Staphylococcus aureus, Pseudomonas aeruginosa) infections. Ceramide molecules may act in these diseases by the alteration of membrane biophysics, the self-association of ceramide molecules within the cell membrane and the ultimate formation of larger ceramide-enriched membrane domains/platforms. These domains were shown to serve the clustering of certain receptors such as CD95 and may also act in the above named diseases. The potential to block the generation of ceramide by inhibiting the ASM has opened up new therapeutic approaches for the treatment of these conditions. Since amitriptyline is one of the longest used clinical drugs and side effects are well studied, it could potentially become a cheap and easily accessible medication for patients suffering from these diseases. In this review, we aim to provide an overview of current in vitro and in vivo studies and clinical trials utilizing amitriptyline to inhibit ASM and contemplate possible future applications of the drug.

We demonstrate that Pim-1 plays a pivotal role in several tumor-relevant signaling pathways and establish the functional relevance of Pim-1 in colon carcinoma. Our results also substantiate the RNAi-mediated Pim-1 knockdown based on polymeric polyethylenimine/small interfering RNA nanoparticles as a promising therapeutic approach.

The framing of HIV/AIDS as a crisis has facilitated the rollout of large-scale intervention programmes that represent an enormous effort at mainstreaming biomedical rationalities and neoliberal notions of responsibilisation and self-care. Based on a 'logic of choice' (Mol 2008) and 'responsibilised citizenship' (Robins 2005a), although veiled in a language of rights and partnership, the heavy focus on individual behaviour and a pharmaceutical 'solution' to AIDS shifts the burden of responsibility for the success of the heavily funded programmes onto the shoulders of the patients and conceals alternative forms of responsibility. Analysing how HIV-positive people in Tanzania navigate life with HIV and the complex treatment regimens, this paper looks beyond biomedical rationality, which places the preservation of individual biological life at the centre of its logic, and analyses people's constant struggle to negotiate the meaning of 'responsible behaviour' in the context of their lived realities. This repositions the notion of responsibility in the realm of the social and reveals the rationality behind apparently irrational practices.