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R Beasley

Publications and source records attributed to R Beasley.

At least 91 records · Page 5Linked to original sources
PubMed1996

Partial vs full beta-receptor agonism. A clinical study of inhaled albuterol and fenoterol.

STUDY OBJECTIVE: To compare the maximal extrapulmonary effects of the beta-agonists albuterol and fenoterol in eight healthy volunteers. SUBJECTS AND METHODS: In this double-blind study, we have examined the maximum cardiac effects (electromechanical systole [QS2I]--a measure of inotropy, heart rate, BP) and metabolic effects (plasma K+ and cyclic adenosine monophosphate [cAMP]) of repeated inhalation of albuternol and fenoterol. In eight healthy volunteers, 400 microg of each drug was administered every 10 min until QS2I and plasma K+ had reached a plateau (+/- 0.1 mmo l/L for K+, and +/- 10 ms for QS2I). The maximum response (Emax) and the dose of albuterol required to produce 50% of the maximum response to fenoterol (ED50F) were calculated. RESULTS: The Emax for fenoterol was significantly greater than albuterol for plasma K+ (-1.4 vs -1.03 mmol/L; p<0.002), QS2I (-71.8 vs 57.5 ms; p=0.047), and cAMP (33.8 vs 18.1 nmol/L; p<0.002). The dose required to produce the ED50f was significantly greater for albuterol than for fenoterol with potency ratios of 1.75, 1.61, and 2.26 for plasma K+, QS2I, and cAMP, respectively. There were no significant differences between fenoterol and albuterol with respect to heart rate (Emax, 44.9 vs 32.5 beats/min; p=0.19; potency ratio, 1.98; p=0.052). CONCLUSIONS: These findings suggest that albuterol behaves as a partial agonist at beta-receptors when compared with fenoterol, and that when inhaled in doses currently recommended for severe asthma, albuterol will result in lesser maximum cardiac and metabolic effects than fenoterol. These findings are consistent with the hypothesis that the property of full receptor agonism may contribute to the increased risk of death associated with fenoterol.

Administration, Inhalation↗
PubMed1996

Lack of evidence of a significant association between HLA-DR, DQ and DP genotypes and atopy in families with HDM allergy.

BACKGROUND: HLA class II genetic polymorphism has been variably implicated in susceptibility to specific immune responsiveness to house dust mite (HDM) allergens, and may also influence the development of atopy. OBJECTIVE: In order to assess accurately the influence of HLA alleles in the atopic immune response, we typed 22 families selected from 131 previously obtained randomly selected families (i.e. without regard to atopy or asthma), chosen on the basis of two or more members having skin prick reactivity to HDM. METHODS: Each individual was fully typed for HLA-DRB1, DQA1, DQB1 and DPB1 class II alleles using a combination of sequence-specific oligonucleotide probes (SSOP) and sequence-specific primer (SSP) polymerase chain reaction (PCR) typing and direct sequencing. RESULTS: Using appropriate statistical tests, no significant allelic associations were found between any DRB1, DQB1 or DPB1 alleles and atopy or skin prick reactivity to Dermataphagoides pteronyssinus (Der p) or D. farinae (Der f). However, positive associations were found between DQA1*0301 and skin prick reactivity to Der f (P = 0.009) and atopy (P = 0.027). Sib-pair analysis revealed no significant sharing of alleles between affected sib pairs for any of the phenotypes studied. CONCLUSION: These results fail to confirm a previously reported association between the DRB1*04 and 07 haplotypes and atopy, and suggest that HLA class II restriction does not play a major role in the development of the IgE response to domestic house dust mite allergens in the British population.

Allergens↗
PubMed1995

End of the New Zealand asthma mortality epidemic.

In 1989, a case-control study reported that inhaled fenoterol was associated with the epidemic of asthma deaths that had affected New Zealand since 1976. The New Zealand Department of Health issued warnings about the safety of fenoterol and restricted its availability. The associated time trends are consistent with the hypothesis that fenoterol was the main factor in the New Zealand asthma mortality epidemic. The epidemic commenced when fenoterol was introduced in 1976, and the New Zealand death rate remained the highest in the world for more than a decade. After publication of the case-control study, the death rate fell by half and has now remained low for a further 3 years (1990-92). Time-trend data do not suggest a class effect of inhaled beta-agonists in the epidemic: there was no association between beta-agonist sales and the start of the epidemic, and total sales of inhaled beta-agonists actually increased slightly during 1989-90 when the epidemic came to an end. Time-trend data are also inconsistent with the hypothesis that the epidemic may have occurred because of underprescribing of inhaled corticosteroids. Similarly, time-trend data is incosistent with hypotheses postulating a major role of social factors such as unemployment. Data on time trends should be assessed with caution, because time trends in asthma deaths can be affected by many factors. Nevertheless, the New Zealand time trends are consistent with fenoterol being the main cause of the New Zealand asthma mortality epidemic and are inconsistent with a significant role for other suggested causes.

Administration, Inhalation↗
PubMed1995

Measuring the prevalence of bronchial hyper-responsiveness in children.

BACKGROUND: The aim of this study was to assess the effectiveness of an asthma prevalence video questionnaire (involving the audiovisual presentation of clinical asthma), a standard written questionnaire (based on the IUATLD Bronchial Symptoms Questionnaire) and a new written questionnaire (designed for an international study of asthma and allergies in childhood [ISAAC]) in predicting bronchial hyper-responsiveness (BHR) (PD20 < or = 7.8 mumol methacholine). METHODS: The IUATLD and video questionnaires were administered to 193 schoolchildren (13-16 years). The ISAAC questionnaire was administered to 87 of these children. All children subsequently underwent bronchial challenge to methacholine. RESULTS: The sensitivity and specificity for predicting BHR were similar for individual questions from the IUATLD and video questionnaires. The video questions with the highest Youden's index related to moderate wheezing at rest (0.46), severe wheezing at rest (0.38), and nocturnal wheezing (0.37). The ISAAC questionnaire was similar in effectiveness to the IUATLD questionnaire in predicting BHR. CONCLUSIONS: The video questionnaire is a valid method of assessing the prevalence of BHR, and may be particularly useful when comparing populations with differing languages and cultures. Some video questions appeared more effective than others in relation to predicting BHR. A new written questionnaire (ISAAC) designed for a large international asthma prevalence study in children also is an effective method for measuring the prevalence of BHR.

Adolescent↗
PubMed1995

Exclusion from proximal 11q of a common gene with megaphenic effect on atopy.

We have typed three markers on proximal 11q in 131 random families with three or more children studied for atopy. A summary map that includes the FCER1B candidate was constructed. Using a 2-locus disease model, we performed combined segregation and linkage analysis of three models, none of which suggested linkage. Nine marker loci on other chromosomes were also negative. In the regions swept by these 12 markers we cannot rule out a rare gene, perhaps of large effect, nor a common gene of small effect. However, a common gene of large effect is excluded. These results and alternative strategies are discussed in the perspective of inconsistent evidence for a major atopy gene.

Alleles↗
PubMed1995

International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods.

The aetiology of asthma and allergic disease remains poorly understood, despite considerable research. The International Study of Asthma and Allergies in Childhood (ISAAC), was founded to maximize the value of epidemiological research into asthma and allergic disease, by establishing a standardized methodology and facilitating international collaboration. Its specific aims are: 1) to describe the prevalence and severity of asthma, rhinitis and eczema in children living in different centres, and to make comparisons within and between countries; 2) to obtain baseline measures for assessment of future trends in the prevalence and severity of these diseases; and 3) to provide a framework for further aetiological research into genetic, lifestyle, environmental, and medical care factors affecting these diseases. The ISAAC design comprises three phases. Phase 1 uses core questionnaires designed to assess the prevalence and severity of asthma and allergic disease in defined populations. Phase 2 will investigate possible aetiological factors, particularly those suggested by the findings of Phase 1. Phase 3 will be a repetition of Phase 1 to assess trends in prevalence.

Adolescent↗
PubMed1994

The effect of hypercapnia and hypoxemia on the cardiovascular responses to isoproterenol.

BACKGROUND: The reason for the increased risk of death with fenoterol and isoproterenol in asthma is unknown but may relate to their cardiovascular effects. Deaths from asthma usually occur outside hospital where hypoxemia, with or without hypercapnia, may exist. Both of these states can influence the cardiovascular system. We investigated whether different gas mixtures modified the cardiovascular effects of isoproterenol. METHOD: Nine healthy men were randomly assigned to receive each of three gas mixtures to achieve (1) normoxia-normocapnia, (2) hypercapnia (end-tidal PaCO2, 50 mm Hg), (3) hypoxemia-hypercapnia (arterial oxygen saturation, 90%; PaCO2, 50 mm Hg). Isoproterenol was administered with each of the gas mixtures. Cardiovascular measurements of heart rate, blood pressure, cardiac index, ejection fraction, fractional shortening, electromechanical systole, and the QTc interval were made before administration of the gases, as well as before and 5 minutes after isoproterenol administration. RESULTS: The changes after hypercapnia were not significantly different from those after normoxia-normocapnia. Hypoxemia-hypercapnia increased heart rate, systolic and diastolic blood pressure, QTc interval, cardiac index, ejection fraction, and fractional shortening. Isoproterenol increased heart rate, systolic blood pressure, QTc interval, cardiac index, ejection fraction, and fractional shortening while the subjects breathed the normoxia-normocapnia gas mixture. It caused similar changes with the other gas mixtures. The changes were additive. CONCLUSION: Isoproterenol and hypoxemia-hypercapnia will increase myocardial oxygen demand and could prove to be detrimental in severe asthma.

Adult↗
PubMed1994

Confounding by severity does not explain the association between fenoterol and asthma death.

Three recent case-control studies from New Zealand, and one from Saskatchewan, Canada, have found that fenoterol increases the risk of death in patients with severe asthma. It has been suggested that these findings may be due to confounding by severity, if fenoterol was selectively prescribed to more severe asthmatics. This 'confounding by severity' hypothesis has now been investigated in further analyses of data from the New Zealand case-control studies. This analysis found that among patients whose asthma was severe enough to require hospital admission (the population in whom the case-control studies were conducted), fenoterol was not preferentially prescribed to the more severe asthmatics. There was greater co-prescribing of other drugs with fenoterol (compared with salbutamol) during the later years of the epidemic, but these differences did not explain the excess risk associated with fenoterol, and there was little evidence of greater co-prescribing during the earlier years of the New Zealand epidemic of asthma deaths. There was no association between the prescription of fenoterol and markers of acute asthma severity or psychosocial problems. Patients were not selectively changed to fenoterol as a result of a severe attack resulting in a hospital admission. Most importantly, in the case-control studies of asthma deaths, the inhaled fenoterol relative risk increased when the analysis was restricted to sub-groups defined by markers of chronic asthma severity; whereas the relative risk would have decreased towards 1.0 in these sub-group analyses if the overall elevated risk for fenoterol was due to confounding by severity.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1994

Genetic analysis of atopy and asthma as quantitative traits and ordered polychotomies.

Traits related to atopy and asthma were defined in a random cohort of 131 families with three or more children. Correlation analysis provides no evidence of imprinting, maternal effect, or a major role of environment shared by sibs. Commingling analysis favours more than one distribution, the upper one being common for asthma and very common for atopy. Segregation analysis of rank-transformed variables provides only equivocal evidence of major genes against a polygenic background but suggests that such genes (if present) are individually common and not of large effect. Segregation analysis under a two-locus model gives consistent results with minimal distributional assumptions. To enter combined segregation analysis we favour a restricted model in which the major locus is additive on the liability scale and the pseudopolygenic modifier locus accounts for at least half the genetic variance. Total IgE and bronchial reactivity are proposed for meta-analysis of atopy and asthma respectively. Genetic analysis of complex inheritance is discussed and it is shown that allelic association with random loci is not a feasible approach.

Adolescent↗
PubMed1994

Prescribed drug therapy and near-fatal asthma attacks.

Inhaled fenoterol has been associated with an increased risk of death in severe asthmatics, when compared to other adrenoceptor agonists. It is plausible that fenoterol may also increase the risk of near-fatal attacks. We have conducted a case-control study to investigate this hypothesis. The cases comprised Intensive Care Unit (ICU) admissions for asthma in the Wellington region during 1977-1988. For each of these cases, two age-matched controls were selected from asthma admissions to the same hospital during the same period. For the 155 cases and 305 controls, information on prescribed drug therapy was collected from the hospital admission records. The relative risk of a near-fatal asthma attack in patients prescribed inhaled fenoterol was 2.00 (95% confidence interval (CI) 1.35-2.97). An increased risk was also observed for oral theophylline (odds ratio (OR) = 1.88; 95% CI 1.26-2.79). For the 65 cases and 104 controls who had a previous admission for asthma in the previous 12 months, information relating to the previous admission was also collected; an increased risk was once again observed for inhaled fenoterol (OR = 2.18; 95% CI 1.10-4.33) and for oral theophylline (OR = 1.18; 95% CI 0.99-3.57). No other asthma drugs showed significantly increased risks. Although the ICU admission cases had generally been prescribed more asthma drugs than the hospital admission controls, and appeared to have more severe asthma, it is possible that the findings reported here are influenced by confounding by severity. We nevertheless estimate that our findings are consistent with the hypothesis that fenoterol increases the risk of near-fatal asthma attacks, and that they complement previous findings on fatal asthma attacks.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗