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9. Belohradsky BH, Bruch K, Geiss D, Kafetzis D, Marget W, Peters G. Intravenouscefotaxime in children with bacterial meningitis. Lancet 1980; i: 61-63.
10. Nair SR, Cherubin CE, Weinstein M. Penetration of cefoxitin into cerebrospinal fluidand treatment of meningitis caused by Gram-negative bacteria. Rev Infect Dis 1979;i: 134-41.
11. Renlund M, Pettay O. Pharmacokmetics and clinical efficacy of cefuroxime in thenewborn period. Proc Roy Soc Med 1977; 70 (suppl. 9): 179-82.
12. Steinberg EA, Overturf GD, Wilkins J, Baraff LJ, Strong JM, Leedom JM. Failure ofcefamandole in treatment of meningitis due to Haemophilus influenzae type b.J Infect Dis 1978; 137 (suppl.): S180-86.
13. Fisher JF, Carter MJ, Parsons J, Rissing JP. Moxalactam (LY127935) in treatment ofmeningitis due to Gram-negative bacilli. Antimicrob Ag Chemother 1981; 19:218-21
14 The Swedish Reference Group for Antibiotics. A revised system for antibiotic
sensitivity testing. Scand J Infect Dis 1981; 13: 148-52.
15. Kenny JF, Isburg CD, Michaels RH. Meningitis due to Haemophilus influenzae type bresistant to both ampicillin and chloramphenicol. Pediatrics 1980; 66: 14-16.
16. Kinmonth A, Storrs CN, Mitchell RG. Meningitis due to chloramphenicol resistantHaemophilus influenzae type b. Br Med J 1978; i: 694.
17. Hoffstedt B, Johansson Ö, Walder M, Cronberg S, Price JD. Cerebrospinal fluidpenetration of cefuroxime. In: Nelson JD, Grassi C, eds. Current chemotherapy andinfectious disease. Washington DC: American Society of Microbiology, 1980:534-35.
18. Müller C, Netland A, Andrew E. The penetration of cefuroxime into the cerebrospinalfluid through inflamed and non-inflamed meninges. J Antimicrob Chemother 1980;6: 279-83.
19. Greenwood D, Pearson NJ, O’Grady F. Cefuroxime: a new cephalosporin antibioticwith enhanced stability to enterobacterial &bgr;-lactamases. J Antimicrob Chemother1976; 2: 337-43.
20. Petz LD. Immunologic cross-reactivity between penicillins and cephalosporins: a
review. J Infect Dis 1978; 137 (suppl.): S74-80.
SINGLE-DOSE SLOW-RELEASEAMINOPHYLLINE AT NIGHT
PREVENTS NOCTURNAL ASTHMA
P. J. BARNESLOUISE NEVILLE
A. P. GREENING
JOSÉ TIMMERSG. W. POOLE
Respiratory Division, Department of Medicine,Hammersmith Hospital, London W12 0HS
Summary Twelve asthmatic patients with nocturnalwheezing were given a single nocturnal
oral dose of slow-release aminophylline or matched placeboin a double-blind crossover trial. A dose of slow-release
aminophylline (mean 683 mg; 10·4 mg/kg) gave a therapeuticplasma-theophylline concentration 10 h later (mean 10·9
mg/l). This was not associated with any adverse effects. Meanpeak expiratory flow on waking was significantly greater withaminophylline (332±31 1/min) than placebo (283±32 1/min),whereas evening values did not differ. There was a significantdifference between morning and evening peak flow onplacebo (mean 22%) but not on aminophylline (5%), indicat-ing abolition of the morning fall in peak flow. This was not atthe expense of response to &bgr;-agonists, since the response toinhaled salbutamol was the same for both treatments. The useof extra metered doses of inhaled &bgr;-agonist during the nightwas significantly less with aminophylline, and there was asubjective improvement in nocturnal symptoms in all
patients. Slow-release aminophylline in adequate dosageappears to be the most effective treatment yet demonstratedfor nocturnal asthma.
Introduction
WHEEZING at night is a very common, troublesome
symptom of asthma, and present treatment is unsatisfactory.The precise mechanism of increased bronchoconstriction atnight remains unclear, and it is likely that there is a
coincidence of several factors. I The circadian fall in
circulating adrenaline at night may encourage the release ofmast-cell mediators in asthmatics,2 and increased
parasympathetic activity may have a direct action on
bronchial smooth muscle. Both (3-adrenoceptor agonists andtheophyllines should prevent nocturnal asthma by a directaction on bronchial smooth muscle and by inhibiting therelease of bronchoconstrictor mediators. As neither inhalednor oral 0-agonists have a sufficiently long-lasting action toprevent nocturnal asthma, a slow-release oral preparation ofsalbutamol is commonly prescribed. However, slow-releasesalbutamol has been found to be beneficial in less than a thirdof patients, despite therapeutic plasma concentrations
overnight. Although this might indicate impaired airway&bgr;-receptor function at night, there is no evidence for circadianvariation in (3-adrenergic responsiveness in asthmatics
(Barnes PJ, Fitzgerald G, Dollery CT, unpublished). Oraltheophyllines have a short and variable plasma half-life, but aslow-release aminophylline preparation (’Phyllocontin’,Napp Laboratories) gives satisfactory and reliable plasmalevels of theophylline up to 12 h after ingestion.4 Thetherapeutic effect of theophyllines is directly related to
plasma concentration,s and now that reliable assays for
plasma theophylline are widely available it is possible todetermine whether dosage is adequate. In previous studies onadults6,7 and children slow-release aminophylline has beenshown to improve early-morning wheeze in a proportion ofasthmatics, but since plasma-theophylline concentrationswere not measured it is not certain whether a poor responsewas due to inadequate dosage.The aim of our study was to examine the effect on nocturnal
asthma of slow-release aminophylline given in a single night-time dose which was adequate to maintain therapeuticallyeffective plasma-theophylline concentrations overnight.
Patients and Methods
Patients
Twelve asthmatic patients (seven men, five women), aged 22 to 72years (mean 42), who attended the chest clinic, HammersmithHospital, were studied (see table). All experienced nocturnalwheeze or chest tightness and had airway reversibility (greater than20% increases in forced expiratory volume in one second afterinhaled 0-agonist). Nine patients had multiple positive immediateskin-prick tests to common allergens. All regularly inhaled
(3-agonists and five regularly inhaled beclomethasone; none wastaking oral 0-agonists or theophyllines or had received oral steroidswithin 4 weeks of the study. During the trial no change was made inregular medication. No patient had liver or heart disease; one (no.11) was a cigarette smoker. (A 13th patient was initially included inthe study but later excluded when it was found that she was taking atheophylline-containing preparation.) The study was approved bythe research ethics committee, Hammersmith Hospital, and allpatients gave their informed consent.
Study DesignThe dose of slow-release aminophylline necessary to give
overnight plasma-theophylline concentrations in the therapeuticrange was determined in an open phase before the trial: plasma-theophylline concentration was measured at 4 - 6 h (peak) and thenat 10 h after a single oral dose. The dose was adjusted if necessary togive a plasma-theophylline concentration at 10 h of approximately10 mg/1. Plasma-theophylline concentration was determined withhigh-pressure liquid chromatography.9 All patients had previousexperience of recording peak expiratory flow (PEF) at home.
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ANTHROPOMETRIC DETAILS AND PLASMA-THEOPHYLLINE CONCENTRATIONS IN 12 ASTHMATIC PATIENTS
The trial lasted 4 weeks, and for the first 2 weeks patients receivedeither -slow-release aminophylline tablets in the previouslydetermined dosage (phyllocontin, available as 225 mg and 100 mgtablets) or matched placebo tablets in randomised double-blindmanner. PEF was recorded at 2300 h (best of three blows) by Wrightpeak-flow meter (Airmed), then repeated 10 min after inhaling twopuffs (200 g) salbutamol. The tablets were then taken. On waking(0600 to 0800 h) PEF before and after salbutamol was similarlyrecorded. Patients were asked to record the number of extra puffs ofsalbutamol taken during the night and to report whether nocturnalsymptoms were better, worse, or unchanged during this period. Atthe end of 2 weeks patients attended the outpatient clinic for aplasma-theophylline determination 10 h after dosing and were thenstarted on the alternative treatment period for 2 weeks. Patientswere asked to record any adverse effects during each treatmentperiod.
Results were analysed with Student’s t-test for paired samples,and all results are expressed as mean + SEM.
Results
All twelve patients completed the 4-week study. During theinitial dosing study the peak (4-6 h) plasma-theophyllineconcentration did not exceed 16 mg/1 in any patient, and nonehad any adverse effects. The dose of slow-release amino-
phylline required to produce trough plasma-theophyllineconcentrations of approximately 10 mg/1 ranged from 550 to775 mg, although the dose/kg was similar for each patient(range 9’1-11’4, mean 10-4 mg/kg). This gave plasma-theophylline concentrations 10 h after dosing at the end of the2-week active period of 8-15 (mean 10-9) mg/1 (see table). Nopatient spontaneously or on direct questioning complained ofadverse effects during the treatment period.The mean morning PEF was significantly (p<0’001)
higher during the aminophylline period (332±311/min) thanduring the placebo period (283±32 1/min), whereas in theevening there was no significant difference in PEF betweenactive (348±321/min) and placebo (345±301/min) treatments(fig.l). As expected there was a significant difference
(p<0’001) between morning and evening PEF during theplacebo period (mean variation 22%) but not during theactive period (mean variation 5%), indicating that the
morning fall in PEF had been abolished by slow-releaseaminophylline. There was some variation in response toaminophylline (fig.2); the two patients (nos.2 and 5) whoshowed little change between active and placebo periods,despite therapeutic plasma-theophylline concentrations, alsohad no significant circadian variation between morning andevening PEF during the placebo period.During the active period the mean number of metered
doses of salbutamol taken at night over 2 weeks (2’ 0± 1 0)
Fig. 1-Mean peak expiratory flow ( + SEM) in 12 asthmatic patientswith placebo (open) and active (stippled) treatment (slow-releaseaminophylline 10.9 mg/kg at night).Values before and afrer bronchodilator (BD; salbutamol 200 g in the
morning and evening) are shown.
Fig. 2-Individual and mean (0) values of peak expiratory flow in tasthmatic subjects on placebo and active treatment (slow-releaseaminophylline).Values for morning and evening are shown.
301
was significantly less (p<0’001) than during the placeboperiod (8’7±1’6). All patients reported a subjectiveimprovement during the active period, but only one (no. 5)during the placebo period.The response to inhaled 3-agonists was significant
(p<0’001) in the morning and evening during bothtreatments. The PEF after bronchodilator in the morningwas significantly (p<0’001) higher during the active period(396±l/min) than during the placebo period (358±32 1/min)(fig. 1), although the bronchodilator response (A PEF) was notsignificantly different (active 98:t63. 1/min, placebo93±73-9 1/min), indicating that the effect of inhaled
(3-agonists was additive. The evening PEF after broncho-dilator was not significantly different between active (394±32ilmin) and placebo (392±31 1/min) periods.
Discussion
Our results show that a single dose of slow-release
aminophylline, sufficient to give adequate plasma-theophylline concentrations through the night, can abolishthe early-morning fall in PEF and improve nocturnal asthma.Furthermore, this improvement in morning PEF is not at theexpense of the response to (3-agonists, for the same
improvement in PEF was found during both placebo andaminophylline treatment, indicating an additive effectbetween theophylline and &bgr;-agonists, as previouslydemonstrated. 10, 11 1
In a previous study slow-release aminophylline given twicedaily resulted in significant improvement in early-morningbronchoconstriction6 but was associated with a highfrequency of side-effects during the day. Another study, inwhich slow-release aminophylline was given at night for 2days, improved nocturnal bronchoconstriction in a
proportion of patients.’ In neither study, however, was theplasma-theophylline concentration measured. In a study inwhich slow-release aminophylline 450 mg was given at nightimprovement in morning PEF was seen in only 5 of 14patients.3 This poor response was almost certainly due toinadequate dosage, since plasma-theophylline concentrationsmeasured 6 h after ingestion were suboptimum and in thepatients who did not respond to aminophylline were less than5 mg/l.The reason for the better results in our study was probably
that a higher dose of slow-release aminophylline (mean dose683 mg) was used than in previous studies. This gave plasmaconcentrations of theophylline ranging from 8 to 15 (mean10’9) mg/l 10 h after ingestion, indicating an effective
plasma-concentration overnight. Despite this higher dose nopatient experienced adverse effects. It is possible that suchdoses during the day may be associated with significant side-effects as previously reported," but such problems may notbe important during sleep. Such high doses must not be usedin patients with liver disease or cardiac failure, 12 but it wouldbe advisable to check plasma-theophylline concentrations10 h after dosing in all patients.We conclude that slow-release aminophylline is an effective
treatment for nocturnal and early-morning wheezing whengiven in adequate single dose (approximately 10 mg/kg) atnight. Furthermore we have demonstrated an additive effectwith inhaled 0-agonists. This dose of slow-release
aminophylline at night is not associated with significant side-effects. Slow-release aminophylline in adequate dosageappears to be the most effective treatment for nocturnalasthma yet demonstrated.
We thank Dr C. Boroda, Napp Laboratories Ltd, for supplying phyllocontinand placebo tablets, and the Department of Child Health, HammersmithHospital, for measuring plasma-theophylline levels.Correspondence should be addressed to A. P. G.
REFERENCES
1. Hetzel MR. The pulmonary clock Thorax 1981; 36: 481-86.2. Barnes P, Fitzgerald G, Brown M, Dollery C. Nocturnal asthma and changes in
circulating epinephrine, histamine and cortisol. N Engl J Med 1980; 303: 263-67.3. Fairfax AJ, McNabb WR, Davies HJ, Spiro SR. Slow release oral salbutamol and
aminophylline in nocturnal asthma: relation of overnight changes in lung functionand plasma drug levels. Thorax 1980; 35: 526-30.
4. Trembath PW, Boobis SW, Richens A. Theophylline biochemical pharmacology andpharmacokinetics. J Int Med Res 1979; 7: suppl 1: 4-15.
5. Mitenko PA, Ogilvie RI. Rational intravenous doses of theophylline. N Engl J Med1973; 289: 600-03.
6. Milledge JS, Morris J. A comparison of slow-release salbutamol with slow-releaseaminophylline in nocturnal asthma. J Int Med Res 1979; 7: suppl 1: 106-10.
7. Cole RB, Al-Khoder A. Effect of slow-release oral aminophylline on circadian variationin airflow obstruction in asthmatics. J Int Med Res 1979; 7 suppl 1: 40-44.
8. Evans PWG, Craven A, Evans N. Nocturnal wheezing in children: management withcontrolled-release aminophylline. Br Med J 1981; 283: 18.
9. McKenzie SA, Edmunds AT, Baillie E, Meek J Clinical applications of serumtheophylline measurement by high pressure liquid chromatography. Arch Dis Child1978; 53: 322-25.
10. Campbell IA, Middleton WG, McHardy GJR, Snotter MV, McKenzie R, Kay AB.Interaction between isoprenaline and aminophylline in asthma. Thorax 1977; 32:424-28.
11. Greening AP, Baillie E, Gribbin HR, Pride NB. Sustained release oral aminophyllinein patients with airflow obstruction Thorax 1981; 36: 303-07
12. Jusko WJ, Koup IR, Vance JW, Schentag JJ, Kuritzky P. Intravenous theophyllinetherapy: nomogram guidelines. Ann Intern Med 1977; 86: 400-04
IRREGULAR BREATHING AND HYPOXAEMIADURING SLEEP IN CHRONIC STABLE ASTHMA
J. R. CATTERALLP. M. A. CALVERLEY
V. BREZINOVA
N.J. DOUGLASH. M. BRASHC. M. SHAPIRO
D. C. FLENLEY
Department of Medicine and Respiratory Medicine,Royal Infirmary and City Hospital, Edinburgh
Summary Breathing patterns, ear oxygen satur-
ation (SaO2), and EEG sleep-stagethroughout an undisturbed night’s sleep were compared inten adult stable asthmatics and ten age-matched healthysubjects. The two groups slept equally long (5·0-7·2, mean6·2 h), but the asthmatics slept less well; they had moreperiods of wakefulness and drowsiness and irregularbreathing than did the healthy subjects. They also had greaterand more frequent falls in SaO2. Most hypoxaemic episodesoccurred in the rapid-eye-movement phase of sleep and wereassociated with hypopnoea or apnoea, but no patient had aclassical sleep-apnoea syndrome. The severity of nocturnalhypoxaemia was related to the level of SaO2 when the subjectswere awake, but did not correlate with the fall in forcedexpiratory volume recorded in eight out of ten asthmaticsafter sleep.
Introduction
ALTHOUGH nocturnal wheeze in asthma was clearlydescribed by Dr John Floyer (himself an asthmatic) in 1698,’ Iit has only recently been associated with a reduced peakexpiratory flow rate (PEFR) in the early hours of the morning(the morning dip).2-4 The wide prevalence of this symptombecomes apparent when asthmatics are asked how they sleep.Furthermore, although death during an asthmatic attack israre, some,S,6 but not all,’,8 surveys have suggested that suchdeaths are commoner at night.Recent interest in disordered breathing during sleep9,IO has
revealed profound transient nocturnal hypoxaemia in
