A randomized phase 1 study of safety, tolerability, and pharmacokinetics of MK-1088, a novel dual adenosine receptor antagonist, in healthy adult participants.

This phase 1 first-in-human study evaluated the safety, tolerability, and pharmacokinetics of MK-1088, a novel, small-molecule dual inhibitor of adenosine A and A receptors. Healthy adult participants were enrolled in two panels (n = 8 each) and randomly assigned to receive MK-1088 (n = 6) or placebo (n = 2) orally in each of five treatment periods. Participants in panel A received single ascending doses of MK-1088 at 1, 10, 50, and 150 mg or placebo in a fasted or fed (50 mg only) state.

Considerations for Cell and Gene Therapy Programs Entering the Clinical Space.

Cell and gene therapy (CGT) describes a broad category of medicinal products with potential applications to prevent and treat human disease in multiple therapeutic areas. These therapies leverage the use of modified nucleic acids, altered cells or tissue, or both. The modality, mechanism, route of administration, and therapeutic indication for a CGT product will influence the challenges and opportunities for early clinical development, some of which may be highly specific to the product under consideration.

A Study to Evaluate Doravirine Pharmacokinetics When Coadministered With Acid-Reducing Agents.

Doravirine is a novel non-nucleoside reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus type 1 infection. Because of potential concomitant administration with acid-reducing agents, a drug-interaction trial was conducted to evaluate the potential impact of these types of medications on doravirine pharmacokinetics. In an open-label, 3-period, fixed-sequence trial, healthy adult participants received the following: period 1, a single dose of doravirine 100 mg; period 2, coadministration of a single dose of doravirine 100 mg and an antacid (1600 mg aluminum hydroxide, 1600 mg magnesium hydroxide, and 160 mg simethicone); period 3, 40 mg pantoprazole once daily on days 1-5 coadministered with a single dose of doravirine 100 mg on day 5.

Atazanavir increases the plasma concentrations of 1200 mg raltegravir dose.

Raltegravir is a human immunodeficiency virus (HIV)-1 integrase strand transfer inhibitor currently marketed at a dose of 400 mg twice-daily (b.i.d.

Broadening the spectrum of β-lactam antibiotics through inhibition of signal peptidase type I.

The resistance of methicillin-resistant Staphylococcus aureus (MRSA) to all β-lactam classes limits treatment options for serious infections involving this organism. Our goal is to discover new agents that restore the activity of β-lactams against MRSA, an approach that has led to the discovery of two classes of natural product antibiotics, a cyclic depsipeptide (krisynomycin) and a lipoglycopeptide (actinocarbasin), which potentiate the activity of imipenem against MRSA strain COL. We report here that these imipenem synergists are inhibitors of the bacterial type I signal peptidase SpsB, a serine protease that is required for the secretion of proteins that are exported through the Sec and Tat systems.

Restoring methicillin-resistant Staphylococcus aureus susceptibility to β-lactam antibiotics.

Despite the need for new antibiotics to treat drug-resistant bacteria, current clinical combinations are largely restricted to β-lactam antibiotics paired with β-lactamase inhibitors. We have adapted a Staphylococcus aureus antisense knockdown strategy to genetically identify the cell division Z ring components-FtsA, FtsZ, and FtsW-as β-lactam susceptibility determinants of methicillin-resistant S. aureus (MRSA).

Genetic and pharmacological evaluation of cathepsin s in a mouse model of asthma.

Cathepsin S (Cat S) is predominantly expressed in antigen-presenting cells and is up-regulated in several preclinical models of antigen-induced inflammation, suggesting a role in the allergic response. Prophylactic dosing of an irreversible Cat S inhibitor has been shown to attenuate pulmonary eosinophilia in mice, supporting the hypothesis that Cat S inhibition before the initiation of airway inflammation is beneficial in airway disease. In addition, Cat S has been shown to play a role in more distal events in the allergic response.

Upregulation of tachykinin NK-1 and NK-3 receptor binding sites in the spinal cord of spontaneously hypertensive rat: impact on the autonomic control of blood pressure.

1 Effects of intrathecally (i.t.) injected tachykinin NK-1 and -3 receptor agonists and antagonists were measured on mean arterial blood pressure (MAP) and heart rate (HR) in awake unrestrained spontaneously hypertensive rats (SHR,15-week-old) and age-matched Wistar Kyoto rats (WKY).

Activation of Rho after traumatic brain injury and seizure in rats.

Traumatic brain injury (TBI) is characterized by a progressive cell loss and a lack of axonal regeneration. In the central nervous system (CNS), the Rho signaling pathway regulates the neuronal response to growth inhibitory proteins and regeneration of damaged axons, and Rho activation is also correlated with an increased susceptibility to apoptosis. To evaluate whether traumatic brain injury (TBI) results in changes in Rho activation in vulnerable regions of the brain, GTP-RhoA pull down assays were performed on rat cortical and hippocampal tissue homogenates obtained from 24 h to 3 days following lateral fluid percussion brain injury (FPI).

The ventral tegmental area as a putative target for tachykinins in cardiovascular regulation.

Tachykinin receptor agonists and antagonists were microinjected into the ventral tegmental area (VTA) to study the relative participation of the three tachykinin receptors in cardiovascular regulation in freely behaving rat. Selective agonists (1-100 pmol) for NK1 ([Sar9, Met (O2)11]SP), NK2 ([beta-Ala8]NKA (4-10)) and NK3 (senktide) receptors evoked increases in blood pressure, heart rate (HR) along with behavioural manifestations (face washing, sniffing, head scratching, rearing, wet dog shake). At 1 pmol, NK1 and NK3 agonists did not affect behaviour and blood pressure but only HR.