Therapeutic possibilities in patients with senile dementia.
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Biomedical subjects
Publications and source records attributed to C M Castleden.
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Muscle cramps are painful and common in elderly patients but have largely escaped medical investigation. Quinine sulphate is usually the sole drug prescribed, even though firm evidence for its efficacy is not available. The results of the present double-blind cross-over study show that quinine was significantly superior to placebo in decreasing the number, severity and duration of nocturnal cramps. Since quinine is not a primary drug in any other condition, further studies of drugs with similar pharmacological actions may thus improve our management of this painful complaint.
The effect of oral mexiletine and intravenous lignocaine was examined in elderly patients with urinary incontinence associated with detrusor instability. Lignocaine had no demonstrable urodynamic effect in 13 patients, but 12 out of 20 patients who completed the study with mexiletine benefited, 10 becoming dry. The incidence of side-effects was high. Since there was no associated urodynamic improvement on the drug, the clinical improvement was probably secondary to the toileting regime instigated in every case. The results of the in vitro experiments on 11 rat bladders supported this contention, since mexiletine caused contractions of the preparation, and increased the rate and magnitude of spontaneous activity. Acetylcholine, histamine and 5-hydroxytryptamine receptors were not involved in these contractions.
Although possible on theoretical grounds, no interaction between cimetidine and tolbutamide could be demonstrated in ten healthy volunteers. The plasma tolbutamide concentrations over 12 h following 0.5 g orally were essentially the same before and after 1 and 7 days cimetidine (400 mg twice daily).
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The effect of ephedrine, an adrenergic receptor agonist, was investigated in 24 elderly patients with urinary incontinence associated with unstable detrusor contractions. After 3 weeks of oral ephedrine repeat cystometry showed mean increases of 21 per cent in bladder capacity and of 23 per cent in urethral pressure. Of 21 patients studied 7 became continent and 12 were improved. However, the urodynamic improvement did not reach statistical significance even in the continent group and, thus, the clinical improvement was unlikely to be owing to ephedrine. Therefore, open studies of drug treatment for detrusor instability may be misleading unless clinical and cystometric data are obtained.
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It is now possible to measure the effect of drugs on CNS function in elderly patients by a number of methods. All are safe, non-invasive and cause minimal discomfort to volunteers. Each has disadvantages and no reliance should be made on one. Computerised Axial Tomography (CAT) scanning is insufficiently sensitive to be used in research but has a place in the selection of subjects. Cerebral blood flow studies with xenon-133 can also be used in this manner as well as to study the effects of drugs on cerebral activity. To date, this use has received insufficient attention. The principle investigative techniques are the Electroencephalogram (EEG) and psychomotor tests. The former is reliable, objective and can measure onset, duration of drug action, and the minimum effective dose. Psychomotor tests are given as a battery which should include tests of performance, memory and learning, visual analogue scales and physical tests such as the measurement of sway. Subject selection is perhaps the most important aspect, since it determines data interpretation. Experiments in drug therapy must be carefully designed and tests selected to answer specific questions before the first subject is enrolled. Bias must be reduced as far as possible by making the experiment double-blind with the code not broken until the results have been analysed. A placebo or a proven reference drug should be included.
Eleven elderly confused patients were given a single dose of chlormethiazole, temazepam and placebo on separate nights with-in a 10-day period. There was no statistically significant difference between the three treatments the next morning in any of the tests, which included subjective and objective measures of mental ability, orientation and hangover effect. These results mirror those previously found in normal, healthy, elderly patients, and do not therefore support the contention that hypnotics increase confusion in demented patients, or that such patients are more sensitive to their actions. Indeed, plasma drug concentrations were on average twice as high in demented as in normal elderly subjects, thus raising the possibility of decreased sensitivity in the demented group. There was little correlation between plasma concentration and pharmacological effect.
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Whole-blood propranolol concentrations were estimated for 12 hours after a single 80 mg oral dose was given in six patients taking cimetidine and two weeks after they had stopped the drug. Mean blood propranolol concentrations were higher throughout the sampling period when the patients were taking cimetidine than when they were not, and the difference was statistically significant between one and four hours (p less than 0.05). The mean relative bioavailability of propranolol, measured as the area under the concentration time curve, was significantly higher when the patients were taking cimetidine (p less than 0.025). The mean increase in bioavailability was 136.5 +/- 57.6%, and the results were consistent in each subject. It is concluded from these results that cimetidine reduces the hepatic first-pass extraction of propranolol.
Clinical details were noted and urodynamic studies carried out on 100 elderly patients referred to an incontinence clinic, of whom 48 attended as day patients. Thirty patients had no problem apart from their incontinence, and only 38 had a clinically detectable neurological lesion. The average mental orientation score in 48 of the patients was 7.6, 23 patients scoring the top score of 10. Most patients were mobile without assistance from another person. Patients could be placed into one of four diagnostic groups according to the appearance of the cystometric tracings, but no bladder capacity or pressure was characteristic of any group. The maximum urethral closure pressure and functional profile length were similar for each group within each sex. There was no correlation between clinical and urodynamic findings, yet each of the four diagnostic categories have different therapeutic implications. It is concluded that urodynamic investigation is necessary in elderly incontinent patients before treatment.
Imipramine was given orally at night to 10 elderly patients with urinary incontinence associated with spontaneous unstable detrusor contractions. The dose was increased for each patient up to a maximum of 150 mg. at night, or until continence was achieved or side effects occurred. Of the 10 patients 6 became continent. In 3 of the 6 patients who underwent repeat cystometry bladder capacity had increased (mean 105 cc), bladder pressure at capacity decreased (mean 18 cm. water) and urethral pressure increased (mean 30 cm. water). There was no correlation between plasma desmethylimipramine and dose, or clinical or urodynamic effect.
1. Responsiveness of the beta-adrenoceptor adenylate cyclase system was measured in lymphocytes from healthy young and old subjects by incubating the cells with isoprenaline in the presence of a phosphodiesterase inhibitor and by measuring production of adenosine 3':5'-cyclic monophosphate (cyclic AMP) with a competitive binding assay. 2. The two groups did not differ significantly in the levels of cyclic AMP produced or in the concentration of isoprenaline required to give half-maximal stimulation of the cells (ED50).
Catheterization of the elderly incontinent patient is frequently unnecessary. It is also often unsuccessful, as most patients have unstable bladders and therefore leakage continues around the tube. Simple measures, like toileting regimens and restricting fluids in the evening, are often effective alone. Incontinence garments restore a patient's self-respect, reduce laundering and should be used more frequently whilst other methods, such as drugs, are being tried.
Although normal pressure hydrocephalus is one of the few remediable causes of dementia, the diagnosis is often not considered in the elderly. Three patients are described who presented to an acute geriatric unit within a six-month period during which normal pressure hydrocephalus was actively sought and treated. Although two made striking initial improvement, the long-term prognosis was poor: complications were frequent, and all three died within two years of operation. This pilot study indicates that normal pressure hydrocephalus may account for a proportion of cases of 'senile' dementia, but that formal controlled studies are required to establish the best means of diagnosis and treatment.
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The effects of a single 384 mg oral dose of chlormethiazole were compared with those of 20 mg of temazepam and placebo in healthy old and young women (mean ages 72.9 and 24.7 years respectively). Both drugs were effective hypnotics and had no detectable pharmacological action the next morning. Even four hours after administration performance of a simple psychomotor test was not impaired and sway (measured by an ataxiameter) was not increased in either age group. Pharmacokinetic studies showed that chlormethiazole was rapidly absorbed, distributed, and eliminated by both groups, so that minimal plasma concentrations existed 11 hours after administration. Temazepam, however, was less quickly absorbed and distributed, especially in the young group, and substantial amounts remained in the plasma 11 hours after administration. No unwanted effects occurred after temazepam, but 17 of the 20 subjects suffered from nasal irritation after taking chlormethiazole. Thus hangover effects may be avoided in elderly subjects after they have taken hypnotic drugs, and temazepam and chlormethiazole allow sleep to be interrupted safely.