Pharmacodynamic steady state of tiotropium in patients with chronic obstructive pulmonary disease.

Tiotropium (Spiriva) is a new once-daily inhaled anticholinergic that has its effect through prolonged muscarinic (M)3 receptor antagonism. It has a clinically documented, long duration of action with once-daily dosing in chronic obstructive pulmonary disease (COPD). A single-centre, double-blind, ipratropium-controlled study was conducted in order to characterize the onset of pharmacodynamic steady state of tiotropium in patients with COPD. Thirty-one patients (25 male, six female) with a mean age of 62 yrs and a mean forced expiratory volume in one second (FEV1) of 1.13 L (38% of predicted) were randomly assigned to receive either tiotropium 18 microg once-daily from a dry-powder inhaler (HandiHaler, 20 patients), or ipratropium 40 microg four-times daily from a pressurized metered-dose inhaler (11 patients) for a period of 1 week. FEV1 and forced vital capacity (FVC) were measured 1 h prior to, and just before inhalation (mean value of the two measurements on test-day 1 was the baseline value, while on all other test days it was the trough value), and 0.5, 1, 2, 3, 4, 5, and 6 h after inhalation of the morning dose of the study drug (one capsule and two puffs) on days 1, 2, 3, and 8. Trough FEV1 following 8 days of tiotropium was 0.19 L (18%) above baseline. Approximately 90% of this increase was achieved within 24 h of the first dose (0.17 L, 16%). Trough FVC increased 0.67 L (27%) on test-day 8. Approximately 70% of the improvement was observed after two tiotropium doses (0.47 L, 19%). Achievement of FVC steady state was delayed compared to FEV1. Ipratropium performed typically with an onset of action within 30 min, a peak response between 1-2 h postdosing and a duration of action of approximately 4 h. It was concluded that forced expiratory volume in one second steady state with tiotropium is reached within 48 h, while continued improvements in forced vital capacity can be expected over or beyond the first week of therapy. The continued increases in forced vital capacity beyond 48 h suggests that maintenance bronchodilator therapy is required to achieve maximal changes in hyperinflation.

['Trigger thumb' in 38 children: good short-term and long-term results from surgery]. / 'Knappende duim' bij 38 kinderen: goede resultaten van operatie op korte en lange termijn.

OBJECTIVE: To determine the direct and long-term effectivity of incision of the pulley in a trigger thumb (tendovaginitis stenosans). DESIGN: Retrospective study with follow-up. METHODS: In the period 1984-1995, 38 children (24 boys and 14 girls) were diagnosed and operated on 45 trigger thumbs in the Onze Lieve Vrouwe Gasthuis (Amsterdam) and Medisch Centrum Alkmaar, the Netherlands. Data were obtained from notes, operation reports and review in follow-up, at least 2 years after the operation. RESULTS: The mean age of the children at the moment of surgery was 3 years and 2 months (range: 11 months-10.33 years). 39 out of 45 thumbs were reviewed. Four thumbs had limited postoperative function. Two of these had a revision operation. There was 1 thumb with a postoperative superficial infection. At follow-up all thumbs had maximal function. The nodule in the tendon, which was palpable in 43 out of 45 thumbs preoperatively, had (almost) disappeared in all 39 thumbs at follow-up. There was a family history of trigger thumb in 33% of the 33 patients with follow up. 18% had bilateral involvement of the thumbs. The 6 digits not included in follow-up had a normal function according to the last notes. CONCLUSION: The results of surgery in the short term are good, in the long term excellent. Few complications occur. Based on the findings, it seems advisable to operate on children with a trigger thumb if there is no spontaneous recovery within half a year. Trigger thumb is the result of a congenital tight pulley.

Radiosynthesis and biodistribution of 123I-labeled antagonists of the histamine H3 receptor as potential SPECT ligands.

We have synthesized three 123I-labeled histamine H3 receptor ligands, i.e., [123I]GR 190028, [123I]FUB 271, and [123I]iodoproxyfan, in moderate to good radiochemical yields via a Cu+-assisted I-for-123I exchange method. Biodistribution in the rat of these compounds revealed high hepatic and pulmonary uptake. Brain uptake was moderate, but for [123I]iodoproxyfan, brain uptake was high enough for a pilot single photon emission computed tomography (SPECT) study in the rabbit. However, for this compound, the cerebral uptake could not be blocked by a pretreatment with [R]-alpha-methylhistamine, a selective, high-affinity histamine H3 receptor agonist, both in the SPECT study in the rabbit and in the biodistribution study in the rat. Apparently, [123I]iodoproxyfan is binding to a non-H3 receptor binding site. None of the three investigated compounds is suitable for use as a SPECT ligand for the H3 receptor in the brain.

Vesamicol and some of its derivatives: questionable ligands for selectively labelling acetylcholine transporters in rat brain.

Presynaptic cholinergic markers could be used for estimating the integrity of the cholinergic systems in the human brain with brain imaging techniques such as Single-photon emission computed tomography (SPECT). Vesamicol, an inhibitor of the vesicular acetylcholine transporter, and some of its derivatives have been suggested as potential ligands for this purpose. However, vesamicol binds not only to acetylcholine transporters but also to sigma binding sites. In the present study, we estimated the contribution of sigma site labelling to [3H](-)-vesamicol binding in different rat brain regions by selectively labelling the acetylcholine transporter, using [3H](-)-vesamicol in the presence of the sigma-ligand 1,3-di(2-tolyl)guanidine to occlude the sigma binding sites. The contribution of sigma site labelling was substantial in all brain regions and ranged from 25% in the striatum to 60% in the medulla. In addition, we investigated, in various experimental set ups, the affinities of several vesamicol derivatives for acetylcholine transporters and sigma binding sites. All vesamicol derivatives used displayed a higher affinity for the sigma1 site than for the acetylcholine transporter and also displayed a high sigma2 site affinity. This poor selectivity limits the usefulness of these compounds as selective cholinergic markers for brain imaging studies.

A simple and efficient method to remove free radioiodide from *I-radiopharmaceuticals.

Removal of free radioiodide from *I-radiopharmaceuticals was easily performed by using a pure metallic silver membrane, placed in a screwable holder. Well-known radiopharmaceuticals such as 3-iodobenzylguanidine, Hippuran, iomazenil and fatty acids were treated successfully, and gave reproducible results. Only a trace of free radioiodide (< or = 1%) was left after passing the silver membrane, while rest activity due to retention of the radiopharmaceutical on the membrane was negligible (2%-5%). This simple and reliable method offers the possibility of application as a last purification step in routine productions, in research or in a nuclear medicine department's pharmacy.

Comparison of performance of four instruments in evaluating the effects of salmeterol on asthma quality of life.

Quality of life measures are increasingly used as important efficacy endpoints in studies of drugs for asthma. The purpose of this study was to assess both the sensitivity to change and the construct validity of four different quality of life instruments in patients with asthma. In a double-blind, parallel group study, 120 moderate asthma patients, aged between 18-70 yrs, received either inhaled salmeterol 50 micrograms b.i.d. or inhaled salbutamol 400 micrograms b.i.d. In addition to respiratory outcomes, quality of life was measured at a 6 weeks follow-up using: 1) Asthma Quality of Life Questionnaire (AQLQ); 2) Living With Asthma Questionnaire (LWAQ); 3) Sickness Impact Profile (SIP); 4) Rating Scale (RS); and Standard Gamble (SG) utilities. Salmeterol led to significant improvements over salbutamol on virtually all clinical outcomes. Although all the quality of life instruments showed the same trend in favour of salmeterol, only the AQLQ and RS utilities showed significantly greater improvement on salmeterol than on salbutamol. Except for the AQLQ, the correlation between change in lung function and change in quality of life was generally low. Whereas, the AQLQ correlated well with the patient's overall assessment of efficacy (r = 0.64), the LWAQ, SIP and utilities failed to show such a correlation. The AQLQ showed the best correlation with symptom scores. The cross-sectional correlation between the AQLQ and the LWAQ was 0.73, whereas the longitudinal correlation was only 0.29. The SG generally showed poor correlation with other measures, including the RS. In conclusion, patients given salmeterol showed a greater improvement in quality of life compared to patients given salbutamol. Of the disease-specific questionnaires the Asthma Quality of Life Questionnaire was found to be more responsive to change than the Living With Asthma Questionnaire and showed greater validity. Of the generic instruments, the rating scale utilities were most responsive. The Standard Gamble showed poor correlation with other measures.