Most attempts at rational development of new analgesics have failed, in part because chronic pain involves multiple processes that remain poorly understood. To improve translational success, one strategy is to select novel targets for which there is proof of clinical relevance, either genetically through heritable traits, or pharmacologically. Such an approach by definition yields targets with high clinical validity. The biology of these targets can be elucidated in animal models before returning to the patients with a refined therapeutic. For optimal treatment, having biomarkers of drug action available is also a plus. Here we describe a case study in rational drug design: the use of controlled inhibition of peripheral tetrahydrobiopterin (BH4) synthesis to reduce abnormal chronic pain states without altering nociceptive-protective pain. Initially identified in a population of patients with low back pain, the association between BH4 production and chronic pain has been confirmed in more than 12 independent cohorts, through a common haplotype (present in 25% of Caucasians) of the rate-limiting enzyme for BH4 synthesis, GTP cyclohydrolase 1 (GCH1). Genetic tools in mice have demonstrated that both injured sensory neurons and activated macrophages engage increased BH4 synthesis to cause chronic pain. GCH1 is an obligate enzyme for de novo BH4 production. Therefore, inhibiting GCH1 activity eliminates all BH4 production, affecting the synthesis of multiple neurotransmitters and signaling molecules and interfering with physiological function. In contrast, targeting the last enzyme of the BH4 synthesis pathway, sepiapterin reductase (SPR), allows reduction of pathological BH4 production without completely blocking physiological BH4 synthesis. Systemic SPR inhibition in mice has not revealed any safety concerns to date, and available genetic and pharmacologic data suggest similar responses in humans. Finally, because it is present in vivo only when SPR is inhibited, sepiapterin serves as a reliable biomarker of target engagement, allowing potential quantification of drug efficacy. The emerging development of therapeutics that target BH4 synthesis to treat chronic pain illustrates the power of combining human and mouse genetics: human genetic studies for clinical selection of relevant targets, coupled with causality studies in mice, allowing the rational engineering of new analgesics.
Analgesics ; therapeutic use ; Animals ; Biopterin ; analogs & derivatives ; metabolism ; Chronic Pain ; drug therapy ; genetics ; Disease Models, Animal ; Drug Discovery ; GTP Cyclohydrolase ; genetics ; metabolism ; Humans ; Rodentia ; Signal Transduction ; drug effects ; genetics

Testosterone deficiency (TD) is an increasingly common problem with significant health implications, but its diagnosis and management can be challenging. A multi-disciplinary panel from BSSM reviewed the available literature on TD and provide evidence-based statements for clinical practice. Evidence was derived from Medline, EMBASE and Cochrane searches on hypogonadism, testosterone therapy (T Therapy) and cardiovascular safety from May 2017 to September 2022. This revealed 1,714 articles, including 52 clinical trials and 32 placebo-controlled randomised controlled trials. A total of twenty-five statements are provided, relating to five key areas: screening, diagnosis, initiating T Therapy, benefits and risks of T Therapy, and follow-up. Seven statements are supported by level 1 evidence, eight by level 2, five by level 3, and five by level 4. Recent studies have demonstrated that low levels of testosterone in men are associated with increased risk of incident type 2 diabetes mellitus, worse outcomes in chronic kidney disease and COVID 19 infection with increased all-cause mortality, along with significant quality of life implications. These guidelines should help practitioners to effectively diagnose and manage primary and age-related TD.