1 Disposition of brotizolam in patients aged 71-93 years was compared with that of healthy young subjects aged 21-26 years.2 The mean elimination half-life of brotizolarh was about twice as long in the elderly as in the young subjects: 9.3 (4.0-19.5) h and 4.8 (3.1-6.3) h respectively. Increase in elimination half-life was attributable to a decrease in hepatic clearance i.e. 40 (20-58) ml/min in the elderly and 109 (77-156) ml/min in the young. Volume of distribution and protein binding were the same with mean values of 0.56 (0.45-0.72) 1/kg and 9.0 (6.8-11.9) No in the elderly and 0.63 (0.40-0.77) 1/kg and 8.4 (7.5-9.4)% in the young. 3 Absorption rate of brotizolam was relatively slow in the elderly with a mean peak time of 1.7 h compared with 1.1 h in the young. Mean bioavailability was almost 70% for both groups. Normalized for body weight and dose (0.25 mg) mean peak concentrations were 247 (137-395) ng ml-' kg in the young and 343 (251-446) ng ml-1 kg in the elderly.4 It is unlikely that substantial drug accumulation will occur if elderly patients ingest 0.25 mg brotizolam nightly.

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Doppler-shifted ultrasound and spectral analysis were used to assess the carotid arteries of 77 elderly stroke patients, which represented 154 carotid bifurcations. Severe carotid disease was demonstrated at 19 of the 154 carotid bifurcations and in eight of these complete occlusion of the internal carotid artery was present. In 12 of the 19 instances the severe disease was in the internal carotid artery associated with the stroke. Localized carotid bruits were present in five patients and only three of these were associated with severe disease of the internal carotid artery. Minor disease was detected in 80 of the 154 carotid bifurcations and no disease was detected at the remaining 55 carotid bifurcations. An abnormally low ankle/arm systolic pressure ratio, which indicated occlusive arterial disease of the legs, was obtained in 19 of the 43 patients examined. No relationship was found between the severity of carotid artery disease and the presence of haemodynamically significant disease of the lower limbs. Ultrasound measurement of aortic compliance gave significantly lower values in elderly stroke patients compared to elderly asymptomatic volunteers. Comparison of flow-velocity transit times from the stroke-affected and non-affected limbs showed no consistent effect of the stroke on vascular tone in the patients assessed.

In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered. Historically, drugs were discovered by identifying the active ingredient from traditional remedies or by serendipitous discovery, as with penicillin. More recently, chemical libraries of synthetic small molecules, natural products or extracts were screened in intact cells or whole organisms to identify substances that had a desirable therapeutic effect in a process known as classical pharmacology. After sequencing of the human genome allowed rapid cloning and synthesis of large quantities of purified proteins, it has become common practice to use high throughput screening of large compounds libraries against isolated biological targets which are hypothesized to be disease‒modifying in a process known as reverse pharmacology. Hits from these screens are then tested in cells and then in animals for efficacy. Depending on product type and development stage, investigators initially enrol volunteers or patients into small pilot studies, and subsequently conduct progressively larger scale comparative studies. Clinical trials can vary in size and cost, and they can involve a single research centre or multiple centres, in one country or in multiple countries. Clinical study design aims to ensure the scientific validity and reproducibility of the results. Costs for clinical trials can range into the billions of dollars per approved drug. The sponsor may be a governmental organization or a pharmaceutical, biotechnology or medical device company. Certain functions necessary to the trial, such as monitoring and lab work, may be managed by an outsourced partner, such as a contract research organization or a central laboratory. Only 10 percent of all drugs started in human clinical trials become approved drugs.

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