Current Opinion in Pharmacology最新文献

Gonadotropin-releasing hormone (GnRH) is the final output of the central nervous system that drives fertility. A characteristic of GnRH secretion is its pulsatility, which is driven by a pulse generator. Each GnRH pulse triggers a luteinizing hormone (LH) pulse. However, the puzzle has been to reconcile the synchronicity of GnRH neurons with the scattered hypothalamic distribution of their cell bodies. A leap toward understanding GnRH pulses was the discovery of kisspeptin neurons near the distal processes of GnRH neurons, which secrete kisspeptins, potent excitatory neuropeptides on GnRH neurons, and equipped with dual, but opposite, self-modulatory neuropeptides, neurokinin B and dynorphin. Over the last decade, this cell-to-cell communication has been dissected in animal models. Today the 50-year quest for the basic mechanism of GnRH pulse generation may be over, but questions about its physiological tuning remain. Here is an overview of recent basic research that frames translational research.

For decades, chemoradiotherapy for early-stage disease and systemic chemotherapy for advanced disease have represented the mainstay of treatment for anal cancer. Over the last few years, however, the advent of immunotherapy has opened interesting therapeutic perspectives, with the establishment of new standards of care, and the development of clinical trials that may further shape the treatment algorithm for this tumour. In this review article, we discuss the rationale behind the use of immunotherapy for anal cancer and provide an overview of the available clinical data and ongoing efforts to build on these.

Individuals with chronic traumatic spinal cord injury (SCI) develop progressive multi-system health problems that result in clinical illness and disability. Systemic inflammation is associated with many of the common medical complications and acquired diseases that accompany chronic SCI, suggesting that it contributes to a number of comorbid pathological conditions. However, many of the mechanisms that promote persistent systemic inflammation and its consequences remain ill-defined. This review describes the significant biological factors that contribute to systemic inflammation, major organ systems affected, health risks, and the potential treatment strategies. We aim to highlight the need for a better understanding of inflammatory processes, and to establish appropriate strategies to address inflammation in SCI.

Recent advances in our understanding of host immune and cancer cells interactions have made immunotherapy a prominent choice in cancer treatment. Despite such promise, cell-based immunotherapies remain inapplicable to many patients due to severe limitations in the availability and quality of immune cells isolated from donors. Reprogramming technologies that facilitate the engineering of cell types of interest, are emerging as a putative solution to such challenges. Here we focus on the recent progress being made in reprogramming technologies with respect to the immune system and their potential for clinical applications.

Functional hypothalamic amenorrhea (FHA) is the most common cause of secondary amenorrhea in women of reproductive age. FHA is predominantly caused by stress, decreased caloric intake, excessive exercise, or a combination thereof. These physical, psychological, and metabolic stressors cause aberration in the pulsatile release of gonadotropin-releasing hormone (GnRH) and subsequently impair function of the hypothalamic–pituitary–ovarian (HPO) axis. Various neurotransmitters acting in the central nervous system are involved in control of the HPO axis and of these, kisspeptin is one of the most important. Corticotropin-releasing hormone (CRH), also inhibits the pulsatile secretion of GnRH and also acts as an intermediary between stress factors and the reproductive system. One of the main ongoing concerns in patients with FHA is chronic hypoestrogenism, a condition, which is associated with sexual dysfunction and infertility. It may also lead to osteoporosis, and predispose to neurodegenerative and cardiovascular diseases.

Treatment of FHA requires the elimination of causative factors, however, making the necessary lifestyle changes is not always easy to initiate and maintain. Broadening our knowledge of the complex neural mechanisms regulating reproductive function in which kisspeptin plays a key role can help in the development of new treatment options such as the potential of kisspeptin receptor agonists for patients with FHA.

The use of illegal androgens by young men is not uncommon. The majority of users take multiple courses of androgens during their lifetime, leading to a high cumulative exposure. An inseparable side effect is suppression of gonadal function. Although this usually recovers, recovery can take a long time and is not without symptoms.

This review focusses on recent studies that have greatly increased our knowledge of the disruption and recovery of testicular function during and after androgen abuse. For the guidance and treatment of (potential) users, in-depth knowledge of this is indispensable.

In the past, the primary approach for the treatment of endometriosis was represented by surgery; however, after the introduction of non-invasive diagnosis of endometriosis with the development of imaging technologies, medical treatment became the preferred approach, particularly in young patients. Hormonal drugs, by blocking menstruation, are the most effective for the treatment of endometriosis-related pain, independently of phenotype (ovarian, deep, or superficial endometriosis).

Gonadotropin-releasing hormone analogs and oral antagonists act on hypothalamus-pituitary-ovary axis inducing iatrogenic menopause, thus reducing dysmenorrhea and all pain symptoms. The side effects, such as hot flushes and bone loss, may be reduced by an add-back therapy. However, the cost in terms of women's health remains high in view of a long-term treatment.

Progestins are considered the first-line treatment, highly effective, and with reduced side effects. In addition to the well-known and largely used Norethisterone acetate and Medroxyprogesterone acetate, recently Dienogest has become one of the most used drugs in all endometriosis phenotypes for long-term treatment. Besides, Intrauterine levornogestrel or subcutaneous etonogestrel are valid alternative for long-term treatment.

Psoriasis and psoriatic arthritis are chronic inflammatory diseases affecting the skin and joints, respectively. Psoriasis and psoriatic arthritis are associated with a high comorbidity burden as well as negative impact on quality of life. Impact on health-related quality of life is optimized when both skin and joint manifestations are effectively treated. The identification of key cytokines involved in disease pathogenesis has led to the development of several therapeutic options for psoriatic disease. When selecting a therapy, it is important to consider disease severity, psoriasis disease subtypes or domains of psoriatic arthritis, comorbidities, patient preference for treatment, among other factors. This review summarizes current biologic and small molecule treatment options as well as emerging therapies for moderate-to-severe adult plaque psoriasis and psoriatic arthritis.

Axial spondyloarthritis (axSpA) is a chronic inflammatory disease that predominantly affects the axial skeleton and is characterized by inflammatory back pain. While much has been published regarding non-steroidal anti-inflammatory drugs and tumor necrosis factor inhibitors, other classes of medications which leverage alternate molecular mechanisms receive less attention. In this review, we summarize a few of the novel targets in axSpA, review the putative mechanism of action of therapies that focus on these targets, and reference the germane recently completed, ongoing, or proposed randomized controlled clinical trials. The agents addressed include inhibitors of interleukin-23, interleukin-17, janus kinases, granulocyte-macrophage colony-stimulating factor, macrophage migration inhibitory factor, antibodies recognizing T cell receptor beta variable 9 gene positive clones, as well as inhibitors of mitogen-activated protein kinase-activated protein kinase-2.

Fibroblast-like synoviocytes (FLS) are mesenchymal-derived cells that play an important role in the physiology of the synovium by producing certain components of the synovial fluid and articular cartilage. In rheumatoid arthritis (RA), however, fibroblasts become a key driver of synovial inflammation and joint damage. Because of this, there has been recent interest in FLS as a therapeutic target in RA to avoid side effects such as systemic immune suppression associated with many existing RA treatments. In this review, we describe how approved treatments for RA affect FLS signaling and function and discuss the effects of investigational FLS-targeted drugs for RA.