Roger Ellul-Micallef

EFFECT OF INTRAVENOUS PREDNISOLONE IN ASTHMATICS WITH DIMINISHED ADRENERGIC RESPONSIVENESS

The beta effects of adrenergic stimulation are often diminished in asthmatics in whom the condition is active. Corticosteroids are thought to lower the threshold of beta-adrenergic receptors to the response of catecholamines. A single intravenous injection of 40 mg prednisolone appeared to restore responsiveness to inhaled isoprenaline in eight out of ten chronic asthmatics who were previously non-responsive to catecholamines.

Intravenous prednisolone in chronic bronchial asthma.

A single injection of 40 mg prednisolone phosphate was given to 10 patients with chronic bronchial asthma. Changes in pulmonary function were followed over a 30-hour period. Statistically significant changes occurred in the tests employed one hour after the injection of prednisolone. The maximum change for the group as a whole was seen to occur after eight hours. This time course of response is very similar to that obtained in previous studies on similar groups of patients with oral prednisolone where the peak effect occurred nine hours after the drug had been given. Intravenous hydrocortisone produces a much earlier peak effect, at five hours, when it is administered to chronic asthmatic patients.

Use of a special inhaler attachment in asthmatic children.

Asthmatics often find difficulties in using an aerosol inhaler correctly as they are unable to co-ordinate the release of a bolus of drug to coincide with an inspiratory effort. This is especially the case with children. The addition of a special attachment to an ordinary inhaler overcame this problem. Twelve asthmatic children produced significantly better PEFR measurements when 0.25 mg terbutaline sulphate was administered via an inhaler with the attachment than when an ordinary inhaler was used alone.

Mutation screening of the muscarinic M2 and M3 receptor genes in normal and asthmatic subjects

Muscarinic receptors are important in the development of airway hyperresponsiveness, and dysfunction of these receptors has been suggested to be present in asthma. The human muscarinic M2 and M3 receptor genes were screened for polymorphic variation using single‐stranded conformation polymorphism (SSCP) analysis, complemented by direct fluorescent sequencing. Forty‐six random DNA samples and 46 respiratory physician diagnosed asthmatic samples were used as a template for analysis. Within the muscarinic M2 receptor gene, we identified two degenerate single base substitutions (1197T→C, Thr→Thr and 976A→C, Arg→Arg) in one random and one asthmatic sample respectively. Analysis of the 3′ UTR region revealed an additional ‘A’ at bp 1793 (c.f. ATG). This was present in all of 49 samples analysed by sequencing or BsmI digest, suggesting that the published sequence (GenBank Accession No. M16404) is incorrect. A common 3′ UTR polymorphism (T→A) was found at bp 1696 (c.f. ATG) (allelic frequency=65%, n=60), but this does not alter transcription factor recognition sites. We were unable to identify any polymorphic variation within the muscarinic M3 coding region or the flanking regions investigated, using the methods described. The coding regions for the human muscarinic M2 and M3 receptor genes are both highly conserved. These data suggest that polymorphic variation within these coding sequences is unlikely to account for inter‐individual variability in response to methacholine or anticholinergic therapy. The potential functional significance of the muscarinic M2 receptor 3′ UTR polymorphism (bp 1696) remains to be determined.

Effect of terbutaline sulphate in chronic "allergic" cough.

The effects of terbutaline sulphate were studied in 30 patients who presented with chronic cough at an allergy clinic. After a three week baseline period terbutaline and its placebo were given for two periods of three weeks each in a randomised, double blind, crossover manner. Patients kept a daily record of day and night cough scores and peak expiratory flow readings. Twenty one patients responded to terbutaline; placebo produced no significant effect. Both day and night cough scores (p less than 0.001) and peak expiratory flow rates were significantly improved (p less than 0.05) by the end of the first week of treatment with terbutaline. This improvement was achieved with only a fairly small change in airway calibre.

The spectrum of bronchial asthma in Kuwait

Kuwait, situated in the north‐west corner of the Arabian Gulf, has an arid climate with very hot dry summers and mild winters. Sandstorms are a regular climatic feature. occurring most frequently in summer. Before the mid‐1950s allergy was not considered to be a problem. Since then it has become a major cause of morbidity; 18% of the population are reported to suffer from its manifestations. Over the past 3 years 1000 asthmatic patients attending a central clinic have been carefully studied. The present paper analyses various aspects of the asthmatic condition in this desert country.

Effect of oral sodium cromoglycate and ketotifen in fish-induced bronchial asthma.

The effects of sodium cromoglycate and ketotifen were studied in a group of 20 patients in whom fish repeatedly provoked an attack of wheezing and dyspnoea within one hour of its being eaten. Fish ingestion resulted in a fall in forced expiratory volume in one second (FEV1) of at least 15%. All patients had a weal greater than 4 mm in response to fish antigen in the skinprick test and most had blood eosinophilia and raised serum IgE levels. Administration of drugs and placebos was carried out under double-blind conditions, in a randomised fashion, on different days. Cromoglycate blocked the fall in FEV1 either completely or significantly in 16 patients. Ketotifen did not appear to have any significant effect in the group as a whole.

A sensitive gas chromatographic/mass spectrometric method for the resolution and quantification of ethosuximide enantiomers in biological fluids.

A modified specific, sensitive and reproducible chiral gas chromatographic (GC) method for the resolution and quantification of ethosuximide enantiomers in urine and plasma was developed. The samples were extracted by liquid-liquid extraction, using diethylether and the enantiomers were separated and quantified on a chiral gas chromatographic column (25QC2 / CYDEX- beta 0.25). The method involved the use of GC/MS instrumentation for the acquisition of data in the electron impact selective-ion monitoring mode, collecting ions characteristic of both ethosuximide and alpha, alpha - dimethyl - beta - methylsuccinimide, the internal standard and of mass-to-charge ratio (m/z) exactly equal to 55 and 70 units. The limit of quantitation of the method was 2.5 microg/ml for both urine and plasma with both enantiomers. The method proved to be linear, precise and reproducible in the 5-300 microg/ml concentration range for urine samples and in the 10-250 microg/ml concentration range for plasma samples. Future research work envisaged the application of this method in pharmacokinetic and pharmacodynamic studies.

The hypereosinophilic syndrome--a diagnostic enigma.

The hypereosinophilic syndrome groups together a number of conditions in which eosinophilia occurs for no apparently identifiable cause. Initial reports indicated a uniformly grave prognosis but recent observations suggest a more favourable outcome in certain cases. Two patients with hypereosinophilic syndrome are described whose course of disease and outcome have been completely different.

Interferon gamma induction in human melanoma cell/allogeneic leukocyte co-cultures is enhanced by interleukin 18 but drug resistant melanoma cells are poorer inducers of IFN-γ

Human melanoma Colo 679 cells were made resistant to doxorubicin (adriamycin, ADM) by continuous exposure to ascending concentrations of the drug and Colo/ADM80; a variant which grew continuously in the presence of 80 ng/ml of ADM was thus established. Human peripheral blood mononuclear cells (PBMC) produced interferon gamma (IFN-gamma) when cultured with mitomycin C (MMC)-treated parental Colo 679 cells. The synthesis of IFN-gamma was synergistically enhanced by adding interleukin-18 (IL-18) and this was IL-12-dependent because a neutralizing antibody against IL-12 almost completely inhibited IFN-gamma production while control antibodies (Abs) were inactive. The cellular sources of IFN-gamma were found to be B cells, CD8+ T cells and CD4+ T cells as revealed by flow cytometry after double staining for surface antigens and staining for intracellular IFN-gamma. Interestingly, the resistant cell line induced much less IFN-gamma production than the parental cell line under the same co-culture conditions; however, IL-18 could still enhance the production of IFN-gamma. In conclusion, our study shows that acquired resistance to anti-cancer agents can also reduce immune responses to cancer cells. However, the immunostimulatory cytokine IL-18 could still enhance IFN-gamma production in drug resistant tumor cell-PBMC cultures indicating that such immunostimulatory agents could still be beneficial in immunotherapy for patients with recurrent drug resistant tumors.