Smoking, nicotine and pregnancy 2 (SNAP2) trial: protocol for a randomised controlled trial of an intervention to improve adherence to nicotine replacement therapy during pregnancy.

INTRODUCTION: Smoking during pregnancy is harmful to unborn babies, infants and women. Nicotine replacement therapy (NRT) is offered as the usual stop-smoking support in the UK. However, this is often used in insufficient doses, intermittently or for too short a time to be effective. This randomised controlled trial (RCT) explores whether a bespoke intervention, delivered in pregnancy, improves adherence to NRT and is effective and cost-effective for promoting smoking cessation. METHODS AND ANALYSIS: A two-arm parallel-group RCT was conducted for pregnant women aged ≥16 years and who smoke ≥1 daily cigarette (pre-pregnancy smoked ≥5) and who agree to use NRT in an attempt to quit. Recruitment is from antenatal care settings and via social media adverts. Participants are randomised using blocked randomisation with varying block sizes, stratified by gestational age (<14 or ≥14 weeks) to receive: (1) usual care (UC) for stop smoking support or (2) UC plus an intervention to increase adherence to NRT, called 'Baby, Me and NRT' (BMN), comprising adherence counselling, automated tailored text messages, a leaflet and website. The primary outcome is biochemically validated smoking abstinence at or around childbirth, measured from 36 weeks gestation. Secondary outcomes include NRT adherence, other smoking measures and birth outcomes. Questionnaires collect follow-up data augmented by medical record information. We anticipate quit rates of 10% and 16% in the control and intervention groups, respectively (risk ratio=1.6). By recruiting 1320 participants, the trial should have 90% power (alpha=5%) to detect this intervention effect. An economic analysis will use the Economics of Smoking in Pregnancy model to determine cost-effectiveness. ETHICS AND DISSEMINATION: Ethics approval was granted by Bloomsbury National Health Service's Research Ethics Committee (21/LO/0123). Written informed consent will be obtained from all participants. Findings will be disseminated to the public, funders, relevant practice/policy representatives, researchers and participants. TRIAL REGISTRATION NUMBER: ISRCTN16830506. PROTOCOL VERSION: 5.0, 10 Oct 2023.

Quantitative biodistribution of biotherapeutics at whole body, organ and cellular levels by autoradiography.

AIM: Tools for mapping and quantifying monoclonal antibody (mAb) and peptide biotherapeutics distribumtion were evaluated by comparing data from three independent methods conducted at the whole body, organ or tissue, and cellular levels. MATERIALS & METHODS: [3H]-mAb1 and [3H]-peptide A were administered intravenously to rats followed by quantitative whole-body autoradiography, kidney macro-autoradiography and micro-autoradiography. RESULTS: [3H]-mAb1 and [3H]-peptide A concentrations were measured in anatomical regions ranging from whole body to whole organ to sub-organ level, such as the kidney glomerulus, with increasing resolution. The tissue/blood [3H]-mAb1 concentrations in selected kidney microenvironments were comparable among the three quantitative methods. CONCLUSION: Quantitative whole-body autoradiography, tissue macro-autoradiography and micro-autoradiography all provide useful tools for quantifying the concentrations of biotherapeutics at different anatomical levels in tissues, facilitating better predictions of efficacy and toxicity.

Disposition, metabolism and mass balance of delafloxacin in healthy human volunteers following intravenous administration.

1. The pharmacokinetics and disposition of delafloxacin was investigated following a single intravenous (300 mg, 100 µCi) dose to healthy male subjects. 2. Mean Cmax, AUC0-∞, Tmax and t1/2 values for delafloxacin were 8.98 µg/mL, 21.31 µg h/mL, 1 h and 2.35 h, respectively, after intravenous dosing. 3. Radioactivity was predominantly excreted via the kidney with 66% of the radioactive dose recovered in the urine. Approximately 29% of the radioactivity was recovered in the faeces, giving an overall mean recovery of 94% administered radioactivity. 4. The predominant circulating components were identified as delafloxacin and a direct glucuronide conjugate of delafloxacin.

Quantitative whole-body autoradiography: past, present and future.

Traditional bioanalytical measurements determine concentrations of drug and metabolites in plasma; however, most drugs exert their effects in defined target tissues. As there is no clear relation between concentrations in plasma and those in tissue, alternative methods must be employed to study the absorption, distribution, metabolism and excretion properties of new therapeutic agents. Quantitative whole-body autoradiography is used in the drug development process to determine the distribution and concentrations of radiolabeled test compounds in laboratory animals. Quantitative whole-body autoradiography can provide information on tissue PKs, penetration, accumulation and retention. Although the technique is considered the industry standard for performing preclinical tissue distribution studies, it is perhaps timely, 60 years after the first reported use of the method, to re-assess the technique against modern alternatives.

Recombinant fusion protein linking factor VIIa with albumin (rVIIa-FP): Tissue distribution in rats.

INTRODUCTION: A novel fusion protein linking coagulation factor VIIa with albumin (rVIIa-FP) is currently undergoing clinical investigations. OBJECTIVE: This study was conducted to examine the biodistribution of rVIIa-FP in comparison to recombinant factor VIIa (rFVIIa). MATERIALS AND METHODS: [(3)H]-rVIIa-FP (10mgkg(-1)) or [(3)H]-rFVIIa (1.6mgkg(-1)) were administered intravenously to rats, followed by quantitative whole-body and knee joint autoradiography for 24 ([(3)H]-rFVIIa) or 240 ([(3)H]-rVIIa-FP) hours post-dose. Pharmacokinetic and excretion balance analyses were performed. RESULTS: In contrast to [(3)H]-albumin, the tissue distributions of [(3)H]-rVIIa-FP and [(3)H]-rFVIIa were similar. Within the knee, both were rapidly present within synovial and mineralized regions. Importantly, rVIIa-FP- and albumin-derived radioactivity were detectable up to 72-120hours, whereas [(3)H]-rFVIIa signals were already close to detection limits at 24hours. The longest rVIIa-FP retention times were observed in bone marrow and endosteum, in which the retention times were up to 5 times longer for rVIIa-FP compared with rFVIIa. Up to 8hours post-dose, 100% of radioactivity was assigned to unchanged [(3)H]-rVIIa-FP. Elimination of both proteins occurred primarily via the urine. CONCLUSIONS: The data suggest that the FVIIa moiety is directing rVIIa-FP's tissue distribution while the albumin moiety is responsible for the prolonged tissue retention. Importantly, rVIIa-FP is highly concentrated and retained over a long period in the growth plate of the knee joint-a vulnerable site in haemophilia patients. Overall, these improved tissue distribution characteristics of rVIIa-FP may enhance compliance and allow a more convenient dosing frequency.

Biodistribution of the recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in rats.

INTRODUCTION: The recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) is undergoing clinical trials for prophylaxis and on-demand treatment of haemophilia B patients. The aim of this study was to investigate the pharmacokinetics, whole-body and knee joint distribution of rIX-FP following intravenous administration to rats, compared with a marketed, non-fused rFIX and recombinant human albumin. MATERIAL AND METHODS: [(3)H]-rIX-FP, [(3)H]-rFIX or [(3)H]-albumin were administered to rats followed by quantitative whole-body autoradiography over 24 or 240 hours, and the tissue distribution as well as elimination of radioactivity were measured. RESULTS: Elimination of all radioactivity derived from the three proteins was shown to occur primarily via the urine. The tissue distribution of [(3)H]-rIX-FP and [(3)H]-rFIX (but not of [(3)H]-albumin) was comparable, both penetrating predominantly into bone, and well-perfused tissues, suggesting that the rIX moiety determines the distribution pattern of rIX-FP, while the albumin moity is responsible for the prolonged plasma and tissue retention. Detailed knee-joint analysis indicated rapid presence of [(3)H]-rIX-FP and [(3)H]-rFIX in synovial and mineralised bone tissue, mostly localised to the zone of calcified cartilage. Longest retention times were observed in the bone marrow and the endosteum of long bones. Intriguingly, [(3)H]-rIX-FP- and [(3)H]-albumin-derived radioactive signals were detectable up to 240 hours, while [(3)H]-rFIX-derived radioactivity rapidly declined after 1hour post-dosing correlating to the extended plasma half-life of [(3)H]-rIX-FP. CONCLUSION: The prolonged plasma and tissue retention of rIX-FP achieved by albumin fusion may allow a reduction in dosing frequency leading to increased therapeutic compliance and convenience.

Quantitative whole-body autoradiography, LC-MS/MS and MALDI for drug-distribution studies in biological samples: the ultimate matrix trilogy.

The drug-development process requires an understanding of the ADME properties of the novel therapeutic agent. Determination of drug concentrations and identity in excreta (urine and feces) examines the products of these processes. Similar measurements made on plasma, while accurately determining exposure, show only what is being transported around the body. Both activities fail to confirm the nature of components at the pharmacologically relevant matrix - the tissue. Attention is therefore being directed towards methods that can be employed to address this lack in our current methodologies, to provide better quality data on which risk assessments can be made, so that pharmacological models can be refined, and drug safety improved. In this article, we will look at the current methods used to obtain tissue drug and drug metabolite concentrations, and their potential use in drug discovery.

Matrix-assisted laser desorption mass spectrometry imaging for the examination of imipramine absorption by Straticell-RHE-EPI/001 an artificial model of the human epidermis.

In order to assess the potential of matrix-assisted laser desorption mass spectrometry imaging for the examination of artificial skin models, the absorption of the tricyclic antidepressant imipramine into Straticell-RHE-EPI/001 an artificial model of the human epidermis has been studied. The presence of imipramine could be clearly discerned in treated samples by imaging the distribution of the protonated molecule at m/z 281.18 in samples taken 2 and 8 h after treatment. No clear evidence of biotransformation of imipramine in the artificial epidermal model was detected, although some signals that could potentially be assigned to the desmethyl metabolite were detected. Further work is required in order to investigate the reasons for the apparent low levels of metabolites detected.

A simple aspiration test to determine the accuracy of oesophageal placement of fine-bore feeding tubes.

OBJECTIVE: To evaluate whether a simple aspiration test can be used to accurately confirm the correct placement of fine-bore feeding tubes in the oesophagus and prevent their inadvertent placement in the bronchial tree. DESIGN: We conducted an ethically approved, randomised, blinded trial to assess the accuracy of a simple aspiration test to differentiate between oesophageal and tracheal placement. SETTING: A tertiary referral cardiothoracic surgical unit. PATIENTS AND PARTICIPANTS: Twenty patients under-going elective cardiac surgery. INTERVENTION: Once anesthetised, a fine-bore feeding tube was inserted into the oesophagus or trachea and a researcher, blinded to the position, then performed the test. This involved attempted aspiration of > or =10 ml of air before and after insufflation of 10 ml of air and comparison with capnography, a test that has been shown to be highly sensitive and specific. MEASUREMENTS AND RESULTS: With this small number of patients, the test accurately differentiated between ten oesophageal and ten tracheal placements. CONCLUSIONS: A simple aspiration test could be a useful adjunct to prevent inadvertent bronchial placement of fine-bore feeding tubes. Careful attention must be paid to the technique to ensure that no false positives occur.

Matrix-assisted laser desorption/ionization-ion mobility separation-mass spectrometry imaging of vinblastine in whole body tissue sections.

During early-stage drug development, drug and metabolite distribution studies are carried out in animal tissues using a range of techniques, particularly whole body autoradiography (WBA). While widely employed, WBA has a number of limitations, including the following: expensive synthesis of radiolabeled drugs and analyte specificity and identification. WBA only images the radiolabel. MALDI MSI has been shown previously to be advantageous for imaging the distribution of a range of drugs and metabolites in whole body sections. Ion mobility separation (IMS) adds a further separation step to imaging experiments; demonstrated here is MALDI-IMS-MS whole body imaging of rats dosed at 6 mg/kg i.v. with an anticancer drug, vinblastine and shown is the distribution of the precursor ion m/z 811.4 and several product ions including m/z 793, 751, 733, 719, 691, 649, 524, and 355. The distribution of vinblastine within the ventricles of the brain is also depicted. Clearly demonstrated in these data are the removal of interfering isobaric ions within the images of m/z 811.4 and also of the transition m/z 811-751, resulting in a higher confidence in the imaging data. Within this work, IMS has shown to be advantageous in both MS and MS/MS imaging experiments by separating vinblastine from an endogenous isobaric lipid.

The effect of videotaped preoperative information on parental anxiety during anesthesia induction for elective pediatric procedures.

BACKGROUND: The purpose of this study was to determine whether audiovisual information, describing the process of undergoing and recovering from anesthesia, could reduce anxiety levels in parents before their child's induction of anesthesia. METHODS: One hundred and eleven parents were recruited into this study. Of these 56 were randomized to a control group and 55 to an intervention group. All parents completed the Amsterdam Preoperative Anxiety and Information Scale (APAIS) questionnaires on admission to hospital on the day of surgery and then again just before accompanying their child to the anesthetic room. In addition to the normal preoperative preparation, parents randomized into the study group watched a short 8-min information video after completing the first questionnaire. The video illustrated the events and procedures surrounding a child's admission to hospital for day-case surgery, including the induction of anesthesia. RESULTS: The results were analyzed using repeated measures of anova. There was a statistically significant reduction in anxiety and desire for information in the intervention group compared with the control group (P < 0.05). CONCLUSIONS: The reduction in anxiety in the intervention group indicates that preoperative information videos are an effective method of reducing anxiety in parents. Furthermore, the reduction in need for information score in the intervention group indicates that preoperative videos may be a useful tool for providing parents with information.