Current Opinion in Pharmacology最新文献

β-blockers are a solid pillar in the treatment of cardiovascular diseases. However, they are highly discussed regarding effectiveness for certain indications and side-effects. Even though there are up to 20 licensed compounds, only four are used for heart failure (HF) therapy. On the receptor level several key characteristics seem to influence the clinical outcome: subtype selectivity, antagonistic vs (inverse/biased) agonistic properties and -in particular- ancillary capacities. On a molecular level, divergent and novel signaling patterns are being identified and extra-cardiac effects on e.g. inflammation, metabolism and oxidative stress are highlighted. This review discusses different well-known and newly discovered characteristics that need to be considered for HF therapy and in the context of co-morbidities.

Neovascular age-related macular degeneration (nAMD) is the leading cause of blindness in the elderly in developed countries. Intravitreal injection of VEGF inhibitors is the mainstream therapy for nAMD, although nearly 50% of the patients do not respond or respond poorly to the therapy. One of the main reasons for the poor outcome of the therapy is the development of subretinal macular fibrosis, a process of excessive deposition of extracellular matrix proteins around the diseased blood vessels. Currently, there is no medication to prevent or treat the condition. Here, we discussed recent advances in the pathogenesis of nAMD-mediated macular fibrosis, with a focus on the role of the complement system. We further proposed approaches to target the complement system for the management of macular fibrosis and highlighted the area of further research for future clinical applications of complement-based therapy.

Several decades of research support the involvement of transient receptor potential (TRP) channels in nociception. Despite the disappointments of early TRPV1 antagonist programs, the TRP family remains a promising therapeutic target in pain disorders. High-dose capsaicin patches are already in clinical use to relieve neuropathic pain. At present, localized injections of the side-directed TRPV1 agonist capsaicin and resiniferatoxin are undergoing clinical trials in patients with osteoarthritis and bone cancer pain. TRPA1, TRPM3, and TRPC5 channels are also of significant interest. This review discusses the role of TRP channels in human pain conditions.

To develop effective therapies for complex blinding diseases such as age-related macular degeneration (AMD), identification of mechanisms involved in its initiation and progression is needed. The estrogen-related receptor alpha (ESRRA) is an orphan nuclear receptor that regulates several AMD-associated pathogenic pathways. However, it has not been investigated in detail in the ocular posterior pole during aging or in AMD. This review delves into the literature highlighting the significance of ESRRA as a molecular target that may be important in the pathobiology of AMD, and discusses data available supporting the targeting of this receptor signaling pathway as a therapeutic option for AMD.

Low back pain (LBP) is a major unmet clinical need. The endocannabinoid system (ECS) has emerged as a promising therapeutic target for pain, including LBP. This review examines the evidence for the ECS as a therapeutic target for LBP. While preclinical studies demonstrate the potential of the ECS as a viable therapeutic target, clinical trials have presented conflicting findings. This review underscores the need for innovative LBP treatments and biomarkers and proposes the ECS as a promising avenue for their exploration. A deeper mechanistic understanding of the ECS in LBP could inform the development of new pain management strategies.

Chronic pain conditions are unmet medical needs, since the available drugs, opioids, non-steroidal anti-inflammatory/analgesic drugs and adjuvant analgesics do not provide satisfactory therapeutic effect in a great proportion of patients. Therefore, there is an urgent need to find novel targets and novel therapeutic approaches that differ from classical pharmacological receptor antagonism. Most ion channels and receptors involved in pain sensation and processing such as Transient Receptor Potential ion channels, opioid receptors, P2X purinoreceptors and neurokinin 1 receptor are located in the lipid raft regions of the plasma membrane. Targeting the membrane lipid composition and structure by sphingolipid or cholesterol depletion might open future perspectives for the therapy of chronic inflammatory, neuropathic or cancer pain, most importantly acting at the periphery.