Patients' opinions of CFC-free inhaler changeover in primary care.

OBJECTIVE: To determine patient's opinions regarding the changeover from CFC containing to CFC-free salbutamol. DESIGN: Patients receiving metered dose salbutamol inhaler therapy were identified and verbal consent was obtained before a semi-structured interview was performed. Setting An outpatient respiratory clinic within a busy teaching hospita. MAIN OUTCOME MEASURES: Knowledge of CFC-free inhaler therapy and acceptance of change. RESULTS: A total of 28 patients were identified of whom only eight (29%) had been changed to a CFC-free product. Six of these (75%) had received counselling from their GP or pharmacist regarding the change. Differences were reported by all of the patients who had been changed to a CFC-free inhaler with comments including difference in taste (6 patients), difference in feel (6), less effective (1) and more effective (1). Three patients preferred the CFC-free inhaler to their previous therapy. Although 13 out of the 20 patients who had not received a CFC-free inhaler stated they were happy with the potential changeover, 10 (80%) has concerns relating to effectiveness. CONCLUSION: The majority of patients still receiving CFC inhalers were aware that the production of CFC-containing products had been restricted although they were unaware of the imminent changes that would take place regarding their inhaler therapy. However, the small sample size recruited in this study may mean that the results are unrepresentative of the CFC-free implementation process in the Grampian Health Board area as a whole. Nonetheless, in view of the differences experienced by patients who received CFC-free inhalers and the concerns stated about potential lack of efficacy by patients about to be changed over, it is essential that healthcare professionals provide advice on CFC-free inhalers to all patients.

An assessment of antibiotic therapy of urinary tract infection in elderly, hospitalised patients.

The aim of the study was to compare the antibiotic treatment actually received by elderly, hospitalised patients with urinary tract infection (UTI) with 'optimal' therapy (as gauged by compliance with antibiotic policy, infecting organism, sensitivity data, patient renal function and cost). UTI was more common in females and in catheterised patients and E.Coli was the commonest pathogen. Trimethoprim and co-amoxiclav were the drugs used most frequently for either empirical or sensitivity data-based treatment. In 96% of infections a drug with appropriate action was administered. Often, however, treatment could have been optimised by substituting a cheaper suitable antibiotic, by standardising duration of therapy and ensuring that doses were adjusted for renal impairment. Savings from the use of 'optimal' therapy were estimated at 17%. There is clearly considerable scope for positive input from the clinical pharmacist in this area.

Comparison of the effects of cromakalim in trachea isolated from normal and albumin-sensitive guinea-pigs.

The effects of the K(+)-channel activator, cromakalim, on spontaneous tone and constrictor responses to vagal stimulation or acetylcholine were compared in trachea isolated from groups of guinea-pigs that were: untreated; sensitized and chronically exposed to inhaled albumin; or sham sensitized. Responses were assessed as changes in intraluminal pressure in the isolated, Krebs-filled trachea, increases and decreases in intraluminal pressure directly reflecting constriction and dilatation, respectively. Cromakalim reduced resting intraluminal pressure in normal trachea but in sensitized trachea mixed effects occurred, many preparations exhibiting increases in intraluminal pressure, particularly at lower concentrations of cromakalim. Cromakalim attenuated the frequency-dependent increases in intraluminal pressure evoked by stimulation of the vagus nerve in a concentration-dependent manner and to a similar degree in trachea from each of the three groups tested. The degree of attenuation was similar in the absence and presence of the cyclo-oxygenase inhibitor flurbiprofen. In untreated trachea, responses to a range of concentrations of applied acetylcholine were attenuated by cromakalim. In sensitized trachea the response to the lowest concentration of applied acetylcholine was attenuated by cromakalim but responses to higher concentrations of were unaffected. The results indicate that the direct relaxant effect of cromakalim is altered in sensitized trachea, which may indicate abnormal K(+)-channel behaviour in the smooth muscle cell membrane. Attenuation by cromakalim of vagal responses occurs in both normal and sensitized trachea, due chiefly to a pre-junctional effect on cholinergic neurotransmission which is independent of the generation of cyclo-oxygenase products.

Effects of calcium modulators on vagally-mediated constriction in the guinea-pig isolated trachea.

1. The effects of calcium modulators on tracheal constriction evoked by vagal stimulation were examined in the isolated, innervated trachea of the guinea-pig. Responses were assessed in the Krebs-filled trachea as changes in intraluminal pressure (ILP), increases and decreases reflecting constriction and dilatation, respectively. 2. Preparations had a positive resting ILP, indicating significant spontaneous tone. Verapamil and nifedipine reduced baseline ILP, whilst Bay K 8644 had mixed effects. 3. Verapamil and nifedipine attenuated vagal responses in a concentration-dependent manner. At lower concentrations attenuation was due entirely to postjunctional effects but at higher concentrations prejunctional effects may have contributed to attenuation. 4. Verapamil and nifedipine attenuated vagal responses in the absence or presence of flurbiprofen, indicating that their effects are largely independent of the generation of cyclo-oxygenase products. Nifedipine, however, was less effective in reducing responses to low frequency vagal stimulation (up to 5 Hz) when flurbiprofen was present. 5. Bay K 8644 augmented vagal responses, the degree varying widely between preparations. 6. It was concluded that influx of Ca2+ through voltage-operated Ca2+ channels contributes significantly to vagally-mediated tracheal constriction in normal trachea and in trachea where endogenous release of cyclo-oxygenase products is inhibited.

Effect of cromakalim on bronchoconstriction evoked by cholinergic nerve stimulation in guinea-pig isolated trachea.

1. Cromakalim reduced intraluminal pressure in the guinea-pig isolated, innervated trachea. 2. Preganglionic stimulation of the cervical vagus nerve elicited a frequency-dependent increase in intraluminal pressure. Cromakalim attenuated responses to vagal stimulation in a concentration-dependent manner at all frequencies tested. 3. Field stimulation caused a frequency-dependent increase in intraluminal pressure mediated by muscarinic cholinoceptors. Cromakalim did not affect the amplitude of responses at any frequency of stimulation, even at high concentrations. 4. Acetylcholine, added to the Krebs solution bathing the adventitial surface of the trachea, evoked a concentration-dependent increase in intraluminal pressure. The concentration-effect curve for acetylcholine was unaltered in the presence of cromakalim. 5. It is concluded that cromakalim modulates cholinergic neuroeffector transmission in the trachea chiefly by a prejunctional mechanism. However, cromakalim probably does not interfere with acetylcholine release from postganglionic cholinergic neurones.

Effects of leukotriene D4 on the mechanical and electrical properties of guinea-pig isolated trachealis.

1. The effects of leukotriene D4 (LTD4) on mechanical and electrical activity were examined in guinea-pig isolated trachealis muscle and compared with two other bronchoconstrictors, methacholine and potassium chloride (KCl). 2. LTD4 elicited concentration-dependent increases in tension in trachealis muscle which were slower in time course than responses induced by either methacholine or KCl. The maximum response to LTD4 was approximately 85% of the methacholine maximum. 3. At a concentration close to the EC50 for tension changes, LTD4 had no significant effect on either transmembrane potential or slow wave activity recorded in single trachealis cells. 4. At a concentration close to the EC90 for tension changes, LTD4 caused significant membrane depolarization, transiently reduced the amplitude and increased the frequency of slow wave discharge and ultimately abolished slow wave discharge. LTD4-induced depolarization was less marked, and developed more slowly, than that evoked by either methacholine or KCl. 5. These results show that LTD4 can elicit substantial increases in tension without altering transmembrane potential and are consistent with the view that LTD4 initiates contraction mainly through potential-independent mechanisms. However, at high concentrations the depolarization evoked by LTD4 allows the possibility that potential-dependent mechanisms may contribute to the spasm.

Comparison of autonomic responses in the trachea isolated from normal and albumin-sensitive guinea-pigs.

1 Mechanical and electrical responses to stimulation of the parasympathetic and sympathetic nerves were compared in the trachea isolated from normal guinea-pigs and from guinea-pigs sensitized to albumin and exposed repeatedly to inhaled albumin (a model of bronchial asthma). 2 Sensitized trachealis exhibited mechanical hyper-responsiveness to vagal stimulation characterized by a shift to the left of the frequency-response relationship and a 71% increase in the maximum response. 3 Transmembrane potential was significantly less negative in sensitized trachealis cells. 4 The amplitude of the depolarization evoked by vagal stimulation (4 or more pulses) was significantly greater in sensitized tissues. Vagally-mediated depolarization was associated with the appearance of regenerative electrical activity (spikes) in sensitized but not in control tissues. 5 Spontaneous discharge of slow waves occurred in cells from both control and sensitized trachea but the proportion of spontaneously active cells was higher in sensitized tissues. Spontaneous depolarization, like nerve-mediated depolarization, gave rise to abortive spikes only in sensitized trachealis. 6 Inhibitory responses to stimulation of the sympathetic stellate ganglion, mediated by beta-adrenoceptors, were unaltered in sensitized trachealis. 7 Possible explanations for the hyper-responsiveness to vagal input in sensitized trachealis are discussed.

Effects of sympathetic stimulation and applied catecholamines on mechanical and electrical responses to stimulation of the vagus nerve in guinea-pig isolated trachea.

Mechanical and electrical responses to stimulation of the vagus nerve were studied in the isolated, innervated trachea of the guinea-pig. In approximately half the preparations tested, the amplitudes of mechanical constrictor responses to stimulation of the vagus were reduced substantially during a period of sympathetic stimulation. Vagal responses were unaltered in the remainder. In single trachealis cells, stimulation of the vagus nerve or sympathetic stellate ganglion elicited depolarization and hyperpolarization, respectively. Vagally-mediated depolarization was decreased, unchanged or increased in amplitude after a period of sympathetic stimulation. Isoprenaline almost abolished mechanical responses induced by stimulation of the vagus, and this effect was blocked by propranolol. Noradrenaline attenuated markedly vagal mechanical responses also, and this effect was blocked by a combination of propranolol and phentolamine. Both noradrenaline and isoprenaline hyperpolarized single trachealis cells and greatly reduced the amplitude of vagally-mediated depolarization. Neither sympathetic stimulation nor applied catecholamines altered mechanical responses to applied acetylcholine, strongly suggesting that their effects on vagal responses are predominantly presynaptic.

Electrophysiology of neuroeffector transmission in the isolated, innervated trachea of the guinea-pig.

Intracellular recordings were made from cells of the guinea-pig trachealis muscle. Some cells were electrically quiescent while others exhibited spontaneous slow waves. In quiescent cells, stimulation of the cervical vagus nerve evoked transient depolarization. Occasionally there was a single depolarization, but more often there were several fluctuations in potential. In spontaneously active cells, vagal stimulation induced a transient increase in amplitude of the slow waves without affecting their frequency. Depolarizing responses could be obtained with a single pulse applied to the vagus nerve, and responses increased in amplitude with number of pulses (up to 16 pulses), and with frequency of stimulation (up to 20 Hz). Depolarization did not give rise to spike discharge. Responses to vagal stimulation were blocked by atropine. In the presence of neostigmine, vagally-mediated depolarization was augmented and abortive spikes were observed in a number of cells. In quiescent cells, repetitive stimulation of the sympathetic stellate ganglion evoked slight hyperpolarization. In spontaneously active cells, sympathetic stimulation evoked attenuation, or temporary cessation of slow wave discharge, with or without hyperpolarization. Sympathetic-induced hyperpolarization and suppression of slow waves were both blocked by propranolol, but unaffected by phentolamine. Electrical changes associated with sympathetic stimulation may be of minor importance in the initiation of relaxation.

Autonomic responses of the isolated, innervated trachea of the guinea-pig: interaction with autonomic drugs, histamine and 5-hydroxytryptamine.

Intraluminal pressure was measured in the isolated, fluid-filled trachea of the guinea pig, with autonomic innervation on the right side intact. Increases or decreases in intraluminal pressure reflected excitatory or inhibitory responses respectively, in the tracheal smooth muscle. Stimulation of the cervical vagus nerve evoked a cholinergic excitatory response. After cholinergic blockade with atropine, a non-adrenergic, non-cholinergic inhibitory response was obtained. Stimulation of the cervical sympathetic trunk, or stellate ganglion, evoked beta-adrenergic inhibitory responses. In the presence of propranolol, sympathetic stimulation evoked alpha-adrenergic excitatory responses which were of low amplitude (less than or equal to 5% of cholinergic excitatory responses). In the presence of phentolamine but not prazosin, beta-adrenergic inhibitory responses were potentiated. Neostigmine potentiated responses to vagal stimulation, increasing the amplitude and duration of response. At higher concentrations neostigmine (i) raised intraluminal pressure, a response blocked by atropine, and (ii) attenuated sympathetic inhibitory responses, an effect largely blocked by atropine. Histamine increased intraluminal pressure and this response was attenuated by atropine. In the presence of histamine, vagal excitatory responses were attenuated. Sympathetic inhibitory responses at low frequencies of stimulation (up to 10 Hz) were inhibited by histamine. 5-Hydroxytryptamine (5-HT) increased intraluminal pressure also, an effect partially blocked by atropine. 5-HT had no effect on vagal excitatory responses. Like histamine, 5-HT attenuated sympathetic inhibitory responses at lower frequencies of stimulation.

Studies on an isolated innervated preparation of guinea-pig trachea.

An isolated preparation of the guinea-pig trachea with intact parasympathetic and sympathetic innervation has been devised. Responses to nerve stimulation were recorded as increases or decreases in intraluminal pressure from the fluid-filled trachea. The preparation maintained a positive resting intraluminal pressure of 3-4 cmH2O. This was unaffected by atropine, hexamethonium or propranolol. Brief pressor responses, which could be completely blocked by atropine or hexamethonium, were obtained by applying short trains of stimuli to the cervical segment of the right vagus. The amplitude of responses was frequency-dependent up to a maximum at 40 Hz. Depressor responses, more delayed and prolonged than the pressor responses and blocked by propranolol but not by hexamethonium, were obtained by stimulation of the right cervical sympathetic trunk or stellate ganglion in 70% of preparations. Dual pressor-depressor responses were observed in the remaining 30% of preparations. The pressor component was blocked by atropine, the depressor component by propranolol. In the presence of atropine and propranolol, sustained sympathetic stimulation sometimes evoked a small, delayed pressor response which was blocked by phentolamine. Under the same conditions, transmural stimulation produced a depressor response evidently due to non-adrenergic, non-cholinergic nerves. Spontaneous activity was observed in some preparations under normal conditions, but could always be evoked by hypoxia. Responses to sympathetic stimulation were reduced both by hypoxia and during periods of spontaneous activity. 8 The principal advantage of this preparation is that it permits both excitatory and inhibitory responses to be elicited by stimulation of vagal and sympathetic nerves separately in the isolated trachea in the absence of agonist and antagonist drugs.

Transmembrane potential of J774.2 mouse macrophage cells measured by microelectrode and ion distribution methods.

The transmembrane potential (Em) of J774.2 macrophage cells measured by microelectrodes was -24.1 +/- 0.7 mV (mean +/- SEM). Em measured by lipophilic ion distribution was -35 +/- 2 mV or -40 +/- 2 mV, using a cation or anion, respectively. By any method, colchicine reduced Em by approximately 3 mV.

Alteration of electrophysiological properties of airway smooth muscle from sensitized guinea-pigs.

Glass microelectrodes were used to study electrophysiological properties of guinea-pig airway smooth muscle (m. trachealis transversus). The resting membrane potential (Em) of airway smooth muscle was found to be -40.4 +/- 0.5 mV (307 cells, 28 preparations). Twenty-seven percent of all cells successfully impaled showed regular spontaneous electrical activity (amplitude of 2-20 mV, with maximum rate of depolarization 15.0 +/- 2.2 mV . sec-1). Forty-four percent of cells showed irregular fluctuations in Em and the remaining cells showed no electrical activity. All three groups of cells had a similar distribution of individual Em values. The sensitization of animals (14 days incubation period) caused a slight but significant increase (P less than 0.001) in Em to -43.1 +/- 0.9 mV. Repeated daily exposure of sensitized animals to aerosolized albumin for two weeks caused a significant reduction of Em to -27.8 +/- 0.8 mV (P less than 0.001). Five weeks repeated exposure caused a further reduction in Em of airway smooth muscle cells to -22.6 +/- 0.7 mV (P less than 0.001). The responses to both histamine (10(-4) M) and isoprenaline (5 x 10(-6) M), as gauged by changes in Em, were altered in the trachea of chronically exposed guinea-pigs. The changes in airway smooth muscle electrical properties were related to the number of times the animals were exposed to inhaled antigen. Even after two weeks of daily exposure, the changes were marked. Airway smooth muscle alteration may be important in the pathogenesis of bronchial asthma.

Reduced myocardial response to calcium during endotoxin shock in the cat.

The hemodynamic effects of short intravenous infusions of calcium chloride were examined in anaesthetized cats before and during shock induced with E coli endotoxin (2 mg/kg). In normal cats calcium (5 mg kg-1 min-1 or 10 mg kg-1 min-1 infused for 5 minutes) increased left ventricular (LV) dP/dtmax, LVdP/dt at fixed isovolumic pressures, systemic arterial blood pressure and, usually, cardiac output. These hemodynamic changes lasted approximately 20 minutes. During endotoxin shock the calcium response (cardiac output, LVdP/dt, blood pressure) was greatly reduced. This diminished responsiveness was evident as early as 0.5--1 hour after endotoxin and lasted throughout the 4-hour shock period. The duration of the hemodynamic response was also decreased during shock. Reduced myocardial sensitivity to a number of cardiac stimulants, including beta-adrenoceptor stimulants and agents augmenting cellular cAMP/levels, occurs in this and other shock models. The present results suggest that this altered sensitivity is attributable to changes in the actual contraction processes rather than beta-adrenoceptor desensitization or a defect in the cAMP system. Since this altered calcium response does not occur in vitro the results might suggest the presence, in shock, of a circulating agent acting at the level of cellular calcium exchange.

Haemodynamic effects of the carboxylic ionophore monensin when administered before and during shock induced by E. coli endotoxin.

The haemodynamic effects of the carboxylic ionophore monensin have been examined in cats anaesthetized with sodium pentobarbitone. Marked increases in left ventricular dP/dtmax (and dP/dt at fixed isovolumic pressures) and slight increases in cardiac output and stroke volume occurred, indicating increased myocardial contractility. Heart rate was unchanged but systemic arterial pressure was substantially increased. Satisfactory increases in contractility and arterial pressure were obtained when monensin was infused intravenously in a total dose of 0.25 mg kg-1 over 10 min. Larger doses, especially if rapidly injected, resulted in very marked increases in myocardial contractility leading eventually to cardiac failure. The haemodynamic effects of monensin were markedly reduced during shock induced by E. coli endotoxin and there was unfortunately no evidence to suggest that this extremely potent compound might be potentially beneficial in this form of profound cardiovascular shock.

Myocardial function in feline endotoxin shock: a correlation between myocardial contractility, electrophysiology, and ultrastructure.

The nature of the myocardial depression observed in patients with septic shock, and in animals late in shock induced by endotoxin, is still under examination. These studies, in cats and kittens administered an LD80 dose of E coli endotoxin, were designed to examine the relationship between changes in myocardial contractility, in cellular electrophysiology and in ultrastructural morphology. There was no difference between tension developed in vitro by cardiac muscle removed from cats five hours after endotoxin administration and from cats not administered endotoxin. There was also no difference in their responses to calcium chloride or to anoxia. The action potential characteristics of ventricular muscle isolated from endotoxin treated cats were also not different from control, and ultrastructural damage was minimal and not extensive. Endotoxin (100 microgram/ml) had no effect on cardiac muscle in vitro, even after a one-hour contact time. It is concluded that the integrity of the myocardium is maintained even late in shock and that endotoxin has no direct effects on the heart.

Failure of exogenous ATP and creatine phosphate to modify the course of E coli endotoxin shock in the cat.

Exogenous adenosine triphosphate (ATP) (in combination with MgCl2) and also creatine phosphate (CrP), have been administered intravenously to endotoxin-shocked cats. Untreated shocked cats exhibited systemic hypotension during the first hour and again from four hours. Cardiac output fell progressively, and markedly elevated arterial lactate levels were evident within one hour of endotoxin administration. Treatment with ATP (10 mg/kg every 30 minutes) during shock led to rapid hemodynamic deterioration in all cats; most of the cats were dead before completion of dosing (at three hours). Long-lasting systemic hypotension and bradycardia were associated with this ATP administration and marked hypoglycemia developed in the survivors. Neither ATP (62 mg/kg) administered before endotoxin, nor CrP (500 mg/kg; administered either prior to endotoxin, or one hour afterwards) significantly modified the hemodynamic or metabolic changes associated with endotoxin shock in this species. Neither ATP nor CrP increased survival (assessed at five hours). Other workers have demonstrated improved survival from shock with ATP treatment. There may be species differences in the responsiveness to exogenous ATP or, alternatively, a difference in the role of high-energy phosphates in different types of shock.