Preventing stillbirths through improved antenatal recognition of pregnancies at risk due to fetal growth restriction.

Most stillbirths used to be categorized as 'unexplained' and were considered, by implication, unavoidable. Recent evidence indicates that they represent a combined challenge for public health and for clinical services. Independent case reviews have found that many deaths are associated with a failure to recognize risk factors and to afford them the appropriate standard of care. The majority of normally formed fetal deaths had preceding, unrecognized intrauterine growth failure. Improved training and adoption of standardized protocols has led to increased antenatal detection of fetal growth restriction, and this in turn has resulted in significant reductions in stillbirths in areas with high uptake of the training programme. A comprehensive, evidence-based growth assessment protocol (GAP) is currently being rolled out across the NHS to implement this strategy for stillbirth prevention.

Reproducible fentanyl doses delivered intermittently at different time intervals from an electrotransport system.

The electrotransport transdermal fentanyl system (ET [fentanyl]), uses a small electrical current to enhance delivery of fentanyl to systemic circulation. Intermittent doses can be administered by periodic application of the current. The purpose of this study was to compare the effects of the frequency of intermittent drug delivery by ET (fentanyl) and compare the drug delivery to systemic circulation by ET (fentanyl) with intravenous administration. The topical safety was also determined for the ET (fentanyl) system. Nine adult male volunteers completed this three-treatment, randomized, 24-h, crossover study. ET (fentanyl) treatments with 200 microA direct current applied for 30 min at frequent (hourly) or infrequent (4-hourly) intervals over a 24-h period were compared. Also, the drug delivery to systemic circulation from ET (fentanyl) was compared with intravenous fentanyl 75 microg infused over 30 min every 4 h over a 24-hour period. The mean serum fentanyl concentration achieved with the hourly ET (fentanyl) regimen was higher than that for the 4-hourly ET (fentanyl) regimen as expected from the higher frequency of drug doses. The amount of fentanyl delivered estimated per dose from the ET (fentanyl) system using the iv fentanyl treatment as the reference was similar for the two ET regimens throughout the dosing period. This indicates consistent drug delivery regardless of the frequency of ET dosing. The majority of subjects reported either no, or barely perceptible, erythema 24 h after removal of the system.

Effect of current density on pharmacokinetics following continuous or intermittent input from a fentanyl electrotransport system.

The pharmacokinetics of fentanyl were determined in two open-label crossover studies following 24-h periods of delivery by an electrotransport transdermal system (E-TRANS [fentanyl] system) in young healthy male volunteers. A direct current was applied continuously in study 1 (at 50, 100, and 200 microA; surface area = 5 cm2; n = 8), but in study 2 it was limited to the first 20 min of each hour (at 150, 200, and 250 microA; surface area = 2 cm2; n = 12). The opioid effects of fentanyl were blocked with naltrexone administered every 12 h. With increasing electrical current, the increase in serum fentanyl concentration, amount absorbed, and AUC values were proportional in study 2 but not in study 1. It is hypothesized that the lack of proportionality in study 1 is due to lower current density (microA/cm2) in this study. It appears that for fentanyl, the current density should be about 75 microA/cm2 or greater for a linear relation between current and amount absorbed as seen in study 2. Compared with intravenously infused fentanyl, the serum concentrations resulting from E-TRANS (fentanyl) system application revealed a slightly dampened rate of increase (stratum-corneum barrier effect) and decrease in serum concentrations, and a similar intersubject variability in fentanyl AUC values. Fentanyl pharmacokinetics with either E-TRANS (fentanyl) or intravenous infusion were time-invariant over a 24-h application period, with similar mean half-life values (about 15-18 h). E-TRANS (fentanyl) administration (either continuous or intermittent input) was safe and well tolerated. Adverse effects were mild to moderate; they consisted mainly of local erythema and pruritus (which resolved in most patients within 24 h after system removal) and occasional opioid effects.

Transdermal fentanyl therapy: system design, pharmacokinetics and efficacy.

The transdermal route of drug delivery has been used for the effective administration of therapeutic agents for more than a decade. The most important consideration in selecting a drug for transdermal delivery is the potential for improving therapeutic efficacy. The development of a transdermal fentanyl system provided an opportunity to add fentanyl to the armamentarium of strong opioids available for the treatment of cancer pain. The transdermal route of administration has advantages over both the oral and parenteral routes. In addition, patient and caregiver factors allow improved acceptance of and compliance to strong opioids and therefore improved analgesic outcome. Four transdermal fentanyl systems are available, providing delivery rates ranging from 25-100 micrograms/h; higher rates can be achieved by multiple system application. The system releases fentanyl continuously for 3 days when applied to the skin. Concentrations of fentanyl in the blood are measurable within a few hours of system application. Fentanyl serum concentrations increase gradually, generally levelling off after 12-24 h and remaining relatively constant for the remainder of the 3-day period. Steady state serum concentrations are reached by the second application. Clinical trials have established the efficacy and safety of transdermal fentanyl for the treatment of cancer pain. Transdermal fentanyl is not licensed for the treatment of acute pain, e.g. postoperative pain, and should not be prescribed for this purpose.

Evaluation of diurnal variation in fentanyl clearance.

Drug disposition kinetics are commonly assumed to be time-invariant as a first approximation. In a preliminary study, 6 healthy volunteers received a constant intravenous infusion of 50 micrograms/h for 48 hours; the serum fentanyl concentration at 36 hours was lower than that at 24 hours for all 6 subjects. This suggested possible diurnal variations in fentanyl clearance. In 2 subsequent studies, with healthy volunteers receiving short infusions of fentanyl (n = 9, 150 micrograms/h for 0.33 hours every 4 hours; n = 12, 150 micrograms/h for 0.33 hours every hour, respectively), the area under the serum fentanyl concentration curve appeared to be independent of the time of infusion. Thus, there was no evidence to support a large diurnal change in fentanyl clearance. The serum fentanyl concentration-time profiles, corrected for carryover from previous doses, within each study were superimposable. This suggests that there are no diurnal changes in the distribution kinetics of fentanyl.

Transdermal fentanyl for cancer pain. Repeated dose pharmacokinetics.

BACKGROUND: The transdermal therapeutic system (fentanyl), or TTS(fentanyl), continuously delivers fentanyl for up to 72 h. The transdermal therapeutic system (fentanyl)-100 delivers approximately 100 micrograms/h. The repeated dose pharmacokinetics of this drug using the recommended dosing interval have not been evaluated previously and were determined in the present study. METHODS: Blood samples were obtained from ten opioid-tolerant cancer patients who received five applications of TTS(fentanyl) at 72-h intervals. A sample of venous blood was taken before each dose; multiple samples were taken during and after the fifth application. A gas chromatographic/mass spectrometry method was used to assay fentanyl (limit of detection 0.2 ng/ml). RESULTS: For the fifth dose, the mean (SD) maximum concentration was 2.6 (1.3) ng/ml and the mean (SD) area under the serum fentanyl concentration-time curve (0-72 h) was 116.9 (59.9). Following removal of the system, the mean (SD) apparent half-life was 21.9 (8.9) h. There were no differences among the serum fentanyl concentrations measured before the second through fifth doses. Fentanyl absorption was 47% complete at 24 h, 88% complete at 48 h, and 94% complete at 72 h. The mean (SD) dose delivered during the 72-h period was 4.3 (1.1) mg. A first-dose trough concentration predicted from fifth-dose kinetics and the actual first-dose trough concentration were very similar. Adverse effects ascribed to the transdermal system were minimal. CONCLUSIONS: These results suggest that steady-state serum concentrations are approached by the second dose of TTS(fentanyl) and that the kinetics are stable with repeated dosing. The apparent half-life following system removal is relatively long, indicating ongoing absorption from a subcutaneous depot.

System functionality and physicochemical model of fentanyl transdermal system.

Fentanyl is an opioid traditionally administered by infusion or injection and more recently in a rate-controlled transdermal dosage form. This system is a four-layer laminate on a protective liner. A backing layer seals and protects the drug reservoir, the source for continuous delivery of fentanyl. A membrane controls the release rate of fentanyl from the system. An adhesive layer attaches the system to skin and releases an initial loading dose of fentanyl. The rate of fentanyl delivery through skin is determined by the system and the skin at the application site. The release rate from the system is approximated by Fick's first law of diffusion and is controlled by the rate-controlling membrane. A complete simulation model that combines both in vitro release data and the pharmacokinetic model has been developed and used to show the influence of various physiologic and system variables on serum fentanyl concentrations.

Optometric and sensory motor changes in an adult.

This case study was designed to determine whether an adult with definable visual problems and sensory motor dysfunction would respond to a prescribed, periodically monitored home program of sensory motor activities. The subject was a 27-year-old college student who reported lifelong difficulties in visual-postural mechanisms which were documented through an Occupational Therapy initial evaluation, administered by Occupational Therapists, and the Functional Visual Evaluation, administered by a Vision Therapist. An individualized home program, which included predominantly vestibular and proprioceptive activities, was followed by the subject for six months. Retesting showed positive increases in both postural mechanisms and the visual system. A need for collaboration between Occupational Therapists, Developmental Optometrists and Vision Therapists for the purpose of specifically recording hard data to document visual deficits and the effects of occupational therapy programs to remediate problem areas is discussed.

Relaxation training for essential hypertension at the worksite: II. The poorly controlled hypertensive.

This article reports the findings of a study designed to evaluate the long-term effectiveness of an industry-based relaxation training program in the treatment of hypertensives whose blood pressures were not well controlled by antihypertensive medication. Following a three-stage screening process, 137 participants were randomly allocated to either relaxation training (RT) or to blood pressure monitoring (BPM) at two worksites. Participants continued to receive medical care from their primary physicians during the course of the study. The advantage for participants receiving RT, in terms of mean blood pressure changes, was modest and of short duration. However, a larger proportion of participants in the RT group came into good control (blood pressures below 90 mm Hg) than in the BPM group following treatment (69.4% vs 41.5%, p less than 0.001). This advantage continued to 24 months' follow-up (63.9% vs 47.7%, p less than 0.05). At 30 months' follow-up there was no significant difference between the groups (75.0% vs 70.8%). Within-group analyses revealed that the BPM group also achieved significant blood pressure lowering which was maintained during the study. The largest initial difference between the two groups was for individuals whose entry diastolic blood pressures were most out of control despite several years of pharmacologic treatment. No difference was found between the two groups in the prescription of antihypertensive medication.

A summer day camp approach to adolescent weight loss.

Twenty-five overweight adolescents completed a summer weight loss day camp program on the Stanford University campus. All participants attended camp four days per week for four hours to learn and practice eating and exercise skills conducive to weight loss. Parents met weekly to discuss the program content and to explore their role in their adolescent's weight management. At posttreatment, reductions were achieved in weight, percent overweight, and skinfold, with greater changes observed for the eight-week group than for the four-week group. Improvements were also evident in participants' self-reported habits and knowledge of weight management concepts. Parent and participant assessment of the camp experience was very positive. The results of the summer weight loss day camp suggest that an intensive program of eating and exercise habit instruction, practice, and monitoring, which allows the participants to remain in the home setting, may provide benefits not found in other more traditional approaches to adolescent weight loss.

Relaxation training. Blood pressure lowering during the working day.

Controlled studies have demonstrated that relaxation training can lead to significant in-clinic blood pressure (BP) reductions in patients with essential hypertension. We examined the BP-lowering effect of relaxation training during the working day. Forty-two patients being treated for essential hypertension with diastolic BPs greater than 90 mm Hg were randomized into either a relaxation training program or no treatment. Multiple BP measurements were made during the working hours, using an ambulatory monitoring device, before and after training. Significant work-site differences between groups were evident after treatment both for systolic and diastolic pressures. These results suggest that relaxation therapy leads to a reduction in BP that is evident in the natural environment, providing new evidence that the procedure is a useful adjunct to the treatment of hypertensive patients.