Scheduling nab-paclitaxel combined with gemcitabine as first-line treatment for metastatic pancreatic adenocarcinoma.

BACKGROUND: Nab-paclitaxel plus gemcitabine (nabP+gemcitabine) offers modest survival gains for patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Sequential scheduling of nabP+gemcitabine in a PDAC mouse model improved efficacy; this hypothesis was tested in a clinical trial. METHODS: Patients with previously untreated metastatic PDAC were randomised to receive nabP+gemcitabine administered either concomitantly on the same day, or sequentially, with gemcitabine administered 24 h after nabP. The primary outcome measure was progression-free survival (PFS). Secondary outcome measures were objective response rate (ORR), overall survival (OS), safety, quality of life (QoL) and predictive biomarkers. RESULTS: In total, 71 patients received sequential (SEQ) and 75 concomitant (CON) treatment. Six-month PFS was 46% with SEQ and 32% with CON scheduling. Median PFS (5.6 versus 4.0 months, hazard ratio [HR] 0.67, 95% confidence interval [95% CI] 0.47-0.95, p = 0.022) and ORR (52% versus 31%, p = 0.023) favoured the SEQ arm; median OS was 10.2 versus 8.2 months (HR 0.93, 95% CI 0.65-1.33, p = 0.70). CTCAE Grade ≥3 neutropaenia incidence doubled with SEQ therapy but was not detrimental to QoL. Strongly positive tumour epithelial cytidine deaminase (CDA) expression favoured benefit from SEQ therapy (PFS HR 0.31, 95% CI 0.13-0.70). CONCLUSIONS: SEQ delivery of nabP+gemcitabine improved PFS and ORR, with manageable toxicity, but did not significantly improve OS. CLINICAL TRIAL REGISTRATION: ISRCTN71070888; ClinialTrials.gov (NCT03529175).

Lack of effect of cold water prawns on plasma cholesterol and lipoproteins in normo-lipidaemic men.

OBJECTIVE: Dietary guidelines for the prevention of coronary heart disease (CHD) have restricted the intake of foods rich in dietary cholesterol, on the grounds that the dietary cholesterol will increase blood cholesterol. In the case of shellfish, this recommendation may limit the intake of a valuable dietary source of long chain n-3 polyunsaturated fatty acids (LC n-3 PUFA). The objective of this study was to undertake a dietary intervention to determine the effects of cold water prawns on plasma lipids and lipoproteins. METHODS: 23 healthy male subjects were randomised to receive either 225 g of cold water prawns or an equivalent weight of fish ('crab') sticks as a control for 12 weeks in a cross-over design. Blood samples were taken at the beginning and end of each intervention for the determination of plasma lipids and lipoproteins by routine enzymatic assays and iodixanol density gradient centrifugation respectively. RESULTS: The diets were well matched for the intake of total energy and macronutrients, and body weight remained stable throughout the study. The prawn intervention increased the intake of dietary cholesterol to 750 mg/d against 200 mg/d on the control. The intake of LC n-3 PUFA from prawns was estimated to be between 0.5-0.7 g/d. The consumption of prawns produced no significant effects on the concentration of plasma total or LDL cholesterol, triacylglycerol, HDL cholesterol or apolipoproteins A-I and B relative to the control, or within each intervention group over time. There was also no significant effect on LDL density (particle size) relative to the control, or any difference between and within treatments in total plasma lipoprotein profiles by density gradient centrifugation. CONCLUSION: These findings provide evidence to suggest that the consumption of cold water prawns, at least in healthy, male subjects, should not be restricted on the grounds of this seafood producing an adverse effect on plasma LDL cholesterol.

The influence of alcohol consumed with a meal on endothelial function in healthy individuals.

BACKGROUND: Alcohol and polyphenols in wine and fruit juices have been strongly implicated in the favourable effects on of these beverages on vascular function. Despite a wealth of information on the metabolic and vascular effects of alcohol and polyphenols, the combined influences of these substances on vascular function, especially when consumed with food, is poorly understood. A study was designed to determine the effects of a phenolic-rich grape juice, with or without alcohol, on vascular endothelial function in the postprandial state. METHODS: Ten subjects consumed a standard meal with a test drink on three separate occasions. On each occasion, the test drink accompanying the meal was either red grape juice, red grape juice plus alcohol (12% v/v), or water. Endothelial function was measured by flow mediated dilatation (FMD) prior to then 30 and 60 minutes after consuming the meal. Blood samples were taken for the determination of plasma glucose, triacylglycerol (TAG) and non esterified fatty acids (NEFA) at regular intervals. RESULTS: There was a significant effect of the three treatments (P = 0.0026) and time (P = 0.021) on percentage FMD. The meals with the grape juice and grape juice plus alcohol produced similar FMD responses but were both significantly greater than the meal with water. The concentration of plasma glucose, TAG and NEFA were similar after each treatment. CONCLUSION: Alcohol had no effect on vascular function in the early postprandial phase. These findings provide new evidence to support the potential benefit of non-alcoholic components within alcoholic beverages on vascular function in the fed state.

Elimination of phenoperidine in liver disease.

The disposition and elimination of phenoperidine was studied in five normal subjects, and in six patients with hepatic disease. Plasma concentrations of phenoperidine were generally higher in patients with hepatic dysfunction. Secondary peaks were observed between 15 and 105 min (particularly in patients with liver disease). In the patients the terminal half-life of phenoperidine was prolonged by approximately 50%, mainly because of a decrease in the clearance of the drug. There was little or no change in the total apparent volume of distribution. However, the differences between normal subjects and patients with hepatic disease were not statistically significant. The results suggest that slight or moderate impairment of hepatic function does not significantly affect the kinetics of the drug, and that modification of its dosage may not be required.

Effects of prostaglandins F-2 alpha and E-2 on cervical extensibility in the late pregnant rat.

The extensibility of the cervix of rats was measured in vitro on Day 19 of pregnancy and was doubled after 2 s.c. injections of PGF-2 alpha (1 mg/kg) or PGE-2 (5 mg/kg) on Day 18. Progesterone (10 mg/kg) given on Day 18 had no effect alone or on the effect of PGE-2 but abolished the action of PGF-2 alpha. PGE-2, but not PGF-2 alpha, increased extensibility when given on Day 18 to rats which had been bilaterally ovariectomized on Day 16 and given oestradiol benzoate plus progesterone twice daily. High concentrations of PGF-2 alpha or PGE-2 had no effect on the extensibility of Day-18 pregnant rat cervix in vitro. It is suggested that PGF-2 alpha acts via the ovaries to decrease progesterone secretion and perhaps release relaxin, but PGE-2 would appear to have another site of action.

The effects of oestradiol benzoate, progesterone, relaxin and ovariectomy on cervical extensibility in the late pregnant rat.

Cervical extensibility increased from Day 16 to term in the pregnant rat. Following ovariectomy on Day 16 of pregnancy the cervix became as inextensible by Day 20 as that of non-pregnant animals. Fetal growth was maintained in rats ovariectomized on Day 16 if given oestradiol benzoate plus progesterone but cervical extensibility only increased to a small extent. Relaxin given to these animals further increased cervical extensibility, suggesting a role for this hormone.

Mechanical responses of the isolated cervix of the day-22 pregnant rat to field stimulation.

Field stimulation of isolated, spirally-cut cervix from day-22 pregnant rats produced contractions which could be inhibited by tetrodotoxin or hyoscine and potentiated by propranolol. The rat cervix would appear to receive both cholinergic and noradrenergic innervations whose transmitters activate muscarinic cholinoceptors and beta-adrenoceptors respectively.

Mechanical responses of the isolated cervix and uterine horn of pregnant rats near term to drugs.

1 The responses of circularly cut strips of cervix and uterine horn from rats on days 20 and 22 of pregnancy to drugs were compared in vitro. 2 The cervix exhibited similar responses and sensitivities to acetylcholine, bradykinin, prostaglandin (PG) F2alpha (day 20) and isoprenaline (day 20) as did the uterine horn but was less sensitive or responded less consistently to isoprenaline (day 22), oxytocin and PG1. PGE2 was more potent on the cervix (day 20). 3 Before term the relatively inextensible connective tissue of the cervix plus contractions of the smooth muscle would help to prevent foetal expulsion. At term the cervical smooth muscle is sufficiently unresponsive to allow cervical dilatation.