Effect of hydrofluoroalkane-ethanol inhalers on estimated alcohol levels in asthmatic subjects.

BACKGROUND AND OBJECTIVE: Inhaled medication administered via a metered dose inhaler (MDI) is often used to treat asthma. Hydrofluoroalkane (HFA) has replaced chlorofluorocarbons (CFC) as the propellant and these new MDI may contain alcohol. This raises concerns that their use may transiently increase breath ethanol concentration (BEC), thereby interfering with random breath testing. It was hypothesized that HFA-ethanol MDI may contribute to raising BEC above the legal limit. METHODS: The effect of a HFA-ethanol MDI on BEC was compared with that of CFC and placebo MDI and the effect of ingesting a standard amount of alcohol was also investigated. Asthmatic (n = 16) and normal control subjects (n = 15) were recruited for the double-blind, placebo-controlled study. Each subject used the three MDI in random sequence. BEC was measured at baseline and at 2, 5 and 15 min after inhalation of each MDI, using the Lion Alcometer SD-400TM. Spirometry was performed at baseline and 20 min after the last inhalation. An identical procedure was followed after alcohol consumption. RESULTS: Use of the HFA-ethanol MDI resulted in a significant increase in BEC from 0.002 to 0.0138 mg/100 mL (28 mg/100 mL of blood, P = 0.001) in asthmatics, and from 0.001 mg/100 mL to 0.016 mg/100 mL (33 mg/100 mL of blood, P = 0.002) in normal subjects. By 5 min, there were no significant differences in BEC of asthmatics (0.0031 mg/100 mL) and normal subjects (0.003 mg/100 mL), when compared with baseline (P > 0.2). CONCLUSIONS: BEC are transiently elevated after inhalation of HFA-ethanol MDI; however, by 5 min, BEC had already returned to baseline levels. Thus the effect of HFA-ethanol MDI on BEC is transient and would be negligible after 5 min.

Pharmacodynamic equivalence study of CFC-free and CFC-containing procaterol hydrochloride metered-dose inhalers.

Equivalence between a CFC-free procaterol hydrochloride metered-dose inhaler using HFA-227 as a propellant (Meptin [HFA]) and a CFC-containing procaterol hydrochloride metered-dose inhaler (Meptin [CFC]) was assessed in 28 patients with bronchial asthma. The study was conducted in a randomized, double-dummy, double-blind crossover manner, using forced expiratory volume in the first second (FEV1) as an index of bronchodilatory effect. In Period I, the patients received 20 microg of either Meptin [HFA] or Meptin [CFC] and then crossed over in Period II after a washout interval of 3-28 days. Pharmacodynamic equivalence was assessed using AUC (FEV1)/h and peak FEV1 as indices, and the data was analyzed by analysis of variance. Factors used for the analysis were the treatment group and/or carryover effect, patients within each group, period, and treatment. The 90% confidence intervals for the differences between the two treatments were -0.0507 to 0.0039 (L) for mean AUC (FEV1)/h and -0.056 to 0.026 (L) for mean peak FEV1, both within the acceptance criteria of -0.15 to 0.15 (L). Meptin [HFA] was therefore assessed as being equivalent to the current Meptin [CFC].

Effects of mometasone furoate dry powder inhaler and beclomethasone dipropionate hydrofluoroalkane and chlorofluorocarbon on the hypothalamic-pituitary-adrenal axis in asthmatic subjects.

STUDY OBJECTIVES: Mometasone furoate dry powder inhaler (MF-DPI) [400 mug] is an inhaled corticosteroid (ICS) that is effective in the treatment of asthma. MF-DPI has a low potential for suppression of the hypothalamic-pituitary-adrenal (HPA) axis at its clinical dose. The effect of MF-DPI, 400 microg qd, on the HPA axis was compared to that of beclomethasone dipropionate (BDP) using hydrofluoroalkane (HFA) and chlorofluorocarbon (CFC) propellants via metered-dose inhalers (MDIs) twice daily. DESIGN AND INTERVENTIONS: This randomized, third-party blind, parallel-group study compared the effects of MF-DPI 400 mug one puff qd in the morning (n = 18), HFA-BDP 200 microg two puffs MDI bid (n = 18), and CFC-BDP 400 microg two puffs MDI bid (n = 17) for 14 days on the area under the 24-h serum cortisol concentrations curve (AUC(0-24)) and on total 24-h urinary free cortisol excretion in mild asthmatic subjects. Effects on morning/evening peak expiratory flow (PEF) and on inhaled albuterol use were also assessed. Adverse events that occurred during or > or = 30 days after the study were recorded. RESULTS: The mean decrease from baseline in the serum cortisol concentrations AUC(0-24) in the MF-DPI group was significantly less than in either the HFA-BDP (p = 0.024) or the CFC-BDP (p = 0.011) groups. Decreases in serum cortisol concentrations AUC(0-24) in the two BDP groups did not differ from one another. The MF-DPI group trended toward higher morning and evening PEF than either BDP group. Treatment-associated adverse events were reported by seven subjects in the MF-DPI group, vs one subject in the HFA-BDP and three subjects in the CFC-BDP groups; these were mild, and no subject discontinued treatment due to an adverse event. CONCLUSIONS: Fourteen days of treatment with MF-DPI 400 microg qd was associated with a significantly lesser decrease in the serum cortisol concentrations AUC(0-24) compared with HFA-BDP 200 microg MDI or CFC-BDP 400 microg MDI bid.

Effects of HFA- and CFC-beclomethasone dipropionate on the bronchial response to methacholine (MCh) in mild asthma.

Metered inhalers using chlorofluorocarbon (CFC) propellents have been gradually replaced by new devices that use hydrofluoroalkanes (HFAs) as their propellents, which are less harmful to the environment. This reformulation led to a substantial improvement of the previous technologies applied to inhalation devices and of the physical characteristics of drugs delivered. In particular, inhaled corticosteroids, such as beclomethasone dipropionate (BDP) which is of fundamental importance in the long-term management of bronchial asthma, took advantage of this reformulation. Unlike the preparation beclomethasone dipropionate and chlorofluorocarbon (BDP-CFC) which was a suspension, that of beclomethasone dipropionate and a hydrofluoroalkane (BDP-HFA) is a solution and produces an aerosol with a mean aerodynamic particle size of 1.1 microm, which is much smaller than the particle size of 3.5-4.0 microm, obtained with the BDP-CFC. The particles of BDP-HFA can then deposit in the lungs in a larger amount, and particularly in the more peripheral airways where the inflammatory process starts in the case of bronchial asthma. A 12-week use of BDP-HFA ensured a significant better control of the bronchial response to methacholine (MCh) than the corresponding use of BDP-CFC for the same duration. The therapeutic performance of BDP-HFA proved much higher and allowed the substantial reduction of the therapeutic daily dose for the clinical asthma management, being the increased and more peripheral deposition of BDP-HFA is presumed to play a crucial role.

Hydrofluoroalkane formulations of inhaled corticosteroids for the treatment of asthma.

Current international guidelines for the treatment of asthma advocate inhaled corticosteroids as first-line therapy for persistent symptoms. As chlorofluorocarbon (CFC)-based products are being phased out because of environmental concerns, new inhaler propellants, such as hydrofluoroalkane (HFA)-134a, have been developed. The reformulation of existing corticosteroid compounds into HFA propellants has resulted in two distinct classes of corticosteroid aerosols consisting of HFA suspensions and HFA solutions. The new HFA formulations of flunisolide and beclomethasone dipropionate exist as solutions, whereas HFA preparations of fluticasone propionate, triamcinolone acetonide, and mometasone furoate are formulated as suspensions. HFA suspensions retain the same particle size, deposition, and efficacy profiles as their CFC counterparts. HFA solutions, however, exist as extra-fine aerosols which have been shown to penetrate more effectively into the peripheral regions of the lung. Comparisons of HFA solutions with their CFC counterparts have demonstrated equivalent efficacy when given in smaller doses. The safety profiles of both HFA suspensions and solutions, given at equivalent doses, are comparable to CFC formulations. Increasing evidence suggests that inflammation of the small airways plays an important role in the pathogenesis of asthma. Currently, the clinical implications of long-term treatment of the peripheral lung using an extra-fine inhaled corticosteroid aerosol remain uncertain. Future studies, involving histopathologic and clinical endpoints, will be necessary to determine whether treatment with HFA solutions offers significant advantages over currently available therapies.

Medical aerosol propellant interference with infrared anaesthetic gas monitors.

BACKGROUND: 1,1,1,2 Tetrafluoroethane is a hydrofluoroalkane (HFA) that is replacing chlorofluorocarbons (CFC) as a medical aerosol propellant in an attempt to reduce damage to the ozone layer. This study compared the effects of HFA- and CFC-based inhalers on four anaesthetic gas monitoring systems. METHODS: The HFA- and CFC-based inhalers were activated in close proximity to the sample line of two Datex Ohmeda, an Agilent and a Siemens infrared anaesthetic agent monitoring systems. The effects were recorded on each system for five common anaesthetic agents. RESULTS: The HFA inhaler caused either maximal false positive readings (with the exception of desflurane) or transient measurement failure on all systems. The Datex Ohmeda AS/3 system misidentified the HFA inhaler as carbon dioxide at low concentration (2 +/- 0 mm Hg). The CFC-based inhaler caused a minor false-positive reading (0.4 +/- 0%) for halothane only on the Datex Ohmeda AS/3 system only and was misidentified as carbon dioxide at 33.3 (sd 2.1) mm x Hg and 22.4 (8.9) mm x Hg by the Agilent and Siemens systems. CONCLUSIONS: The HFA inhaler adversely affected all equipment tested. The infrared spectra of HFA and the common anaesthetic gases have considerable overlap at the 8-12 microm range that is not shared by the CFCs. The differences in spectral overlap explain the different effects of the HFA and CFC propellants. Anaesthetic gas concentration data may be erroneous using the HFA-based inhalers.

Intermittent cryogen spray cooling for optimal heat extraction during dermatologic laser treatment.

Fast heat extraction is critically important to obtain the maximal benefit of cryogen spray cooling (CSC) during laser therapy of shallow skin lesions, such as port wine stain birthmarks. However, a film of liquid cryogen can build up on the skin surface, impairing heat transfer due to the relatively low thermal conductivity and higher temperature of the film as compared to the impinging spray droplets. In an attempt to optimize the cryogen mass flux, while minimally affecting other spray characteristics, we apply a series of 10 ms spurts with variable duty cycles. Heat extraction dynamics during such intermittent cryogen sprays were measured using a custom-made metal-disc detector. The highest cooling rates were observed at moderate duty cycle levels. This confirms the presence, and offers a practical way to eliminate the adverse effect of liquid cryogen build-up on the sprayed surface. On the other hand, lower duty cycles allow a substantial reduction in the average rate of heat extraction, enabling less aggressive and more efficient CSC for treatment of deeper targets, such as hair follicles.

Modulite technology: pharmacodynamic and pharmacokinetic implications.

In the drive to replace chlorofluorinated hydrocarbons (CFCs) by alternative more environmentally friendly propellants in pressurized metered dose inhalers (pMDIs), Chiesi has developed new inhalers using Modulite technology. The aim was to obtain CFC-free pMDIs which are equivalent, in terms of safety and efficacy, to the previous CFC devices at the same dose. When beclometasone dipropionate (BDP) and budesonide Modulite formulations were compared to the equivalent CFC products there was no significant difference in morning serum cortisol or urinary cortisol excretion, at the maximum recommended daily dose (2000 micrograms or 1600 micrograms respectively). Single dose pharmacokinetic studies in both healthy volunteers and asthmatic patients compared systemic exposure (B17MP levels) for BDP-CFC with BDP Modulite and extrafine BDP-HFA (QVAR). B17MP levels for BDP-CFC and BDP Modulite were comparable, but substantially less than that seen with extrafine BDP-HFA. After 6 weeks of treatment in asthmatic patients, B17MP AUC after inhalation of BDP (1000 micrograms twice-daily) from BDP Modulite was comparable with that obtained after BDP-CFC (Becloforte). Plasma profile of BDP and B17MP were similar after inhalation from BDP Modulite with standard actuator or delivered via a spacer, suggesting that pulmonary delivery of BDP to the lung is similar with both actuators.

Cryogen spray cooling in laser dermatology: effects of ambient humidity and frost formation.

BACKGROUND AND OBJECTIVE: Dynamics of cryogen spray deposition, water condensation and frost formation is studied in relationship to cooling rate and efficiency of cryogen spray cooling (CSC) in combination with laser dermatologic surgery. STUDY DESIGN/MATERIALS AND METHODS: A high-speed video camera was used to image the surface of human skin during and after CSC using a commercial device. The influence of ambient humidity on heat extraction dynamics was measured in an atmosphere-controlled chamber using an epoxy block with embedded thermocouples. RESULTS: A layer of liquid cryogen may remain on the skin after the spurt termination and prolong the cooling time well beyond that selected by the user. A layer of frost starts forming only after the liquid cryogen retracts. Condensation of ambient water vapor and subsequent frost formation deposit latent heat to the target site and may significantly impair the CSC cooling rate. CONCLUSIONS: Frost formation following CSC does not usually affect laser dosage delivered for therapy of subsurface targets. Moreover, frost formation may reduce the risk of cryo-injury associated with prolonged cooling. The epidermal protection during CSC assisted laser dermatologic surgery can be further improved by eliminating the adverse influence of ambient humidity.

An analysis of heat removal during cryogen spray cooling and effects of simultaneous airflow application.

BACKGROUND AND OBJECTIVE: Cryogen spray cooling (CSC) is a method used to protect the epidermis from non-specific thermal injury that may occur as a result of various dermatological laser procedures. However, better understanding of cryogen deposition and skin thermal response to CSC is needed to optimize the technique. STUDY DESIGN/MATERIALS AND METHODS: Temperature measurements and video imaging were carried out on an epoxy phantom as well as human skin during CSC with and without simultaneous application of airflow which was intended to accelerate cryogen evaporation from the substrate surface. An inverse thermal conduction model was used to estimate heat flux and total heat removed. RESULTS: Lifetime of the cryogen film deposited on the surface of skin and epoxy phantom lasted several hundred milliseconds beyond the spurt, but could be reduced to the spurt duration by application of airflow. Values over 100 J/cm(3) were estimated for volumetric heat removed from the epidermis using CSC. CONCLUSIONS: "Film cooling" instead of "evaporative cooling" appears to be the dominant mode of CSC on skin. Estimated values of heat removed from the epidermis suggest that a cryogen spurt as long as 200 milliseconds is required to counteract heat generated by high laser fluences (e.g., in treatment of port wine stains) in patients with high concentration of epidermal melanin. Additional cooling beyond spurt termination can be avoided by simultaneous application of airflow, although it is unclear at the moment if avoiding the additional cooling would be beneficial in the actual clinical situation.

Pharmacokinetics, pharmacodynamics, and the delivery of pediatric bronchodilator therapy.

beta(2)-adrenergic receptor agonists have long been used for the amelioration of acute asthma symptoms and in the prophylactic treatment of exercise-induced asthma in both adults and children. To maximize the amount of drug that reaches the airways, small doses of the drug can be inhaled in aerosol form that preferentially activate pulmonary beta(2)-receptors, thereby reducing systemic absorption and adverse effects. Potential adverse effects of beta(2)-agonists include tremor, increased heart rate, and metabolic imbalances. Because of its specialized nature, aerosolized delivery to the airways has many additional variables that can alter the pharmacokinetics and pharmacodynamics of the administered drug.

From hydrofluoroalkane pressurized metered dose inhalers (pMDIs) and comparability with chlorofluorocarbon pMDIs.

Fluticasone propionate pressurized metered dose inhalers (pMDIs) containing the hydrofluoroalkane (HFA) propellant, HFA 134a, are being developed to replace existing chlorofluorocarbon (CFC) pMDIs. This is part of the ongoing worldwide project to limit the damage to the earth's ozone layer. The in vivo performance and dose proportionality of fluticasone propionate HFA 134a pMDIs was examined for fluticasone propionate doses of 400, 1000 and 2000 microg using the 50, 125 and 250 microg strength pMDIs, respectively. The 125 and 250 microg strength HFA 134a pMDIs were compared with corresponding fluticasone propionate CFC pMDIs. Twenty-three healthy subjects participated in this single dose, randomized, five-way, cross-over study. Serial blood samples were collected 24 h post-dose to measure fluticasone propionate plasma concentrations. Twenty-four hour urinary-free cortisol was also measured before and after dosing. A dose-proportional increase in plasma fluticasone propionate concentrations was observed with increasing dose for the HFA 134a pMDIs. This was associated with a dose-related decrease in urinary cortisol excretion. Similar or lower fluticasone propionate systemic exposure was observed with the HFA 134a pMDIs compared to the corresponding CFC inhalers. The differences in systemic exposure observed for the HFA 134a and CFC pMDIs were too small to produce a differential effect on urinary cortisol excretion. Since fluticasone propionate has negligible oral bioavailability, the systemic exposure, which arises only from pulmonary absorption, is a measure of lung deposition. There was a good correlation between the in vitro fine particle mass produced by the different strengths and types of pMDI and the systemic exposure to fluticasone propionate. Therefore, the fluticasone propionate HFA 134a pMDI is an acceptable pharmaceutical alternative to the current CFC pMDI, producing similar lung deposition and no increase in systemic exposure at microgram equivalent doses.

The chlorofluorocarbon to hydrofluoroalkane transition: the effect on pressurized metered dose inhaler suspension stability.

The phase out of chlorofluorocarbon (CFC) propellants has necessitated the reformulation of pressurized metered dose inhalers (pMDIs) with hydrofluoroalkane (HFA) propellants. One of the main challenges has been that conventional surfactants used for CFC-based pMDIs were not soluble in HFAs. Since one of the main aims of a pMDI is to deliver a reproducible dose of medication to the patient, it is vital that, for suspension-type pMDI formulations, the suspension is stabilized sufficiently for a reproducible dose to be delivered. A new technique has been developed that measures suspension stability more objectively than before. This technique, optical suspension characterization, was used to compare the performance of different formulations of respiratory drugs in HFAs. The optical suspension characterization data were correlated with conventional analytic techniques for the determination of the stability of the suspension formulation.

Comparative effects of hydrofluoroalkane and chlorofluorocarbon beclomethasone dipropionate inhalation on small airways: assessment with functional helical thin-section computed tomography.

A double-blind, randomized, parallel-group pilot study compared the relative efficacy of hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP [QVAR]; mass median aerodynamic diameter, 0. 8-1.2 m) versus cholorofluorocarbon-11/12 BDP (CFC-BDP [Beclovent]; mass median aerodynamic diameter, 3.5-4.0 m) in 31 steroid naive patients with mild to moderate asthma (PC(20,) 4 mg/mL). Functional high-resolution computed tomography was used to assess the relative efficacy of HFA-BDP and CFC-BDP on regional air trapping, as an indirect measure of small airways function and on regional hyperreactivity. Pretreatment functional computed tomography was performed at residual volume before and after methacholine challenge. After 4 weeks of treatment, functional imaging was repeated before and after the same concentration of methacholine that was administered before the treatment (n = 19 patients). Quantitative assessment of changes in distribution of lung attenuation was performed. After 4 weeks of treatment, the HFA-BDP group showed significantly more improvement in air trapping overall (a shift in the lung attenuation curve at residual volume toward more attenuation) on the posttreatment computed tomography scan (P <.05; Fisher's Exact Test). After an equal constrictor stimulus (methacholine concentration), subjects treated with HFA-BDP (n = 10 patients) showed less increase in air trapping overall than subjects treated with CFC-BDP (n = 9 patients) on the posttreatment scans compared with the pretreatment scans (P <.001; Fisher's Exact Test). No significant difference was demonstrated between the 2 treatment groups with respect to improvement in symptoms, spirometry, or methacholine responsiveness assessed by FEV(1), except for a greater reduction in breathlessness in the HFA-BDP group (P <.05). We conclude that HFA-BDP may have greater efficacy in the peripheral airways and that this effect is better assessed with functional imaging computed tomography techniques than with conventional physiologic tests.

A comparative study of human skin thermal response to sapphire contact and cryogen spray cooling.

Surface cooling, in conjunction with various thermally mediated therapeutic procedures, can provide a means to protect superficial tissues from injury while achieving destruction of deeper targeted structures. We have investigated the thermal response of in-vivo human skin to: 1) contact cooling with a sapphire window (6-12 degrees C); and 2) spray cooling with a freon substitute cryogen [tetrafluoroethane; boiling point approximately -26 degrees C at 1 atmospheric pressure (atm)]. Measurements utilizing infrared radiometry show surface temperature reductions from 30 degrees C to 14-19 degrees C are obtained within approximately 1 s in response to sapphire contact cooling. Surface temperature reductions to values between 5 degrees C and -9 degrees C are obtained in response to 20-100-ms cryogen spurts. Computational results, based on fitting the measured radiometric surface temperature to estimate heat transfer parameters, show: 1) temperature reductions remain localized to approximately 200 microns of superficial tissue; and 2) values of heat flux and total energy removed per unit skin surface area at least doubled when using cryogen spray cooling.

Continuing patient care with metered-dose inhalers.

International guidelines recommend inhaled therapy over oral therapy for asthma because of greater efficacy and safety. Metered-dose inhalers (MDIs) are the delivery system of choice for the majority of patients with asthma. They have been well tried and tested and proven to be safe, reliably delivering a reproducible and precise dose, and account for 85% of the 400 million inhalers currently sold worldwide. Current products using chlorofluorocarbon (CFC) 11/12 as the propellant are being reformulated. Under the Montreal Protocol, CFCs are to be phased out worldwide, though MDIs have been granted temporary exemption, thus far until 1997. Two propellants, hydrofluoroalkane (HFA) 134a and 227, have been identified by the pharmaceutical industry to replace CFCs. However, they have different properties and reformulation has been difficult in relation to surfactants, valves and elastomeric seals. The manufacturing process has been re-engineered to take place at high pressure, because at normal pressure HFA134a is a gas, in contrast with CFC 11 which is a liquid at room temperature. Glaxo has carried out an extensive toxicological assessment of HFA134a and thorough clinical testing has shown it to be well tolerated. To date they have carried out safety and efficacy testing on reformulations of salbutamol, salmeterol and fluticasone propionate (FP). Single-dose studies of salbutamol, 200 micrograms, with HFA134a have been shown to provide equivalent protection against bronchial provocation by histamine in both adults and children with asthma when compared with the currently available CFC preparations. In a subsequent 4-week study, both formulations had similar effects on morning peak flow and the patients believed that the two preparations were equivalent.

Propellant-driven aerosols for delivery of proteins in the respiratory tract.

Metered-dose propellant-driven aerosols of an antigenically reactive protein were produced by combining bovine gammaglobulin (BGG) with one of several surfactants soluble in Freon or dimethylether propellants. Small-particle protein aerosols were most effectively produced by lyophilizing surfactants and proteins prior to the addition of propellants. Up to 26% of the total aerosolized protein was of respirable size. Aerosol metering valves delivering small volumes were most effective in producing respirable-sized (< or = 4 micron median mass aerodynamic diameter) protein aerosols. Proteins were suspended in liquified propellants as both propellant-soluble molecules and visible sedimenting clusters which both contributed to making respirable-sized protein aerosol particles. Electron microscopy showed that respirable-sized protein particles were composed of variable-sized chain aggregates of spherical subunits. Proteins were antigenic after suspension in liquified propellant and release as aerosols, but antigenicity diminished with extended propellant exposure. Local immunity in the respiratory tract is a key factor in resistance to respiratory infections. Metered-dose propellant-driven aerosols offer a potentially attractive method for delivering small-particle aerosols of immunizing antigens or other therapeutic proteins to the respiratory tract.

Incidence of acute decreases in peak expiratory flow following the use of metered-dose inhalers in asthmatic patients.

This study aimed to investigate and compare the incidence of metered-dose inhaler (MDI)-associated bronchoconstriction in an asthmatic population, following the use of three different MDIs. Two different placebo metered-dose inhaler preparations containing the same chlorofluorocarbons but differing in dispersant chemicals, one containing oleic acid (MDI-OA) and the other lecithin NF (MDI-L), were compared with a MDI containing salmeterol xinafoate (25 micrograms) and lecithin NF (MDI-S). The study population comprised 11,850 asthmatic patients, who were assigned to receive two puffs from one of the three inhalers: MDI-S (n = 3,948); MDI-L (n = 3,942); or MDI-OA (n = 3,960). Peak expiratory flow (PEF) was measured before and 5 min after inhalation. A 20% fall in PEF was defined as a clinically significant bronchoconstriction. Overall 180 (1.5%) patients demonstrated bronchoconstriction, 43 (1.1%) in the MDI-S group, 67 (1.7%) in the MDI-L group and 70 (1.8%) in the MDI-OA. A significantly lower incidence of bronchoconstriction was seen with the salmeterol xinafoate MDI compared to either of the other two preparations. The risk of acute bronchoconstriction was also shown to increase with age and with decreasing pretreatment PEF. The study has shown that acute bronchoconstriction is an uncommon adverse reaction following the use of metered-dose inhalers. In addition, the study suggests that one of the inert constituents currently within metered-dose inhalers is the likely source of the irritant leading to bronchoconstriction.

A proposed mechanism for cardiac sensitisation: electrophysiological study of effects of difluorodichloromethane and adrenaline on different types of cardiac preparations isolated from sheep hearts.

Difluorodichloromethane (FC12) inhaled at high concentrations sensitises, as do numerous other volatile organic compounds, mammalian heart to adrenaline induced arrhythmias. In this study three types of cardiac tissue (spontaneously beating sinusal and Purkinje preparations and stimulated Purkinje fibres) were isolated from sheep hearts and perfused for electrophysiological recording to examine the effect of FC 12. Preparations were perfused alternately with a control solution of physiological fluid and a trial solution with dissolved FC 12, the partial pressure of oxygen remaining identical. Sensitisation to adrenaline was studied by injecting adrenaline at a dose causing a notable effect without producing arrhythmias in the control preparations. Examination of transmembrane potential recordings confirmed that FC 12 inhibits sinus node pacemaker stimulation by adrenaline. Conversely, the adrenaline induced acceleration of latent pacemakers in certain types of Purkinje fibres appeared to be potentialised by FC 12. The various types of arrhythmia observed in vitro were explained by the effect of FC 12 on cell membranes, an affect which can oppose or favour that of adrenaline. These phenomena explain the arrhythmias observed in isolated hearts or whole animal preparations and permit a better understanding of the mechanism involved in cardiac sensitisation to adrenaline induced arrhythmia, a mechanism in which variability in time and location is the essential factor in the FC 12 effect.