Comparison of the extrapulmonary beta2-adrenoceptor responses and pharmacokinetics of salbutamol given by standard metered dose-inhaler and modified actuator device

1. Ten healthy subjects were randomised to inhale salbutamol via a standard metered-dose inhaler (MDI), or via a modified metered-dose actuator device (MA). Previously published radiolabelled aerosol data had shown that the MA device produced a lower aerosol velocity, reduced oropharyngeal deposition, but with unchanged pulmonary deposition. 2. Dose-response curves (DRC) were constructed with the following cumulative doses of salbutamol: 200 microg, 600 microg (200 microg + 400 microg), 1400 microg (600microg + 800 microg) ad 2600 microg (1400 + 1200 microg). Dose increments were made every 30 min and measurements of extrapulmonary beta2-adrenoceptor responses were performed 20 min after each dose. In addition, plasma salbutamol concentrations were also measured immediately before and for up to 60 min after the last dose. 3. Baseline values were not significantly different between the two study days for any of the measured parameters. 4. Cmax (ng ml(-1)) for plasma salbutamol (as means and 95% CI for difference between MA and MDI) was: 2.0 (0.3-3.7), P = 0.03. Values for t(max) (min), median and range: MA 5 (5-10) vs MDI 5 (5-10); and AUC 0-60, (ng ml(-1) min, mean and 95% CI for difference between MA and MDI): 69 (-5-143), were not significantly different between the two devices. 5. There was a significant (P < 0.01) left shift in the DRC with the MA device compared with the MDI, for hypokalaemic, finger tremor, chronotropic and electrocardiographic (Twave, Q-Tc) responses to salbutamol. Values for the hypokalaemic response (mmol l(-1)) at 2600 microg were (as change from baseline, means and 95% CI for difference between MA and MDI): 0.23 (0.10-0.36). 6. Thus, the MA device produced greater systemic absorption of salbutamol, and associated extrapulmonary beta2-adrenoceptor responses compared with a standard MDI. These results, therefore, suggest that data from radiolabelled aerosol deposition studies may not predict the systemic absorption of inhaled beta2-adrenoceptor agonists.     

Subsensitivity of beta-adrenoceptor responses in asthmatic patients taking regular low dose inhaled salbutamol

Summary Tremor (Tr), chronotropic (HR) and metabolic (K, Glu) responses to cumulative doses of inhaled salbutamol (100 g to 4000 g) were compared in an age and sex matched group of 7 normal (N) and asthmatic (A) subjects.Comparison of regression lines between groups showed differences in HR and K. This was also reflected in attenuation of maximum responses in group A, for HR and K.These results show subsensitivity of chronotropic and hypokalaemic responses in patients with asthma, which may reflect tachyphylaxis from the effects of long term inhaled salbutamol therapy.     

Rheumatoid arthritis and its animal models: the role of TNF-alpha and the possible absence of specific immune reactions

Rheumatoid arthritis is an organ-specific inflammatory disease of humans. Recent studies have focused on associations with non-MHC genes, new autoantigens and the role of innate immune responses. The success of anti-TNF-alpha in the majority (but, interestingly, not all) of patients has implications for disease mechanisms but the dangers of long-term therapy are becoming clearer. A number of new models of arthritis have been defined and emphasize the importance of the genetic make-up of the host. Attention has also focused on why the joint is a particularly vulnerable site for inflammatory responses.     

Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: PHYSIOLOGICAL ACTIONS OF ANGIOTENSIN II MEDIATED BY AT1 AND AT2 RECEPTORS IN THE BRAIN

• 1 Autoradiographic binding studies have shown that the AT₁ receptor is the predominant angiotensin II (AngII) receptor subtype in the central nervous system (CNS). Major sites of AT₁ receptors are the lamina terminalis, hypothalamic paraventricular nucleus, the lateral parabrachial nucleus, rostral and caudal ventrolateral medulla, nucleus of the solitary tract and the intermediolateral cell column of the thoraco-lumbar spinal cord.
• 2 While there are differences between species, AT₂ receptors are found mainly in the cerebellum, inferior olive and locus coeruleus of the rat.
• 3 Circulating AngII acts on AT₁ receptors in the subfornical organ and organum vasculosum of the lamina terminalis (OVLT) to stimulate neurons that may have a role in initiating water drinking.
• 4 Centrally administered AngII may act on AT₁ receptors in the median preoptic nucleus and elsewhere to induce drinking, sodium appetite, a sympathetic vasoconstrictor response and vasopressin secretion.
• 5 Recent evidence shows that centrally administered AT₁ antagonists inhibit dipsogenic, natriuretic, pressor and vasopressin secretory responses to intracerebroventricular infusion of hypertonic saline. This suggests that an angiotensinergic neural pathway has a role in osmoregulatory responses.
• 6 Central angiotensinergic pathways which include neural inputs to the rostral ventrolateral medulla may use AT₁ receptors and play a role in the function of sympathetic pathways maintaining arterial pressure.

     

Predictive testing for BRCA1 and 2 mutations: a male contribution.

BACKGROUND: Management strategies for women carrying BRCA1 and 2 mutations are becoming clearer and predictive testing for a known family mutation is commonly undertaken. Implications for men are not as clear and they participate less frequently. PATIENTS AND METHODS: Twenty-six men from 10 extended families underwent predictive testing. Their motivation, reaction and outcome were studied. Subjects had appropriate pre- and post-test counselling. Informed consent was obtained before predictive testing for known deleterious mutations. DNA analysis followed standard procedures. RESULTS: Eighteen tested positive and eight negative. Four had adverse psychological reactions and three reneged on their commitments to impart results. The spouse of another man had an adverse psychological reaction to the disclosure of his positive result. Two, already suffering from prostate cancer, were phenocopies and paternal lineage transmission was unexpectedly determined in another. Risk was removed from 33 offspring and confirmed for 56. CONCLUSIONS: Complex themes associated with genetic testing are confirmed and the spectrum extended. Men appear to understand the importance of participating in this process. Methods of avoiding adverse reactions merit further study along with other aspects of the process.     

Macronutrient disposal during controlled overfeeding with glucose, fructose, sucrose, or fat in lean and obese women

BACKGROUND: Previous short-term studies (< or =6 h) showed differences in energy expenditure (EE) and macronutrient oxidation in response to overfeeding with different types of dietary carbohydrate. This finding could have implications for obesity. OBJECTIVE: We used 96-h continuous whole-body calorimetry in 8 lean and 5 obese women to assess metabolic disposal (energy dissipation and glycogen or fat storage) of a controlled excess of dietary energy supplied as different carbohydrate sources or as fat. DESIGN: Five dietary treatments were applied in random order: energy balance (control) and overfeeding by 50% of energy requirements with fat (O(fat)) or predominantly with glucose, fructose, or sucrose (O(cho)). Macronutrient oxidation rates were assessed from nonprotein gaseous exchanges. Net macronutrient balances were calculated as cumulative differences between intake and oxidation. RESULTS: Increased EE in response to overfeeding dissipated 7.9% of the energy excess with a variation in EE of <1.7% across overfeeding treatments (NS). EE during the O(fat) treatment significantly exceeded that during the control treatment in the lean but not in the obese women. There were no significant differences between lean and obese women in macronutrient oxidation or balances, so data were pooled. O(cho) induced glycogen storage on day 1 ( approximately 100 g) but thereafter progressively stimulated carbohydrate oxidation so that balance was reached on days 3 and 4. Fat oxidation was proportionately suppressed. Of the excess carbohydrate, 74% was oxidized; there were no significant differences between the various O(cho) treatments. O(fat) stimulated fat oxidation by 18% and suppressed carbohydrate oxidation. On average, 12% of the excess energy was stored as glycogen and 88% as fat; there was no significant difference between overfeeding treatments. CONCLUSION: There was no significant difference in fat balance during controlled overfeeding with fat, fructose, glucose, or sucrose.     

Comparison of recoveries in breath carbon dioxide of H13CO-3 and H14CO-3 administered simultaneously by single 6 h constant unprimed intravenous infusion

The aim of this study was to assess the bioequivalence of H13CO-3 and H14CO-3, by administering both labels simultaneously by single infusion and comparing their recovery in breath CO2 and urinary urea. Six healthy male subjects (age range 24-41 years; weight 76.7 (sd, 18.6) kg; height 1.79 (sd 0.05) m) were infused with unprimed solutions of HCO3- (110.0 mmol/kg) labelled with 13C (0.76 mmol 13C/h) and 14C (48 Bq/h) at a constant rate for 6 h, in a whole-body calorimeter (1400 litres) for measurement of CO2 production. Samples of breath were collected hourly in a Douglas bag and all urine was collected into two batches (0-4 h and 4-6 h) for estimating recovery of infused label by measurement of enrichment or specific activity. Recovery in breath CO2 of both labels increased from about 25 % for the first hour to 88 % and above for hours 3-4 onwards. Mean recovery of 13C in breath CO2 was slightly higher than that of 14C for all periods (mean difference always less than 1 % of infused label) but was significant only for the first 3 h (P < 0.05). Recovery of 14C in urea was significantly higher (P < 0.01) than 13C, but was confounded by substantial variability and uncertainties concerning 13CO2 background enrichments. These results suggest that there is no compelling need to alter factors currently used for recovery of 14C in breath when using 13C instead, and vice versa.