Understanding the UK Psychoactive Substances Act.

This review paper is based on a talk given at the British Pharmaceutical Society Winter Meeting in 2018 derived from the Home Office Report on the workings of the UK Psychoactive Substances Act (PSA) published in November 2018. The review deals with the context in which the PSA 2016 arose and how this piece of legislation differs from other UK drug regulations. It attempts to put the PSA in context with other control schemes being instituted around the world and to assess the success of the Act in its first 2 years of implementation. For more details the reader is referred to Review of the Psychoactive Substances Act 2016, Home Office, November 2018.

Partnership between small biotech and big pharma.

The process involved in the identification and development of novel breakthrough medicines at big pharma has recently undergone significant changes, in part because of the extraordinary complexity that is associated with tackling diseases of high unmet need, and also because of the increasingly demanding requirements that have been placed on the pharmaceutical industry by investors and regulatory authorities. In addition, big pharma no longer have a monopoly on the tools and enabling technologies that are required to identify and discover new drugs, as many biotech companies now also have these capabilities. As a result, researchers at biotech companies are able to identify credible drug leads, as well as compounds that have the potential to become marketed medicinal products. This diversification of companies that are involved in drug discovery and development has in turn led to increased partnering interactions between the biotech sector and big pharma. This article examines how Merck and Co Inc, which has historically relied on a combination of internal scientific research and licensed products, has poised itself to become further engaged in partnering with biotech companies, as well as academic institutions, to increase the probability of success associated with identifying novel medicines to treat unmet medical needs--particularly in areas such as central nervous system disorders, obesity/metabolic diseases, atheroma and cancer, and also to cultivate its cardiovascular, respiratory, arthritis, bone, ophthalmology and infectious disease franchises.

New treatments for neuropathic pain.

Existing treatments for neuropathic pain deliver inadequate pain relief, unacceptable side effects, or both. The unmet medical need for more effective treatment is driving a large volume of research to discover new drugs. Most existing treatments are drugs introduced to treat other pain conditions or other medical conditions, such as antidepressants and anticonvulsants, which were found empirically to be effective for neuropathic pain. Only recently have drug discovery efforts have become mechanistically driven, addressing targets identified by a molecular neurobiological approach to the pathophysiology of neuropathic states.

The bradykinin B1 receptor antagonist B9858 inhibits a nociceptive spinal reflex in rabbits.

There are two bradykinin receptor subtypes, designated B1 and B2. Whilst both have been implicated in nociception, it is believed that there is a low level of constitutive expression of B1 receptors and that their expression is induced by inflammation or tissue damage. The present study investigated the role of B1 receptors in spinal nociceptive processing using an in vivo electrophysiological assay in decerebrate, spinalized rabbits, a species that shares close B1 receptor homology with the human receptor. Inflammation was induced in the paw by an injection of complete Freund's adjuvant at least 1 h before recording single motor unit activity of the semitendinous/biceps femoris muscle in response to a noxious pinch of the foot. Control animals received an intraplantar injection of saline. The peptide B1 receptor antagonist B9858 was administered i.v. and caused dose-dependent and complete inhibition of the nociceptive spinal reflex (ID50 = 1 mg x kg(-1)). In control animals without paw inflammation, B9858 had no effect. These findings are consistent with other evidence that peptide B1 receptor antagonists inhibit spinal nociceptive reflexes only after induction of B1 receptors by inflammation and support the potential therapeutic utility of B1 receptor antagonists as analgesic and anti-inflammatory drugs.

Immunohistochemical localization of calcitonin receptor-like receptor and receptor activity-modifying proteins in the human cerebral vasculature.

Calcitonin gene-related peptide and adrenomedullin belong to a structurally related neuropeptide family and are potent vasodilators expressed in the trigeminovascular system. The molecular identity of receptors for these proteins has only recently been elucidated. Central to functional binding of these neuropeptides is the G-protein-coupled receptor, the calcitonin receptor-like receptor (CRLR), whose cell surface expression and pharmacology is determined by coexpression of a receptor activity-modifying protein (RAMP). CRLR combined with RAMP binds calcitonin gene-related peptide with high affinity, whereas CRLR coexpression with RAMP2 or -3 confers high-affinity binding of adrenomedullin. The authors investigated the expression of these receptor components in human cerebral vasculature to further characterize neuropeptide receptor content and the potential functions of these receptors. Localization has been carried out using specific antisera raised against immunogenic peptide sequences that were subsequently applied using modern immunohistochemical techniques and confocal microscopy. The results are the first to show the presence of these receptor component proteins in human middle meningeal, middle cerebral, pial, and superficial temporal vessels, and confirm that both calcitonin gene-related peptide and adrenomedullin receptors may arise from the coassembly of RAMPs with CRLR in these vessel types. These novel data advance the understanding of the molecular function of the trigeminovascular system, its potential role in vascular headache disorders such as migraine, and may lead to possible ways in which future synthetic ligands may be applied to manage these disorders.

Enantioselective inhibition of the formalin paw late phase by the NK1 receptor antagonist L-733,060 in gerbils.

Intravenous administration of the NK1 receptor antagonist L-733,060 to gerbils 3 h before intraplantar injection of formalin caused a dose-dependent and complete inhibition of the late, but not early, phase nociceptive response (paw licking). The ID50 for L-733,060 (0.17 mg/kg) revealed a greater than 50-fold separation in potency over its less active enantiomer L-733,061 (ID50 > or = 10 mg/kg). In contrast, the non-brain penetrant quaternary ketone NK1 receptor antagonist, L-743,310 (3 mg/kg), did not attenuate the response to formalin, indicating that the antinociceptive effect of blockade of NK1 receptors by L-733,060 in this assay is centrally-mediated. These findings add to the preclinical evidence that NK1 receptor antagonists may be of therapeutic use as centrally-acting analgesics.