Pulmonary administration of aerosolised fentanyl: pharmacokinetic analysis of systemic delivery

Aims Pulmonary drug delivery is a promising noninvasive method of systemic administration. Our aim was to determine whether a novel breath-actuated, microprocessor-controlled metered dose oral inhaler (SmartMist^TM, Aradigm Corporation) could deliver fentanyl in a way suitable for control of severe pain.
Methods Aersolised pulmonary fentanyl base 100–300  μg was administered to healthy volunteers using SmartMist^TM and the resultant plasma concentration-time data were compared with those from the same doses administered by intravenous (i.v.) injection in the same subjects.
Results Plasma concentrations from SmartMist^TM were similar to those from i.v. injection. Time-averaged bioavailability based upon nominal doses averaged 100%, and was >50% within 5  min of delivery. Fentanyl systemic pharmacokinetics were similar to those previously reported with no trends to dose-dependence from either route. Side-effects (e.g. sedation, lightheadedness) were the same from both routes.
Conclusions Fentanyl delivery using SmartMist^TM can provide analgetically relevant plasma drug concentrations. This, combined with its ease of noninvasive use and transportability, suggests a strong potential for field and domicilliary use, and for patient controlled analgesia without the need for i.v. cannulae.     

Nasal mask positive pressure ventilation in paediatric patients with type II respiratory failure

We report our experience with nasal mask ventilation in children and adolescents with type II respiratory failure admitted to the paediatric intensive care unit (PICU) over an 18-month period. Seven patients were treated with nasal mask ventilation during part of their PICU stay. All showed significant improvement in arterial pH, Pa_CO2, and Pa_O2/FiO₂ from presentation to discharge, although at discharge Pa_CO2 and Pa_O2/FiO₂ fell outside of the normal range. Complications occurred in four patients. When compared to 11 patients with type II respiratory failure not treated with nasal mask ventilation, the nasal mask ventilation group had a similar PICU length of stay and incidence of complications. We conclude that nasal mask ventilation may be useful in maintaining near normal alveolar ventilation in selected children with type II respiratory failure and that a prospective study of this technique is indicated.     

New insights into the therapy and pathophysiology of patients with obstructive sleep apnoea syndrome

Abstract The objective of this study was to investigate the effects of obstructive sleep apnoea on: (i) PaCO₂ levels; (ii) coagulation systems (plasma fibrinogen levels and whole blood viscosity); and (iii) heat shock proteins (HSPs) levels, which are also called stress proteins, in patients with obstructive sleep apnoea syndrome (OSAS). Patients treated with or without nasal continuous positive airway pressure (NCPAP) had arterial blood gases, plasma fibrinogen, haematocrit, serum total protein and changes in PaCO₂ (estimated by transcutaneous PaCO₂) measured before and after polysomnography. Heat shock protein 72 levels in peripheral blood mononuclear cells were also measured during sleep with and without NCPAP. OSAS patients with hypercapnia demonstrated significant increases in PaCO₂ in the morning compared with the previous night. In such OSAS patients, treatment with NCPAP resulted in a normalization of the 20 mg/dL increase in fibrinogen levels which had been seen previously in the morning after sleep. Basal HSP 72 levels (08.00 pm before sleep) were high in OSAS patients compared to normal subjects and progressively decreased during sleep in the absence of NCPAP therapy. NCPAP relieved disabling day-to-day symptoms in addition to improving cardiovascular morbidity in patients with OSAS. Therefore it is important to understand the effects of OSAS on various organ systems as the prevalence of patients with OSAS is high.     

A simplified surfactant dosing procedure in respiratory distress syndrome: the "side-hole" randomized study

Abstract The aim of this study was to compare the incidence of acute adverse events and long-term outcome of two different surfactant dosing procedures in respiratory distress syndrome (RDS). The effects of two surfactant dosing procedures on the incidence of transient hypoxia and bradycardia, gas exchange, ventilatory requirements and 28 d outcome were compared. The patients, comprising 102 infants (birthweight 600–2000 g) with RDS on mechanical ventilation with F_iO₂ 0.4, were randomized at 2–24 h to receive 200 mg kg^-1 of Curosurf® in 56 it was given by bolus delivery, and in 55 by a simplified technique (dose given in 1 min via a catheter introduced through a side-hole in the tracheal tube adaptor. The baby's position was not changed and ventilation was not interrupted). Two additional surfactant doses (100 mg kg^-1) were also given, by the same method, if ventilation with F_iO₂ 0.3 was needed 12 and 24 h after the initial dose. The number of episodes of hypoxia and/or bradycardia was similar in both groups. A slight and transient increase in Paco₂ was observed in the side-hole group. The efficacy of the surfactant, based on oxygenation improvement, ventilator requirements, number of doses required and incidence of air leaks, was similar. No differences were observed in the incidence of intraventricular haemorrhage, patent ductus arteriosus, bronchopulmonary dysplasia or survival. In conclusion, a simplified surfactant dosing procedure not requiring fractional doses, ventilator disconnection, changes in the baby's position or manual bagging was found to be as effective as bolus delivery. The number of dosing-related transient episodes of hypoxia and bradycardia was not decreased by the slow, 1 min, side-hole instillation procedure.     

Prophylactic epidural administration of fentanyl for the suppression of tourniquet pain

Severe dull pain on the side of tourniquet application and marked rises in blood pressure and heart rate associated with that pain are often observed even under adequate regional analgesia. The purpose of this study was to evaluate the effect of epidural fentanyl on the suppression of tourniquet pain during orthopedic surgical procedures. Forty-five patients undergoing orthopedic surgery of the lower extremities with a tourniquet were maintained by continuous epidural anesthesia with 2% lidocaine through an epidural indwelling polyethylene catheter (L3–4). The patients were randomly allocated to the following three groups: epidural fentanyl (100μg) (epidural group,n=15); intravenous fentanyl (100μg) (intravenous group,n=15); control (no fentanyl) (control group,n=15). The epidural or intravenous fentanyl was administered at the time of the second lidocaine injection. The severity of tourniquet pain based on the patient's level of complaint and the total dose of supplemental analgesics requested in the epidural group were significantly lower than those in the control group. Blood pressure during tourniquet application in the epidural group was more stable than in the other two groups. No severe side-effects were observed in any patient. Prophylactic epidural administration of fentanyl might be useful in the suppression of tourniquet pain.     

Effects of tryptophan and/or acute running on extracellular 5-HT and 5-HIAA levels in the hippocampus of food-deprived rats

The present microdialysis study has examined whether exercise-elicited increases in brain tryptophan availability (and in turn 5-HT synthesis alter 5-HT release in the hippocampus of food-deprived rats. To this end, we compared the respective effects of acute exercise, administration of tryptophan, and the combination of both treatments, upon extracellular 5-HT and 5-hydroxyindoleacetic acid (5-HLAA) levels. All rats were trained to run on a treadmill before implantation of the microdialysis probe and 24 h of food deprivation. Acute exercise (12 m/min for 1 h) increased in a time-dependent manner extracellular 5-HT levels (maximal increase: 47%). these levels returning to their baseline levels within the first hour of the recovery period. Besides, exercise-induced increases in extracellular 5-HIAA levels did not reach significance. Acute administration of a tryptophan dose (50 mg/kg i.p.) that increased extracellular 5-HIAA (but not 5-HT) levels in fed rats, increased within 60 min extracellular 5-HT levels (maximal increase: 55%) in food-deprived rats. Whereas 5-HT levels returned toward their baseline levels within the 160 min that followed tryptophan administration, extracellular 5-HIAA levels rose throughout the experiment (maximal increase: 75%). Lastly, treatment with tryptophan (60 min beforehand) before acute exercise led to marked increases in extracellular 5-HT and 5-HIAA levels (maximal increases: 100% and 83%, respectively) throughout the 240 min that followed tryptophan administration. This study indicates that exercise stimulates 5-HT release in the hippocampus of fasted rats, and that a pretreatment with tryptophan (at a dose increasing extracellular 5-HT levels) amplifies exercise-induced 5-HT release.     

In-vitro Cell Culture Models of the Nasal Epithelium: A Comparative Histochemical Investigation of Their Suitability for Drug Transport Studies

Purpose. To evaluate different in-vitro cell culture models for their suitability to study drug transport through cell monolayers. Methods. Bovine turbinate cells (BT; ATCC CRL 1390), human nasal septum tumor cells (RPMI, 2650; ATCC CCL 30), and primary cell cultures of human nasal epithelium were characterized morphologically and histochemically by their lectin binding properties. The development of tight junctions in culture was monitored by actin staining and transepithelial electrical resistance measurements. Results. The binding pattern of thin-sections of excised human nasal respiratory epithelium was characterized using a pannel of fluorescently-labelled lectins. Mucus in goblet cells was stained by PNA, WGA and SBA, demonstrating the presence of terminal N-acetylglucosamine, N-acetylgalactosamine and galactose residues respectively in the mucus of human nasal cells. Ciliated cells revealed binding sites for N-acetylglucosamine, stained by WGA, whereas Con A, characteristic for mannose moieties, labelled the apical cytoplasm of epithelial cells. Binding sites for DBA were not present in this tissue. Comparing three different cell culture models: BT, RPMI 2650, and human nasal cells in primary culture using three lectins (PNA, WGA, Con A) as well as intracellular actin staining and transepithelial electrical resistance measurements we found, that only human nasal epithelial cells in primary culture showed differentiated epithelial cells, ciliated nasal cells and mucus producing goblet cells, which developed confluent cell monolayers with tight junctions. Conclusions. Of the in-vitro cell culture models studied, only human nasal cells in primary culture appears to be suitable for drug transport studies.     

Phase I trial of a novel matrix metalloproteinase inhibitor batimastat (BB-94) in patients with advanced cancer

Summary Degradation of basement membrane and extracellular matrix by matrix metalloproteinases (MMPs) is believed to be required for tumor invasion, tumor-induced angiogenesis and vascular invasion. A synthetic hydroxamate, batimastat (also known as BB-94), inhibits MMPs by binding the zinc ion in the active site of the MMP. Batimastat inhibits at least 50% of MMP activity at concentrations less than or equal to 10 ng/ml in vitro. Batimastat retarded ascites accumulation and increased survival in mice with human ovarian tumor xenografts. Acute and long-term toxicological studies revealed no major toxicity in animals. Batimastat is poorly soluble and was administered intraperitoneally (i.p.) as a suspension. Previous studies in patients with malignant ascites have shown no major toxicities at doses as high as 1350 mg/m².     

Effects of acute or chronic administration of low doses of a dopamine agonist on drinking and locomotor activity in the rat

Low doses of piribedil (0.25–5.0 mg/kg) administered acutely produced reliable decrements in locomotor activity in thirsty and non-thirsty animals, the greatest effect occurring at the highest dose. A sequence of ten daily injections of piribedil produced indications of the development of tolerance, at the two highest doses (2.5 and 5.0 mg/kg) in thirsty animals. The smallest doses used, given either acutely or chronically, produced a weak enhancement of drinking behaviour within the first 15 min of a drinking test, as shown by a reduction in latency to drink and an increase in the amount of water consumption. Tolerance did develop with respect to drinking behaviour; animals treated chronically with piribedil displayed higher levels of drinking at several dose levels when compared with acutely treated subjects. The tolerance displayed at the two highest doses could have a close affinity with that shown with regard to locomotor activity.     

Insulin precipitation in artificial infusion devices

Summary Precipitation of insulin is a problem with mechanical insulin infusion devices. Therefore conditions affecting insulin precipitation have been studied in a recirculating system using a peristaltic pump. Acetate buffer favoured precipitation and a pH of 2, 3 or 8 resulted in no less (and often more) precipitation than a pH of 7 using either acetate or phosphate buffer. However, no precipitation occurred in a phosphate buffered neutral preparation after ten days of pumping through tubing pretreated with EDTA. In comparison at pH 7, using acetate buffer with untreated tubing, more than 95% of insulin was precipitated in ten days. A heavy metal-insulin association appears to be a major factor in the precipitation. However, some formation of insulin fibrils is probable as the precipitate is autocatalytic and partially acid insoluble. Phosphate buffered highly purified porcine insulin is suitable for relatively prolonged infusion if metal ion contamination of the delivery system is minimised.