Nivolumab plus ipilimumab in advanced melanoma.

Background: In patients with melanoma, ipilimumab (an antibody against cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4]) prolongs overall survival, and nivolumab (an antibody against the programmed death 1 [PD-1] receptor) produced durable tumor regression in a phase 1 trial. On the basis of their distinct immunologic mechanisms of action and supportive preclinical data, we conducted a phase 1 trial of nivolumab combined with ipilimumab in patients with advanced melanoma.

Methods: We administered intravenous doses of nivolumab and ipilimumab in patients every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses (concurrent regimen).

Single-dose pharmacokinetics of boceprevir in subjects with impaired hepatic or renal function.

Background And Objective: Boceprevir is a novel inhibitor of the hepatitis C virus NS3 protease and was recently approved for the treatment of patients with chronic hepatitis C infection. The objective of this study was to evaluate the impact of impaired hepatic or renal function on boceprevir pharmacokinetics and safety/tolerability.

Methods: We conducted two open-label, single-dose, parallel-group studies comparing the safety and pharmacokinetics of boceprevir in patients with varying degrees of hepatic impairment compared with healthy controls in one study and patients with end-stage renal disease (ESRD) on haemodialysis with healthy controls in the other.

Determination of flunixin in edible bovine tissues using liquid chromatography coupled with tandem mass spectrometry.

An accurate, reliable, and reproducible assay was developed and validated to determine flunixin in bovine liver, kidney, muscle, and fat. The overall recovery and percent coefficient of variation (%CV) of twenty-eight determinations in each tissue for flunixin free acid were 85.9% (5.

Determination and confirmation of 5-hydroxyflunixin in raw bovine milk using liquid chromatography tandem mass spectrometry.

A method was developed and validated to determine 5-hydroxyflunixin in raw bovine milk using liquid chromatography tandem mass spectrometry (LC/MS/MS). The mean recovery and percentage coefficient of variation (%CV) of 35 determinations for 5-hydroxyflunixin was 101% (5% CV). The theoretical limit of detection was 0.

Flunixin residues in milk after intravenous treatment of dairy cattle with (14)C-flunixin.

Flunixin meglumine is used in veterinary medicine as an alternative to narcotic analgesics and as an antiinflammatory agent. Eight Holstein dairy cows were dosed intravenously once daily on three consecutive days with (14)C-flunixin meglumine at approximately 2.2 mg of flunixin free acid/kg of body weight.

Dermal penetration of 4"-(epi-methylamino)-4"-deoxyavermectin B1a benzoate in the rhesus monkey.

The dermal absorption of the experimental avermectin insecticide emamectin benzoate was studied in the Rhesus monkey. Dermal absorption was calculated by comparing radioactivity levels in excreta following dermal application of the compound with those following administration of an equivalent intravenous dose. After i.

Dermal penetration of avermectin B1a in the rhesus monkey.

Forearms of rhesus monkeys were treated with [3H]avermectin B1a in three different vehicles and concentrations so that the penetration of avermectin B1a through skin could be determined. In order to simulate exposure of farm workers, such as mixer-loaders, applicators, and harvesters, to this pesticide, avermectin B1a was applied to the forearms of the monkeys as an emulsifiable concentrate (300 micrograms/monkey), a diluted emulsifiable concentrate (4.5 micrograms/monkey), and as a suspension in water (216 micrograms/monkey).

Studies on the mechanism of mitochondrial protection by polymeric prostaglandin PGBx.

On the basis of the interaction between tritiated PGBx and rat liver mitochondria, it appears that PGBx interacts with rat liver mitochondria to form a complex. At low PGBx-mitochondrial ratios, one effect of this complex formation is to stabilize the phosphorylation activity of rat liver mitochondria when exposed for short times to hypotonic solutions. At higher PGBx-mitochondrial ratios, PGBx fails to show this effect.

Mechanism of polymeric prostaglandin PGBx for in vitro stabilization of rat liver mitochondrial oxidative phosphorylation.

The mechanism of the in vitro PGBx effect on mitochondria was studied by determining the specific requirements of the assay system composition. These studies showed that (a) rat liver mitochondria must first be exposed to hypotonic media containing PGBx under aerobic conditions, (b) oxygen, Pi, Mg++, phosphate acceptor (nucleotides), and some oxidizable substrates are essential components to yield optimal phosphorylation values. KCl and bovine serum albumin are non-essential components.

Interaction of bovine serum albumin with PGBx (polymeric 15-keto-prostaglandin B1).

Bovine serum albumin (BSA) interacts with PGBx, a polymeric derivative of 15-keto-prostaglandin B1, to form a complex that does not exhibit the fluorescence of free BSA. The complex is soluble at pH 5.2 in contrast to free PGBx, which is insoluble.