Results of a phase I trial to assess the safety of macitentan in combination with temozolomide for the treatment of recurrent glioblastoma.

Background: There is an urgent need for additional therapies to treat recurrent glioblastoma (GBM). Preclinical studies suggest that high dose macitentan, an oral dual endothelin receptor antagonist, enhances the cytotoxic effects of temozolomide (TMZ) in GBM, improving survival. This phase I trial investigated the maximum tolerated dose of macitentan combined with TMZ in patients with recurrent GBM and assessed the safety and tolerability of high dose macitentan in these patients (NCT01499251).

Pharmacokinetics, Tolerability, and Safety of Murepavadin, a Novel Antipseudomonal Antibiotic, in Subjects with Mild, Moderate, or Severe Renal Function Impairment.

This open-label, nonrandomized, single-dose, phase 1 study evaluated the pharmacokinetics and safety of murepavadin, a novel peptide antibiotic for the treatment of serious infections. The study was conducted in 32 subjects of either sex in 4 groups (up to 8 per group) with mild (group 1), moderate (group 2), and severe (group 3) renal function impairment or with normal renal function (group 4). The degree of renal impairment of the subjects was classified at screening according to the estimated creatinine clearance (CL) according to the Cockcroft-Gault equation.

Lucerastat, an Iminosugar for Substrate Reduction Therapy: Tolerability, Pharmacodynamics, and Pharmacokinetics in Patients With Fabry Disease on Enzyme Replacement.

Lucerastat is a glucosylceramide synthase inhibitor aimed at reducing production of glycosphingolipids (GSLs), including those accumulating in Fabry disease. The safety, tolerability, pharmacodynamics, and pharmacokinetics of oral lucerastat were evaluated in an exploratory study in patients with Fabry disease. In this single-center, open-label, randomized study, 10 patients received lucerastat 1,000 mg b.

Lucerastat, an Iminosugar for Substrate Reduction Therapy: Pharmacokinetics, Tolerability, and Safety in Subjects With Mild, Moderate, and Severe Renal Function Impairment.

Lucerastat, an inhibitor of glucosylceramide synthase, has the potential for substrate reduction therapy in glycosphingolipid storage disorders such as Fabry disease. In pharmacokinetic studies in rats, dogs, and healthy subjects, the main route of elimination was renal. The pharmacokinetics, tolerability, and safety of lucerastat were evaluated in subjects with mild (group A), moderate (group B), and severe (group C) renal impairment.

Effect of Hepatic or Renal Impairment on the Pharmacokinetics, Safety, and Tolerability of Ponesimod, a Selective S1P1 Receptor Modulator.

Ponesimod, a selective S1P1 receptor modulator, is a potential therapeutic agent for autoimmune disorders. The impact of hepatic or renal impairment on the pharmacokinetics, safety and tolerability of ponesimod and its inactive metabolites, ACT-204426 and ACT-338375, was evaluated. Two separate single-centre, open-label studies with 32 (hepatic study) and 24 (renal study) male and female individuals were conducted.

Discovery of camphor-derived pyrazolones as 11β-hydroxysteroid dehydrogenase type 1 inhibitors.

Starting from screening hit, (4S,7R)-1,7,8,8-tetramethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (7), we optimized the potency and pharmacokinetic properties. This led to the identification of compounds with good in vivo activity in a mouse pharmacodynamic model of inhibition of 11βHSD1.

Discovery of pyrazolo[3,4-d]pyrimidine derivatives as GPR119 agonists.

We designed and synthesized a novel series of phenylamino- and phenoxy-substituted pyrazolo[3,4-d]pyrimidine derivatives as GPR119 agonists. SAR studies indicated that electron-withdrawing substituents on the phenyl ring are important for potency and full efficacy. Compound 26 combined good potency with a promising pharmacokinetic profile in mice, and lowered the glucose excursion in mice in an oral glucose-tolerance test.

7-Phenyl-pyrido[2,3-d]pyrimidine-2,4-diamines: novel and highly selective protein tyrosine phosphatase 1B inhibitors.

High throughput screening of the Roche compound collection led to the identification of diaminopyrroloquinazoline series as a novel class of PTP1B inhibitors. Structural modification of diaminopyrroloquinazoline series resulted in pyrido[2,3-d]pyrimidine-2,4-diamine series which was further optimized to give compounds 5 and 24 as potent, selective (except T-cell phosphatase) PTP1B inhibitors with good mouse PK properties.

The emerging role of the intestine in metabolic diseases.

The intestine is an important metabolic organ that has gained attention in recent years for the newly identified role that it plays in the pathophysiology of various metabolic diseases including obesity, insulin resistance and diabetes. Recent insights regarding the role of enteroendocrine hormones, such as GIP, GLP-1, and PYY in metabolic diseases, as well as the emerging role of the gut microbial community and gastric bypass bariatric surgeries in modulating metabolic function and dysfunction have sparked a wave of interest in understanding the mechanisms involved, in an effort to identify new therapeutics and novel regulators of metabolism. This review summarizes the current evidence that the gastrointestinal tract has a key role in the development of obesity, inflammation, insulin resistance and diabetes and discusses the possible players that can be targeted for therapeutic intervention.

Recombinant tissue factor pathway inhibitor in severe community-acquired pneumonia: a randomized trial.

Rationale: Severe community-acquired pneumonia (sCAP) is a leading cause of death worldwide. Adjunctive therapies for sCAP are needed to further improve outcome. A systemic inhibitor of coagulation, tifacogin (recombinant human tissue factor pathway inhibitor) seemed to provide mortality benefit in the sCAP subgroup of a previous sepsis trial.

Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial.

Context: The expression and release of tissue factor is a major trigger for the activation of coagulation in patients with sepsis. Tissue factor pathway inhibitor (TFPI) forms a complex with tissue factor and blood protease factors leading to inhibition of thrombin generation and fibrin formation.

Objectives: To determine if administration of tifacogin (recombinant TFPI) provides mortality benefit in patients with severe sepsis and elevated international normalized ratio (INR) and to assess tifacogin safety in severe sepsis, including patients with low INR.

Assessment of the safety of recombinant tissue factor pathway inhibitor in patients with severe sepsis: a multicenter, randomized, placebo-controlled, single-blind, dose escalation study.

Objective: To identify a safe and potentially effective recombinant tissue factor pathway inhibitor (rTFPI) dose for further clinical evaluation in patients with severe sepsis.

Design: Prospective, randomized, single-blind, placebo-controlled, dose escalation, multicenter, multinational phase II clinical trial.

Setting: Thirty-eight intensive care units in the United States and Europe.

Correlation between 5-HT7 receptor affinity and protection against sound-induced seizures in DBA/2J mice.

Audiogenic seizures can be induced in DBA/2J mice following intense auditory stimulation. A number of neurotransmitters, including 5-hydroxytryptamine (5-HT), are believed to be involved in mediating this effect since it has been shown previously that depletion of 5-HT or blockade of 5-HT receptors protects DBA/2J mice from these audiogenic seizures. The present study was undertaken to determine whether antagonism of the newly identified 5-HT7 receptor may protect DBA/2J mice from audiogenic seizures by attempting to correlate in vivo potency of compounds with their affinity at the 5-HT7 receptor.

Interaction of tryptamine and ergoline compounds with threonine 196 in the ligand binding site of the 5-hydroxytryptamine6 receptor.

We examined the ligand-binding site of the 5-hydroxytryptamine6 (5-HT6) receptor using site-directed mutagenesis. Interactions with residues in two characteristic positions of trans-membrane region V are important for ligand binding in several bioamine receptors. In the 5-HT6 receptor, one of these residues is a threonine (Thr196), whereas in most other mammalian 5-HT receptors, the corresponding residue is alanine.

p55 Tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis and septic shock. A randomized controlled multicenter trial. Ro 45-2081 Study Group.

Objective: To evaluate the safety and efficacy of p55 tumor necrosis factor receptor fusion protein, a recombinant chimeric protein of human p55 (type I) tumor necrosis factor receptor (CD120a) extracellular domain and IgG1 sequences (referred to as p55-IgG), in the treatment of patients with severe sepsis or septic shock.

Design: Randomized, prospective, multicenter, double-blind, placebo-controlled clinical trial.

Setting: Forty-four community and university-affiliated hospitals in the United States and Europe.

Functional and radioligand binding characterization of rat 5-HT6 receptors stably expressed in HEK293 cells.

We have stably expressed the rat 5-HT6 receptor in HEK293 cells at a density of > 2 pmol/mg protein, as determined in equilibrium binding studies with [3H]-LSD and [3H]-5-HT and compared the affinity of a range of compounds in competition binding experiments with either [3H]-LSD or [3H]-5-HT as radioligand. A variety of tryptamine derivatives were tested and showed a significantly higher affinity when the 5-HT6 receptor was labelled with [3H]-5-HT, whereas ergoline compounds and several antagonists had higher affinities when [3H]-LSD was used as radioligand. Subsequently we examined the ability of LSD, 5-HT and a number of tryptamine derivatives to stimulate cAMP accumulation in order to determine their agonist potency and efficacy.

Pharmacologic evaluation of the discriminative stimulus of metachlorophenylpiperazine.

A pharmacologic analysis of the discriminative stimulus of metachlorophenylpiperazine (mCPP) is reported. mCPP and m-trifluoromethylphenylpiperazine generalised, whereas 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole, 6-chloro-2-(1-piperazinyl)-pyrazine, and mesulergine partially generalised to the mCPP discriminative cue. However, although mianserin, methiothepin, ritanserin, mesulergine and N-(1-methyl-5'-indolyl)-N'-(3-pyridyl)urea hydrochloride (SB 200646) all antagonised the effect of 5-hydroxytryptamine (5-HT) on IP3 formation in the rat choroid plexus, they failed to antagonise the mCPP response in the drug discrimination studies.

Identification of 5-hydroxytryptamine7 receptor binding sites in rat hypothalamus: sensitivity to chronic antidepressant treatment.

Due to the high level of expression of mRNA for the 5-hydroxytrytamine (5-ht7) receptor in the hypothalamus and the high affinity of 5-HT for this receptor, [3H]5-HT binding was performed in rat hypothalamus to determine whether 5-ht7 receptor binding sites are present in animal tissue. [3H]5-HT binding was performed in the presence of 100 nM pindolol, which is inactive at 5-ht7 receptors but prevents the binding of [3H]5-HT to 5-HT1A and 5-HT1B receptor binding sites. Under these conditions, [3H]5-HT bound to a binding site with an affinity of 1.

Ceftriaxone--bilirubin-albumin interactions in the neonate: an in vivo study.

The in vivo bilirubin-albumin binding interaction of ceftriaxone (CRO) was investigated in 14 non-jaundiced newborns, aged 33-42 weeks of gestation, during the first few days of life after they had reached stable clinical condition. CRO (50 mg/kg) was infused intravenously over 30 min. The competitive binding effect of CRO on the bilirubin-albumin complex was estimated by determining the reserve albumin concentration (RAC) at baseline, at the end of CRO infusion, and at 15 and 60 min thereafter.