Risankizumab.rzaa: an interleukin monoclonal antibody antagonist binding to the p19 subunit of human IL-23 cytokine.

Plaque psoriasis is the commonest form of psoriasis affecting about 85% of those patients with the condition. Risankizumab was developed as a high-affinity humanized monoclonal antibody specific for the p19 subunit of interleukin-23 (IL-23p19). Clinical trials demonstrated that risankizumab was very effective in patients with moderate to severe plaque psoriasis causing total clearing of the condition as evidenced by Psoriasis Scalp Severity Index (PSSI100) and static Physician's Global Assessment (sPGA) of 0 in more than 50% of patients after 52 weeks of treatment. Risankizumab has been approved by the Food and Drug Administration (FDA) for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy as a dose of 150 mg administered by subcutaneous injection at week 0, week 4 and every 12 weeks thereafter.

Nusinersen: antisense oligonucleotide to increase SMN protein production in spinal muscular atrophy.

Patients with spinal muscular atrophy (SMA) have an autosomal recessive disease that limits their ability to produce survival motor neuron (SMN) protein in the CNS resulting in progressive wasting of voluntary muscles. Detailed studies over several years have demonstrated that phosphorothioate and 2'-O-methoxyethyl- modified antisense oligonucleotides (ASOs) targeting the ISS-N1 site increase SMN2 exon 7 inclusion, thus increasing levels of SMN protein in a dose- and time-dependent manner in liver, kidney and skeletal muscle, and CNS tissues only when administered intrathecally. On a dose basis, nusinersen was found to be the most potent ASO for SMN2 splicing correction in the CNS of adult mice. After nusinersen was found to increase levels of SMN protein in the CNS of mice and subhuman primates without causing significant adverse events, it was advanced into clinical studies in patients with SMA. These trials in SMA patients have demonstrated significant improvements in various measures of motor function and in progression to movement developments not normally seen in SMA patients. In addition, there have been significant extensions in life expectancy. These findings led to the U.S. and European approval of nusinersen for use in SMA patients of all ages.

Lifitegrast: First LFA-1/ICAM-1 antagonist for treatment of dry eye disease.

Dry eye disease is an extremely common condition affecting millions worldwide. The underlying pathophysiological mechanism is thought to be localized inflammation of the ocular surface resulting in the localization of T cells at this surface followed by their activation and subsequent liberation of cytokines. This effect on T cells results from the binding of lymphocyte function-associated antigen-1 (LFA-1) located on T cells to intercellular adhesion molecule 1 (ICAM-1) expressed on inflamed epithelium and endothelium, and on T cells. Lifitegrast is a T-cell integrin antagonist designed to mimic ICAM-1, thus blocking the interaction of LFA-1 and ICAM-1. Lifitegrast enters the systemic circulation to a limited extent thus reducing the likelihood of unwanted systemic reactions. Clinical trials in over 2,500 subjects with dry eye disease have shown that 5.0% lifitegrast given by ocular instillation causes a significant reduction in objective and subjective signs and symptoms of the disease. These beneficial effects are associated with a relatively low incidence of unwanted effects, almost all local in nature. In light of these findings, lifitegrast was approved by the Food and Drug Administration (FDA) in 2016 for the treatment of dry eye disease, the first drug with this mechanism of action to be so approved.

Thyroid status and dietary fatty acids affect beta-adrenoceptor agonist stimulation of tension development in rat myocardium.

1. The inotropic responses to the beta-adrenoceptor agonists adrenaline, noradrenaline and isoprenaline were examined in papillary muscles isolated from hypothyroid rats and euthyroid controls that had been fed diets enriched in either n-6 or n-3 fatty acids. 2. In hypothyroid animals fed the n-6 diet, the maximum developed tension in the presence of isoprenaline was only 54% greater than resting tension compared to 160% in euthyroid animals. Maximum tension was 105% greater than resting in hypothyroid animals fed the n-3 diet compared to 399% in controls. Similar responses to adrenaline and noradrenaline were seen, i.e. maximum tension was significantly greater in both hypothyroid and euthyroid animals fed the n-3 diet, but tension was depressed in the hypothyroid state. 3. Binding of the beta-adrenoceptor antagonist [3H]-dihydroalprenolol to ventricular membranes was saturable and of high affinity, irrespective of thyroid state and diet. While binding site density (Bmax) was not affected by the hypothyroid state or diet, binding affinity (Kd) was higher in hypothyroid animals fed the n-6 diet. 4. The inotropic response to forskolin was the same in hypothyroid animals, irrespective of diet, but maximum developed tension was significantly greater in euthyroid animals fed the n-6 compared to the n-3 diet. The dose-response curve for forskolin was shifted to the right in hypothyroid animals fed the n-3 diet indicating a decrease in sensitivity. 5. These results indicate that the depressed contractility in the hypothyroid heart may be due in part to an altered lipid environment of the beta-adrenoceptor complex and that n-3 fatty acids can significantly increase maximum developed tension in the hypothyLroid state.

Euglobal-In-1, a new euglobal from Eucalyptus incrassata.

From the juvenile leaves of Eucalyptus incrassata, a new euglobal having an acylphloroglucinol-sesquiterpene structure, euglobal-In-1 (1), has been isolated along with the known euglobal-III (2) and -V (3). The structure and stereochemistry of 1 were established by spectroscopic methods.