L Lu un ng g d de ep po os si it ti io on n o of f b bu ud de es so on ni id de e f fr ro om m T Tu ur rb bu uh ha al le er r¤ ¤ i is s t tw wi ic ce e t th ha atABSTRACT: The pulmonary and systemic availability of budesonide after inhalation from a dry powder inhaler, Turbuhaler®, and from a pressurized metered-dose inhaler (P-MDI) were compared in healthy volunteers. Two different methods were used to assess pulmonary availability: 1) calculated from the systemic availability corrected for an oral availability of 13% (n=24); and 2) after blocking of gastrointestinal absorption by administration of a charcoal suspension (n=13). An intravenous infusion of budesonide was used as a reference.The systemic availability of budesonide, calculated as a geometric mean and expressed as percentage of the metered dose, was 38% for Turbuhaler® and 26% for P-MDI. The pulmonary availability, calculated using the first method, was 32% and 15% for Turbuhaler® and P-MDI, respectively; and, using the second method, 32% and 18%, respectively.The results of the present study indicate that administration of budesonide via Turbuhaler® gives rise to a lung deposition which is approximately twice that of a P-MDI, with less variability, but that systemic availability is only increased by approximately 50%. Thus, the present data suggest that by administrating budesonide via Turbuhaler®, instead of a P-MDI, the same degree of asthma control can be achieved with a lower dose, which, in turn, reduces the risk of undesired systemic effects.

1Neuropeptides released from sensory nerves may account for cutaneous flare and wheal following local trauma. In 28 normal subjects we have studied the effects of four sensory neuropeptides given by intradermal injection on the forearm or back. 2 All peptides caused a flare distant from the site of injection, presumably due to an axon reflex. Substance P (SP) was the most potent (geometric mean dose causing 50% ofmaximum flare, 4.2 pmol). Neurokinin A (NKA) was the next most potent with neurokinin B (NKB) and calcitonin gene-related peptide (CGRP) the least. The distant flare response to SP, NKA and NKB was maximal at 5 min and disappeared within 2 h. 3 CGRP caused a local erythema over the site of injection at doses above 0.5 pmol which at higher doses lasted for up to 12 h. 4 SP, NKA and NKB caused wheals at doses above 5 pmol with SP and NKB being the most potent. CGRP (up to 250 pmol) did not consistently cause wheal formation. There was no significant effect of coinjection ofCGRP upon the response to SP although there was a tendency for an enhancement ofthe wheal response. 5 The H,-histamine antagonist terfenadine (60mg orally) significantly inhibited the wheal and distant flare response to histamine (5 nmol) and NKA, but not that caused by NKB. The distant flare of CGRP was also reduced but the local erythema was unaltered. 6 Aspirin (600 mg orally) significantly inhibited the distant flare response to SP, NKA and CGRP, but not that caused by NKB or histamine; the local erythema induced by CGRP was unaffected by aspirin. Aspirin also inhibited the wheal formed by NKA but not the wheal induced by the other substances. 7 These results suggest that tachykinins cause a distant flare response partially via the release of histamine and cyclo-oxygenase products, but cause a wheal by a direct effect on the skin microvasculature. The order of potency SP > NKB > NKA suggests that an SPp or NK, receptor is involved in the wheal response. CGRP by contrast has a direct vasodilator effect which is very prolonged.

SUMMARY Sixteen patients treated with a noninvasively programmable pacemaker were examiined after a prolonged period of ventricular inhibited (VVI) and atrial synchronous ventricular inhibited (VDD) pacing. Maximal working, capacity was determined by bicycle ergometry. Atrial and ventricular rates, brachial artery cuff pressure and breathing rate were determined at rest and during exercise. There was a mean increase in working capacity of 24% with VDD compared with VVI pacing (p < 0.001). Thirteen of the patients were catheterized. During VDD pacing, cardiac output was significantly higher, particularly during exercise (i 32%) due to the capability of heart rate increase and despite a substantial compensatory stroke volume increase during VVI pacing. Arteriovenous oxygen difference was much higher during VVI pacing, reaching 164 14 mi/I during the highest work load, while the corresponding level during VDD pacing was 140 ± 14 ml/l (p < 0.001). During exercise, arterial blood lactate was significantly higher during VVI than during VDD pacing. Heart size was significantly smaller, 568 ± 98 vs 530 96 ml/m2 BSA (p < 0.05), during VDD pacing. A questionnaire was completed by the patients to evaluate subjective symptoms and pacemaker preference. This part of the study favored the VDD mode of pacing. maker exchange. The VDD pacemaker we described' can be programmed noninvasively to either the VVI or the VDD mode, permitting comparisons of prolonged periods of pacing in either mode.The aim of the present study was to compare the acute and chronic hemodynamic performance at rest and during exercise with VVI and VDD pacing and to study the maximal exercise capacity after a prolonged period of VVI and VDD pacing. Material and Methods PatientsSixteen patients treated with a VDD pacemaker gave informed consent to the study. Thirteen of the patients participated in the complete study and three agreed to the noninvasive part only (patients 9, 14 and 15). Selected data from the patients are presented in table 1. The PacemakerThe pacemaker (Medtronic 2409) has been described in detail.9 Briefly, it is a VDD unit with a ventricular escape rate variable from 50-80 beats/min and a maximum atrial synchronous rate variable from 100-175 beats/min. These rates can be noninvasively programmed. When the backup rate is programmed, the mode is also programmed to VVI at the selected rate. Programming the upper rate limit simultaneously programs the mode to VDD without changing the previously programmed backup rate. ProcedureThe study started with a period of pacing planned to last at least 3 months. During this period, patients 1-9 846 by guest on May 9, 2018 http://circ.ahajournals.org/ Downloaded from

1. The nucleoside, adenosine, was infused into six conscious healthy male subjects at rates up to 100 micrograms kg‐1 min‐1. 2. Compared with a control 0.9% saline infusion, adenosine in all subjects caused dose dependent increases in heart rate, skin temperature and minute ventilation with corresponding falls in PaCO2, estimated transcutaneously. 3. There were no changes in systemic blood pressure, airways resistance (measured by forced partial expiratory manoeuvres), or plasma catecholamines. At the top infusion rates subjects experienced tolerable chest and abdominal discomfort. 4. These findings conflict with some previous studies in anaesthetised man and animals, in which higher doses of adenosine and its long acting analogues have caused hypotension and central respiratory depression. 5. Although some of these changes may have been due to symptoms, the cardiovascular changes may have been due to a vasodilator action and the respiratory stimulation may have been due to an action on peripheral chemoreceptors.