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Biomedical subjects

J E Garrett

Publications and source records attributed to J E Garrett.

At least 37 records · Page 2Linked to original sources
PubMed1998

The effect of adding ipratropium bromide to salbutamol in the treatment of acute asthma: a pooled analysis of three trials.

OBJECTIVE: To assess the effect on FEV1 and clinical outcomes of adding ipratropium bromide to salbutamol in the treatment of acute asthma. METHODS: We conducted a pooled analysis of three randomized double-blinded clinical trials conducted in the United States, Canada, and New Zealand. The studies enrolled 1,064 patients aged 18 to 55 years who presented at the emergency department with acute asthma. Patients were randomized to treatment with a combination of nebulized 2.5 mg salbutamol plus 0.5 mg ipratropium bromide, or 2.5 mg salbutamol alone. Medications were administered at baseline and, in the US study, at 45 min. FEV1 was measured at baseline, 45 min, and 90 min. Patients were followed up for 48 h after hospital discharge for occurrence of asthma exacerbation and hospitalization. RESULTS: Treatment groups were comparable at baseline. Of the 1,064 patients randomized, 1,015 patients (95%) remained in the study for measurement at 45 min, and 961 patients (90%) completed the final measurement at 90 min. Comparison of overall improvement in FEV1 at 45 min indicated a better response for patients receiving combination therapy (mean difference=43 mL, 95% confidence interval [CI]=-20, 107). The distribution of change in FEV1 was skewed by a small number of patients with extreme values (38 of 1,064=3.6%) that may have been due to unreliable lung function testing. Removing these outliers produced a larger and more precise estimate of effect (mean difference=55 mL, 95% CI=2,107). Because the distribution was skewed, we performed nonparametric analyses that showed evidence of a beneficial effect of combination therapy. The difference between median values at 45 min is 40 mL (Wilcoxon p value=0.03). In addition, 4.9% (95% CI=-1%, 11%) more patients in the combination group achieved at least 20% of their potential improvement, as measured by the difference between their baseline FEV1 and their predicted FEV1. Patients receiving combination therapy had lower risk for each of three clinical outcomes: the need for additional treatment (relative risk [RR]=0.92, 95% CI=0.84, 1.0), risk of asthma exacerbation (RR=0.84, 95% CI=0.67, 1.04), and risk of hospitalization (RR=0.80, 95% CI=0.61, 1.06). CONCLUSION: Adding ipratropium bromide to salbutamol in the treatment of acute asthma produces a small improvement in lung function, and reduces the risk of the need for additional treatment, subsequent asthma exacerbations, and hospitalizations. These apparent benefits of adding ipratropium bromide were independent of the amount of beta-agonist that had been used earlier in the attack, and possibly related to a recent upper respiratory tract infection. Confirmatory studies are needed, especially for clinical outcomes.

Acute Disease↗
PubMed1998

Allosteric activation of the Ca2+ receptor expressed in Xenopus laevis oocytes by NPS 467 or NPS 568.

The Ca2+ receptor is a G protein-coupled receptor that enables parathyroid cells and certain other cells in the body to respond to changes in the concentration of extracellular Ca2+. In this study, two novel phenylalkylamine compounds, NPS 467 and NPS 568, were examined for effects on Xenopus laevis oocytes expressing the bovine or human parathyroid Ca2+ receptors. Increases in chloride current (ICl) were elicited in oocytes expressing the bovine Ca2+ receptor when the extracellular Ca2+ concentration was raised above 1.5 mM, whereas Ca2+ concentrations > 3 mM were generally necessary to elicit responses in oocytes expressing the human Ca2+ receptor. NPS 467 and NPS 568 potentiated the activation of ICl by extracellular Ca2+ in oocytes expressing either Ca2+ receptor homolog, and this resulted in a leftward shift of the Ca2+ concentration-response curve. Neither compound was active in the absence of extracellular Ca2+. Certain inorganic and organic cations known to activate the Ca2+ receptor were substituted for elevated levels of extracellular Ca2+ to increase ICl and the effects of these agonists were also potentiated by NPS 568 or NPS 467. The effects of NPS 568 were stereoselective and the R-enantiomer was about 10-fold more potent than the corresponding S-enantiomer. Neither NPS 467 nor 568 affected ICl in water-injected oocytes or in oocytes expressing the substance K receptor or the metabotropic glutamate receptor 1a. These results provide compelling evidence that NPS 467 and NPS 568 act directly upon the parathyroid Ca2+ receptor to increase its sensitivity to activation by extracellular Ca2+. This activity suggests that these compounds are positive allosteric modulators of the Ca2+ receptor. As such, these compounds define a new class of pharmacological agents with potent and selective actions on the Ca2+ receptor.

Allosteric Regulation↗
PubMed1997

Nebulized salbutamol with and without ipratropium bromide in the treatment of acute asthma.

BACKGROUND: Routine addition of ipratropium bromide to beta-agonist therapy in acute asthma is of uncertain benefit. OBJECTIVE: This study was carried out to evaluate: (1) whether nebulized ipratropium (0.5 mg) plus salbutamol (2.5 mg) (Combivent) confers additional bronchodilation over nebulized salbutamol (2.5 mg) alone in patients with acute asthma and (2) whether adjustment for prognostic indicators of outcome influences any benefit seen with ipratropium. METHODS: A double-blind, two-center, randomized, single-dose study was performed in 338 patients with asthma, aged 18 to 55 years, who attended the emergency department for treatment of acute asthma. The primary end point was FEV1 at 90 minutes. RESULTS: The mean absolute difference in FEV1 at 90 minutes for Combivent compared with salbutamol was 113 ml (SEM +/- 48 ml, p < 0.05). Independent of the study drug received, a poor response to treatment was predicted by frequent use of inhaled beta-agonist before presentation (p < 0.0001), severity of the attack (p < 0.05), and longer duration of attack (p < 0.05). Subjects who had taken more than 10 puffs of inhaled beta-agonist through a metered-dose inhaler or who had serum salbutamol levels of greater than 2 mmol/L on presentation demonstrated no benefit from the addition of ipratropium. Patients with an FEV1 less than 1 L on presentation also responded less well to Combivent, which was explained by the association between severity of attack and greater use of inhaled beta-agonist therapy. CONCLUSION: A single dose of nebulized Combivent confers additional bronchodilation over salbutamol alone (p < 0.05) in acute asthma. Patients who exhibited most benefit from the addition of ipratropium were those who had consumed the least inhaled beta-agonist before presentation, not those with the most severe asthma.

Acute Disease↗
PubMed1997

Combined anticholinergic therapy in the management of acute asthma.

In a hospital setting, first-line drugs for treatment of acute severe asthma are usually nebulized short-acting beta 2-agonists and systemic corticosteroids. Combining a nebulized beta 2-agonist with the anticholinergic agent ipratropium bromide may produce better bronchodilation than either drug alone, particularly in patients with more severe episodes. A recent study from New Zealand compared nebulized beta 2-agonist alone or in combination in patients presenting with acute severe asthma to the emergency department. Combined treatment produced a significantly greater change in forced expiratory volume in 1 s (FEV1) than salbutamol alone. Factors predicting a poor bronchodilator response (irrespective of study drug received) were frequent use of inhaled beta 2-agonist before presenting at the emergency department, increased severity and duration of attack and older age. Patients presenting with more severe asthma had taken more inhaled bronchodilator before presentation and were therefore likely to be higher on the dose-response curve and thus less likely to derive benefit from additional bronchodilator therapy. The patients most likely to benefit from the addition of nebulized ipratropium bromide were those who had taken less inhaled beta 2-agonist in the previous 6 h. A combined analysis of three large studies on anticholinergic therapy, including the New Zealand study, has shown a 17% reduction in risk of subsequent admission (R = 0.83, 95% CI 0.63-1.1). Thus, nebulized ipratropium bromide imparts a small improvement in lung function when compared with salbutamol alone; however, further studies are needed to determine if multiple doses of combined anticholinergic/beta 2-agonist treatment reduce need for admission.

Acute Disease↗
PubMed1996

The prescription of domicilary long-term oxygen therapy in Auckland.

AIMS: (a) To assess the mode of referral and the demographic and clinical characteristics of patients prescribed oxygen between 1 January and 31 December 1994. (b) To assess whether international guidelines for prescribing oxygen were adhered to. (c) To assess the rate and pattern of prescription of oxygen in Auckland compared with other developed countries, and (d) based on these findings, to ascertain whether changes need to be made to our practise. METHOD: Notes of all patients referred to the oxygen service in 1994 were reviewed. RESULTS: The oxygen service received 304 referrals in 1994 and 196 (including 23 infants), were commenced on long-term oxygen therapy. The primary diagnosis was chronic obstructive pulmonary disease (COPD) in 90 (52%), other chronic respiratory diseases 25 (14%) and terminal malignancy in 48(28%). Of the 173 adult patients prescribed oxygen 79% of patients were referred as a result of hospital admission. Thirty three percent of chronic obstructive pulmonary disease patients died within 6 months of receiving domiciliary oxygen which is higher than any previously published report. Mortality rates were no different between patients with chronic obstructive pulmonary disease and other respiratory disorders. CONCLUSIONS: International guidelines for oxygen therapy were generally adhered to in Auckland though improvements could be made to ensure better quality information on referral and by use of blood gas analysis rather than oximetry. Fewer chronic obstructive pulmonary disease patients are receiving oxygen therapy in Auckland than expected and it is often prescribed late and as a result of hospital admission. Closer adherence to more recently published international guidelines and better targeting of patients with respiratory failure will impose a greater financial burden on the oxygen service, but may result in improved survival and reduced need of hospital admission. These findings have important resource implications, for oxygen services in New Zealand if they are to comply with International Guidelines for Domiciliary Oxygen Therapy.

Adult↗
PubMed1996

Risk of severe life threatening asthma and beta agonist type: an example of confounding by severity.

BACKGROUND: A study was undertaken to test the hypothesis that a particular inhaled beta agonist, fenoterol, increases the incidence of severe life threatening asthma. METHODS: A retrospective cohort was assembled comprising 655 patients with asthma aged 15-55 years who attended a single Auckland hospital for acute asthma between 1 January 1986 and 31 December 1987 (the "index event"). Patients were followed for the occurrence of death from asthma or admission to the intensive care unit for asthma, until death or 31 May 1989. Data on asthma medications and asthma severity were obtained from forms used specifically for managing patients with acute asthma in the emergency department and maintained as part of the hospital record and/or from the hospital record (when patients were admitted). RESULTS: Following the index event 90 admissions to the intensive care unit (ICU) and 15 asthma deaths were identified. Before adjusting for asthma severity, patients using inhaled fenoterol had a greater incidence of severe life threatening asthma than patients using inhaled salbutamol (RR = 2.1, 95% CI 1.4 to 3.1). After controlling for two markers of severe asthma used in previous studies-a hospital admission in the previous year and prescribed oral corticosteroids-the relative risk estimate declined to 1.5 (95% CI 1.0 to 2.3). After controlling further for the number of hospital admissions during the study period, continuous oral corticosteroid use rather than short courses of treatment, severity of the previous attack requiring a hospital visit, and race, fenoterol was not associated with severe life threatening asthma at the time of attendance for a previous hospital visit (RR = 1.0, 95% CI 0.6 to 1.7). CONCLUSION: Fenoterol is used more often by patients with severe asthma and, after adjusting for differences in baseline risk, it does not increase the risk of severe life threatening asthma.

Adolescent↗
PubMed1996

Clustered inactivating mutations and benign polymorphisms of the calcium receptor gene in familial benign hypocalciuric hypercalcemia suggest receptor functional domains.

The predominant variety of familial benign hypocalciuric hypercalcemia (FBHH) is FBHH(3q), which is associated with presumed inactivating mutations of the cell surface calcium receptor (CaR) gene on chromosome 3q13.3-q21. We sought mutations of the CaR gene in FBHH by direct sequencing of PCR-amplified genomic DNA from 14 affected families: 8 mapped to 3q13, 1 mapped to chromosome 19p, and 5 unmapped. We sequenced the entire coding region of the gene (exons 2-7) in one or two affected members of each family and found six point mutations that altered one amino acid, cosegregated with hypercalcemia, and were absent in more than 100 unaffected persons. Four mutations were unique (S53P, D215G, S657Y, and P748R), and two had been reported previously (P55L and R185Q). Of four mutant CaR proteins expressed in Xenopus oocytes, three were deficient in extracellular Ca2+-induced signaling. No CaR mutations were found in eight families, including the one mapped to chromosome 19p. Three benign polymorphisms occurred in the COOH-terminal region of the CaR protein in 10%, 15%, and 30% of more than 100 unaffected persons. Thus, FBHH-causing CaR mutations were clustered in the NH2-terminal extracellular and membrane-spanning regions of the receptor protein. We suggest that these are important functional domains, probably for calcium binding and signal transduction, respectively. Finally, mutations in regulatory or intronic regions of the CaR gene may also underlie many cases of FBHH.

Amino Acid Sequence↗
PubMed1996

The association between asthma drugs and severe life-threatening attacks.

OBJECTIVES: To measure the association between asthma drugs and death or ICU admission due to asthma (severe life-threatening attack of asthma [SLTA]), and to assess the possibility that these associations may not be causal but due to the prescription of these drugs to patients with more severe disease (confounding). DESIGN: Retrospective cohort study of 655 asthmatics who attended an emergency department in 1986 to 1987 followed till death or May 1989. METHODS: Outcome events were death or ICU admission due to asthma (SLTA). All hospital attendances were identified and patients classified at each according to drug exposure and a wide variety of measures of asthma severity. Incidence rates were computed as total outcome events divided by person-time contributed for each subject classified according to drug use and asthma severity. Rate ratio (RR) estimates for severe asthma outcomes associated with use as compared to nonuse of asthma drugs were calculated. Severity markers were identified and used to adjust the crude RR estimates. RESULTS: One hundred five SLTAs (15 deaths, 90 ICU admissions) occurred in 66 patients. Like inhaled fenoterol, oral beta-agonists, theophylline, cromolyn, inhaled steroids, and oral steroids were all associated with an increased risk of SLTA. When adjusted progressively for measures of severity, these increased risks became insignificant except for cromolyn. CONCLUSION: Unadjusted RR estimates for severe asthma events comparing exposure to a particular drug with nonuse are overestimates due to confounding. Control with two severity markers (hospital admission in the last year, use of oral corticosteroid at the time of previous admission) removes some confounding but control for additional severity markers not available in previous studies reduces the effect estimates further. These results suggest that the problem of confounding is substantial in nonrandomized epidemiologic studies of asthma drugs. Previous studies reporting RR estimates are likely to be confounded.

Acute Disease↗
PubMed1995

Molecular cloning and functional expression of human parathyroid calcium receptor cDNAs.

Parathyroid cells express a cell surface receptor, coupled to the mobilization of intracellular Ca2+, that is activated by increases in the concentration of extracellular Ca2+ and by a variety of other cations. This "Ca2+ receptor" (CaR) serves as the primary physiological regulator of parathyroid hormone secretion. Alterations in the CaR have been proposed to underlie the increases in Ca2+ set-point seen in primary hyperparathyroidism due to parathyroid adenoma. We have isolated human CaR cDNAs from an adenomatous parathyroid gland. The cloned receptor, expressed in Xenopus oocytes, responds to extracellular application of physiologically relevant concentrations of Ca2+ and other CaR agonists. The rank order of potency of CaR agonists displayed by the native receptor (Gd3+ > neomycin B > Ca2+ > Mg2+) is maintained by the expressed receptor. The nucleotide sequence of the human CaR cDNA predicts a protein of 1078 amino acids with high sequence similarity to a bovine CaR, and displays seven putative membrane-spanning regions common to G protein-coupled receptors. The deduced protein sequence shows potential sites for N-linked glycosylation and phosphorylation by protein kinase C and has a low level of sequence similarity to the metabotropic glutamate receptors. Comparison of the cDNA sequence to that of the normal human CaR gene showed no alteration in the coding region sequence of the CaR in this particular instance of parathyroid adenoma. Human cDNA clones with differing 5'-untranslated regions were isolated, suggesting alternative splicing of the parathyroid CaR mRNA. A rare variant cDNA clone representing a 10 amino acid insertion into the extracellular domain was also isolated. Northern blot analysis of normal and adenomatous parathyroid gland mRNA identified a predominant transcript of approximately 5.4 kilobases, and less abundant transcripts of approximately 10, 4.8 and 4.2 kilobases in RNA from the adenoma. While there is no evidence for alteration of the primary amino acid sequence of the CaR in this adenoma, modulation of CaR biosynthesis through alternative RNA processing may play a role in set-point alterations.

Adenoma↗
PubMed1995

Roxithromycin 150 mg b.i.d. versus amoxycillin 500 mg/clavulanic acid 125 mg t.i.d. for the treatment of lower respiratory tract infections in general practice.

Two hundred and forty-two patients over 16 years of age with community-acquired lower respiratory tract infection (LRTI), matched for age and sex, were randomised to receive either roxithromycin 150 mg b.i.d. or amoxycillin 500 mg/clavulanic acid 125 mg t.i.d. for 7 days, with a further 7 days if insufficient response was seen. Clinical efficacy at 7 days was 69% for roxithromycin and 56% for amoxycillin/clavulanic acid (p = 0.05) and at study end it was 91% for both antibiotics. There were fewer second treatment courses in the roxithromycin group (26% vs. 38%, p = 0.04) and a shorter treatment duration (8.29 days vs. 9.34 days, p > 0.05). Twelve patients (9.8%) treated with roxithromycin and 19 (17.1%) treated with amoxycillin/clavulanic acid had adverse effects possibly, or probably, related to the antibiotic. Roxithromycin appears to be a more appropriate choice than amoxycillin/clavulanic acid for the treatment of LRTI in the community given its more appropriate in vitro spectrum, efficacy against most common and atypical pathogens, greater cost-effectiveness, more convenient dosage regimen (b.i.d.), and superior tolerability profile.

Adolescent↗
PubMed1995

Calcitonin-secreting cells of the thyroid express an extracellular calcium receptor gene.

Calcitonin (CT) secretion by parafollicular cells of the thyroid (C cells) is regulated by small changes in the concentration of extracellular calcium ([Ca2+]e). Elevation of [Ca2+]e elicits a rise in the C cell cytoplasmic calcium concentration and stimulates CT release. The molecular entity through which C cells detect changes in [Ca2+]e and modulate hormone secretion is unknown. Recently, an extracellular calcium-sensing receptor (CaR) complementary DNA was isolated from bovine parathyroid gland. To assess whether parathyroid cells and C cells use similar mechanisms to detect changes in ambient Ca2+, rat, human, and sheep C cells were examined for expression of the parathyroid CaR or a related receptor isoform. Reverse transcription-polymerase chain reaction analysis identified CaR transcripts in rat and human thyroid gland. Northern blot analysis demonstrated CaR messenger RNA (mRNA) in rat thyroid gland, a human medullary thyroid carcinoma (MTC) isolate, and a highly enriched preparation of sheep C cells. Rat MTC 44-2 cells, a cell line responsive to changes in [Ca2+]e, express abundant levels of CaR mRNA. Human TT cells, a C cell line lacking the extracellular calcium-sensing function, have undetectable levels of CaR mRNA by Northern blot analysis. Western blot analysis, using antiserum specific to the parathyroid CaR, detected CaR protein in rMTC 44-2, but not TT cells. Immunostaining of both dispersed sheep C cells and rat thyroid gland sections identified C cell-specific expression of the CaR protein, and in situ hybridization analysis confirmed the C cell-specific expression of CaR mRNA in the intact rat thyroid. The nucleotide sequence of the coding region of the rMTC 44-2 CaR transcripts was found to encode the same CaR protein as that expressed in the parathyroid and kidney. The results demonstrate that C cells express the same extracellular calcium-sensing receptor that is found in parathyroid and kidney, and the presence of this receptor protein in C cell lines correlates with the extracellular calcium-sensing function. This CaR is likely to represent the primary molecular entity through which C cells detect changes in [Ca2+]e and control CT release, suggesting that activation of the same receptor can either stimulate or inhibit hormone secretion in different cell types.

Amino Acid Sequence↗
PubMed1991

The severity of asthma in relation to beta agonist prescribing.

OBJECTS: to investigate the relationship between indices of acute and chronic asthma severity and beta agonist prescribing. METHOD: the severity of asthma was assessed in 120 patients with asthma attending an emergency room. Seventy-seven patients were on salbutamol MDI, 38 on fenoterol MDI and five on different beta agonists. RESULTS: patients prescribed fenoterol MDI had more symptoms of chronic severity than those on salbutamol MDI and were more likely to have had a previous hospital admission. There was no difference in objective measurements of severity on presentation to the emergency room between the groups. CONCLUSIONS: either regular fenoterol MDI use leads to more chronic severe asthma or patients with chronic severe asthma are more likely to have been prescribed fenoterol. Fenoterol use is not associated with delay in presentation with acute asthma.

Acute Disease↗
PubMed1991

In situ histochemical analysis of region-specific gene expression in the adult rat epididymis.

The epididymal tubule is a dynamic structure, in which spermatozoa undergo distinct physiological and morphological changes. The epithelial cells lining the ductuli vary dramatically in their histochemical and cytological properties according to the region of the tubule in which they are located. Additionally, regional variation is observed regarding the biosynthetic, secretory, and absorptive properties of the epithelial cells. Using in situ histochemical analysis, we document here the region-specific expression of a variety of genes that are transcriptionally active in the adult rat epididymis. Radiolabeled antisense riboprobes were used to localize, within the efferent duct/caput epididymis, transcripts encoding protein B/C, protein D/E (acidic epididymal glycoprotein), sulphated glycoprotein 1, sulphated glycoprotein 2, cellular retinol-binding protein, and the neuroendocrine peptide precursor proenkephalin. Each species of mRNA exhibits a unique pattern of hybridization, revealing that gene transcription within the efferent duct/caput epididymis is also highly region specific. This observation may partially elucidate the molecular basis underlying the phenomenon of regional alterations in the composition of protein factors within the tubule lumen.

Animals↗
PubMed1991

Differential patterns of regulated gene expression in the adult rat epididymis.

Specialization among the principal epithelial cells of the epididymal tubule is documented following the analysis of transcriptional activity of four distinct species of mRNA. In situ histochemical analysis revealed a unique pattern of expression for each transcript. This observation supports the concept that region-specific patterns of transcriptional expression along the epididymal tubule serve as the major molecular basis underlying region-specific patterns of luminal proteins within the tubule. Additionally, multiple testicular factors appear to regulate expression of these mRNAs. The transcript encoding peptidyl-prolyl cis-trans isomerase is constitutively expressed. Those encoding the major secretory proteins, protein B/C and protein D/E, are directly regulated by testicular androgen. That encoding the opioid peptide precursor, proenkephalin, is regulated by a non-androgen testicular factor(s), specifically, spermatozoa or a spermatozoa-related factor. Thus, a complex array of nuclear events and signals received by the principal cells serve to determine the transcriptional status of genes expressed within this epididymal cell type.

Animals↗