DRUG DISPOSITION

Clin. Pharmacokinet. 21 (4): 262-273. 1991 0312-5963/91/00 I0-0262/$06.00/0 © Adis International Limited. All rights reserved. CPK1051

Clinical Pharmacokinetics of Anxiolytics and Hypnotics in the Elderly Therapeutic Considerations (Part II) David J. Greenblatt, Jerold S. Harmatz and Richard 1. Shader Division of Clinical Pharmacology, Departments of Psychiatry, Pharmacology, and Medicine, Tufts University School of Medicine and New England Medical Center Hospital, Boston, Massachusetts, USA

Contents 262 262 263 263 266 266 267 267 268

Summary

Summary 4. Pharmacodynamic Changes in Old Age 4.1 Naturalistic Studies 4.2 Controlled Laboratory Studies 5. Experimental Models and Findings 5.1 Plasma Versus Target Organ Pharmacokinetics 5.2 Age-Dependent Concentration-Response Relationships 5.3 Receptor Number, Affinity and Function 6. Clinical Implications

Part I of this article, which appeared in the previous issue of the Journal, discussed the scope of and scientific basis for special pharmacokinetic studies of anxiolytic and hypnotic drugs in the elderly, and examined the methodology and results of such studies and the prediction of pharmacokinetic changes. In Part II the authors continue their review, focusing on age-related pharmacodynamic changes in the effects of these drugs, the attempts to correlate pharmacokinetic with pharmacodynamic findings, and the clinical applications of these data.

4. Pharmacodynamic Changes in Old Age Many reports and studies in the literature support the concept that elderly individuals are more 'sensitive' to the clinical action of benzodiazepine derivatives (Pomara et al. 1990); most evaluate the 2 extreme ends ofthe pharmacological cascade (fig. 1). That is, they evaluate the relation between dose

and pharmacodynamic effect, and generally conclude that a given dose of a benzodiazepine produces a greater pharmacodynamic action in elderly than in young individuals, or that a lower dose is necessary to produce a given clinical effect in the elderly. Among the data sources are the epidemiological studies described previously (BCDSP 1973; Greenblatt & Divoll Allen 1978; Greenblatt et al. 1977), in which the frequency of unwanted drow-

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Anxiolytics and Hypnotics in the Elderly

siness in hospitalised medical patients receiving various benzodiazepines (chlordiazepoxide, diazepam, flurazepam, nitrazepam) increased with the age of the patients. Data are also available in the context of clinical observation. Giles et al. (l978) assessed the intravenous dose of diazepam necessary to produce a given degree of clinical sedation among 19 patients receiving that drug prior to endoscopy. Older patients required significantly lower doses than did younger persons, but prior use of diazepam also had a significant influence on the intravenous dosage necessary to produce a given degree of sedation. In a study of fixed doses of flunitrazepam 0.015 mg/kg given intravenously before general surgical procedures in 20 patients, Kanto et al. (1981) found a significant increase with age in the overall degree of sedation. This apparently was not explained by age-related pharmacokinetic changes. In the context of therapeutic trials, several controlled clinical studies suggest that reduced doses of various benzodiazepine hypnotics (flurazepam, triazolam, brotizolam, nitrazepam) are sufficient to produce clinically acceptable hypnotic efficacy in elderly patients (Frost & DeLucchi 1979; Roehrs 1985; Viukari et al. 1984). Some studies assessing adverse effects or intensity of pharmacodynamic actions of benzodiazepines in the elderly either do not concurrently study young control subjects or do not assess plasma drug concentrations (Hinrichs & Ghoneim 1987; Nikaido et al. 1987, 1990; Pomara et al. 1984; Satzger et al. 1990), thereby not addressing the question of true 'biological' sensitivity. Although access to the target organ uptake and neuroreceptor phenomena involved in the pharmacological cascade (fig. I) is not ordinarily possible in humans, studies utilising systemic pharmacokinetics, in addition to dose alone, potentially provide more mechanistic information about altered drug sensitivity in the elderly. 4.1 Naturalistic Studies Important data have been provided by 2 studies done in the clinical context of intravenous diazepam administration to patients undergoing cardioversion and dental or endoscopic procedures.

Reidenberg et al. (1978) studied 23 cardiac patients requiring elective cardioversion. Patients received an infusion of intravenous diazepam until a fixed 'sedation' end-point was reached (the patient did not respond to verbal stimuli, but did respond to painful tactile stimuli). The administered dose was recorded and a plasma sample was drawn immediately after cardioversion. There was a significant negative correlation of age with the diazepam dose required to obtain the end-point, as well as between age and the measured plasma concentration. The findings indicate that increasing age is associated with a lower dosage requirement, as well as a lower plasma concentration, of diazepam necessary to produce a given degree of sedation. Cook et al. (l984) studied the dose and both total and unbound plasma concentrations of diazepam associated with a fixed sedation end-point in patients receiving intravenous drug for sedation prior to dental procedures or endoscopy. Their findings were very similar to those of Reidenberg et al. (1978). The dose necessary to produce sedation declined significantly with age; similarly, age was negatively correlated with the total and unbound plasma concentrations necessary to produce the sedation endpoint. These authors found that diazepam sensitivity was also influenced by prior use of a significant amount of alcohol, or the regular use of other sedative-hypnotic medications. Both of these studies suggest an increased biological sensitivity to diazepam in the elderly, such that a lower plasma concentration is required to produce a given degree of sedation. 4.2 Controlled Laboratory Studies 4.2.1 Methodological Issues The human pharmacology laboratory has also provided important data on the relative contributions of pharmacokinetic as opposed to pharmacodynamic factors in explaining altered clinical sensitivity to benzodiazepines in the elderly. The usual design involves intensive study of limited numbers of young and elderly healthy volunteers, who are administered single doses of a test benzodiazepine vs placebo in a crossover design. Plasma

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Table I. Laboratory methods for assessment of pharmacodynamic response to benzodiazepines Subjective measures Self-rating instruments visual analogue discrete ratings global ratings Semi-objective measures Psychomotor testing digit-symbol substitution (OSST) reaction time card sorting tracking arithmetic simulated driving Flicker fusion frequency (visual or auditory) Information acquisition and recall Objective measures Electroencephalography Saccadic eye movement velocity postural sway Plasma concentrations growth hormone cortisol catecholamines

concentrations and various pharmacodynamic measures are assessed at numerous time points following administration. Such studies have the advantages of intensive design, and evaluation of placebo response as a source of variation. Various pharmacokinetic-pharmacodynamic modelling procedures can be applied to the data from such studies, to establish quantitative estimates of drug sensitivity which can be compared as a function of age. However, the utility and validity of the data ultimately rest on the reliability of methods used to quantify pharmacodynamic outcome (table I). These methods in general can be categorised as the subjective, the semi-objective and the objective types. The various self-rating instruments generally utilise descriptors relating to sedation, fatigue, anxiety and tension (Lapierre et al. 1990; Sheikh

C/in. Pharmacokinet. 21 (4) 1991

1990). Subjective self-rating instruments use descriptors of drug effect that can be close to the primary target action of the drug, such as increased sedation or reduced anxiety. However, absolute scores on these rating scales have little meaning; quantification of drug effects must be based on change scores relative to a well established predrug baseline score. Furthermore, drug-associated changes can only be considered in the context of placebo response, which must be equally rigorously documented. Semi-objective measures of pharmacodynamic response include the large group of psychomotor test procedures, visual and auditory fusion frequencies, and various tests of information acquisition and recall (that is, memory). These testing procedures have all been documented to be sensitive to the effects of benzodiazepines and related compounds. Furthermore, absolute scores in themselves may be meaningful, thereby facilitating comparison of subject populations. These procedures are very sensitive to practice effects, in that repeated exposure to the testing procedures inherently leads to improvement in performance. Practice effects must be accounted for in the study design either by exposing subjects to multiple practice sessions until performance stabilises prior to the study, or by appropriate interpolation of placebo trials. Of critical importance are population differences in baseline performance, as discussed and illustrated by Hinrichs and Ghoneim (1987). In many tests of psychomotor skill, cognitive performance and memory, healthy untreated elderly individuals achieve lower performance scores than do young subjects (Craik 1977; Welford 1977). The question of how such differences in baseline performance influence the interpretation of additional drug-induced impairment is not yet resolved. Investigators must develop some scheme to account for these baseline differences when assessing differential drug effects on psychomotor performance or memory in elderly compared with young individuals. In any case, study results must always be interpreted with the understanding that the relationship of performance in various laboratory testing procedures to performance in 'real life' is not

Anxiolytics and Hypnotics in the Elderly

established. For example, it cannot be stated that drug effects on an individual's performance on a laboratory driving simulator will translate to similar decrements in driving ability in real life. Nor can a lack of effects in the laboratory exclude the possibility of significant effects in real life. Many of the problems associated with subjective and semi-objective pharmacodynamic measures are obviated by the use of objective measures of drug response, which include quantitative analysis of the electroencephalogram (EEG), saccadic eye movement velocity, postural sway and plasma concentrations of growth hormone, cortisol or catecholamines. Predrug baselines must still be established, and there may be population differences (that is, young vs elderly) in baseline values. However, assessment of drug response is objective, and placebo response is usually negligible. These objective measures are used with increasing frequency in pharmacokinetic-pharmacodynamic studies. 4.2.2 Results of Individual Studies Castleden et al. (1977) administered single oral doses of nitrazepam and placebo to young and elderly volunteers. As might be expected, placebo performance scores were considerably lower in the elderly subjects. Nonetheless, absolute and relative decrements in performance at 12 and 36h after dosage were greater in the elderly even though there were no significant differences in plasma nitrazepam concentrations between the groups at corresponding times. Swift et al. (1985a) administered single oral doses ofloprazolam to groups of healthy young and elderly volunteers: its CL was reduced, and t'l2/3 prolonged, in elderly as opposed to young subjects. However, in the first several hours after dosage, there were no significant differences in plasma concentrations between the 2 groups. Nonetheless, elderly subjects had greater decrements in postural sway, flicker fusion threshold and reaction time. Most of the age-associated differences did not reach statistical significance, due to large inherent variability in the data. The same group of investigators (Swift et al. 1985b) used a similar study design to evaluate the

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effects of single oral doses of diazepam 10mg and placebo in young and elderly volunteers. During the first 16h after administration, elderly subjects did not have higher plasma concentrations of unbound diazepam; in fact, the values were slightly although significantly lower at 2.5 and 14h after the dose. At other times, plasma concentrations did not differ significantly. Reductions in digit-symbol substitution test (DSST) scores were observed in both groups, but no age effects were evident. However, the elderly volunteers showed far greater increments in postural sway. Pomara et al. (1985) administered single oral doses of diazepam 2.5mg and placebo to groups of young and elderly volunteers. Again, the elderly group had lower baseline scores on various memory tests. The low dose of diazepam produced no impairment relative to placebo in any of the tests of young subjects, but impairments in several measures of memory and reaction time were observed in the elderly group relative to placebo. Plasma diazepam concentrations were significantly higher at Ih after administration in the elderly volunteers, but no effect of age was observed at 3h. In a subsequent study, Pomara et al. (1989) studied the effects of single and multiple oral doses of diazepam 2.5 and iOmg and placebo, in groups of young and elderly volunteers. The elderly subjects again had lower baseline scores in memory performance, and appeared to be more sensitive to the memory-impairing effects of diazepam than did the young subjects; these differences were not completely explained by the higher plasma concentrations which were observed in the elderly group at some times following the dose. Greenblatt et al. (1990) administered single intravenous doses of midazolam and placebo to groups of young and elderly volunteer subjects: at a number of time points after the dose, the density ofEEG {3 activity was assessed together with plasma midazolam concentrations. Pharmacokinetic-pharmacodynamic modelling indicated a significant shift in the plasma concentration-EEG response relationship in the elderly as opposed to young subjects, consistent with increased intrinsic sensitivity to midazolam (on the order of 1.5- to 2.5-

266

fold). In a study of the triazolobenzodiazepine triazolam, Greenblatt et al. (1991) administered placebo and triazolam 0.125 and 0.25mg to young and elderly volunteers. As discussed above, triazolam CL was reduced, and plasma concentrations were higher, in elderly vs young subjects. Elderly persons also had greater reductions in DSST and memory performance; however, the relation between plasma triazolam concentration and impairment of DSST or memory performance was not significantly different between the 2 groups, indicating that the greater impairment induced by triazolam in the elderly subjects was not due to an increased intrinsic sensitivity but rather a consequence of higher plasma concentrations due to reduced CL. Taken collectively, these studies generally confirm an increased clinical sensitivity to the central nervous system depressant effects of benzodiazepines among healthy elderly individuals. This can be attributed either to an increased intrinsic sensitivity (that is, a shift in the concentrationresponse relationship) or to higher plasma concentrations, or to a combination of the 2. Thus, both pharmacokinetic and pharmacodynamic factors may contribute to altered benzodiazepine sensitivity in aging individuals.

5. Experimental Models and Findings Intact animal models have been of limited value in predicting or explaining age-related changes in the systemic pharmacokinetics ofbenzodiazepines. In studies of rats and rabbits, diazepam Vd and t'h/3 both increased in aging as opposed to young animals (Klotz 1979; Tsang & Wilkinson 1982); however, the age groups did not differ in plasma clearance of the drug. This contrasts with the agerelated changes in diazepam pharmacokinetics observed in humans (see above). Barnhill et al. (1990) did find a reduction in CL, and a prolongation of t'h/3, of the benzodiazepine clonazepam in mice aged I or 2 years compared with those aged 6 weeks or 6 months. A number of studies evaluated in vitro drug metabolising capacity using liver tissue from aging animals (Schmucker 1985a,b). However, few of such studies specifically evaluated the age effects

Clin. Pharmacokinet. 21 (4) 1991

on benzodiazepine metabolising capacity. Recently, Fujita et al. (1990) studied in vitro capacity for N-demethylation and 3-hydroxylation of diazepam in tissue from male and female Fischer-344 rats aged 3 to 30 months. Significant decrements in metabolising activity were observed in aging male rats, but not in aging female animals. Behavioural results in any case suggest that the sensitivity to benzodiazepines may increase with age in some species of rats (Guthrie et al. 1987; Komiskey et al. 1987) and mice (Barnhill et al. 1990). These models have provided useful opportunities to elucidate the effects of age on some components of the concentration-response relationship (fig I). 5.1 Plasma Versus Target Organ Pharmacokinetics The interpretation of plasma concentrationresponse relationships in humans depends on the assumption that unbound plasma concentrations of benzodiazepines reflect the concentration available for receptor binding at the target organ. Furthermore, comparison of young and aging populations further assumes that the brain: free plasma concentration ratio itself is not influenced by age. This assumption seems reasonable, since passive diffusion of unbound drug from plasma to brain (Arendt et al. 1987) as such should not be influenced by age as long as the integrity of the bloodbrain barrier is maintained. Nevertheless, the findings of Rahman et al. (1986) were not consistent with this hypothesis. These investigators administered single intravenous doses of radiolabelled diazepam 0.18 mg/kg to young, mature and old male Fischer-344 rats. For the first 60 min after administration, the ratio of mean brain diazepam AVC to mean unbound plasma AVC in young animals was 2.29, increasing to 4.11 and 4.31 in mature and old animals, respectively. This finding suggests that brain uptake of diazepam relative to plasma concentrations of unbound drug may be higher in aging animals. In 2 other studies, the findings were consistent with age-independent passive diffusion of benzo-

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Anxiolytics and Hypnotics in the Elderly

diazepines into brain tissue. Scavone et al. (1987) studied brain and plasma concentrations of diazepam (and the metabolites demethyl-diazepam, oxazepam and temazepam), alprazolam and triazolam at 1h after a single intraperitoneal dose (1.25 to 5 mg/kg) of these benzodiazepines in young, middle-aged and old Fischer-344 rats. Although the brain: plasma concentration ratio differed significantly among the various benzodiazepines, there was no significant effect of age on the ratio for any of the individual drugs. Barnhill et al. (1990) studied brain: plasma concentration ratios of cIonazepam after single intraperitoneal injections (2 mg/ kg) administered to mice aged 6 weeks, 6 months, I year and 2 years. Ratios were measured at a number of time points, starting at 2h, until 12 to 14h after administration. The overall mean brain: plasma ratio was 1.82, and did not differ significantly among the 4 age groups. These data suggest that the equilibrium brain: plasma concentration ratios of benzodiazepines are independent of age. 5.2 Age-Dependent Concentration-Response Relationships Guthrie et al. (1987) studied the pharmacokinetics and behavioural effects of single intraperitoneal doses of diazepam administered to young (4 months) and old (24 to 26 months) rats. Despite receiving the same weight-corrected dose (30 mg/ kg), old rats had a substantially longer sleeping time than young animals. However, there were no significant differences between young and old animals in mean plasma or brain concentrations of diazepam at 2h after the dose, nor in the plasma fu. Barnhill et al. (1990) administered single intraperitoneal doses of cIonazepam 2 mg/kg to 4 groups of mice as described above. Rotarod ataxia, used as a measure of central nervous system depression, was quantitatively greater and of longer duration in older animals (fig. 6). This was only partially explained by pharmacokinetic differences, since there was a significant shift in the relationship of cortex cIonazepam concentration versus rotarod ataxia in the aging animals. That is, a given cortex

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concentration produced greater rotarod ataxia in 1year-old animals than in those aged 6 weeks or 6 months (fig. 7). There was an analogous shift in the relationship of percentage receptor occupancy versus rotarod ataxia, with a lower degree of receptor occupancy necessary to produce a given degree of rotarod ataxia in 1-year-old animals than in those that were younger (fig. 7). This study demonstrates that the enhanced central depressant effect of cIonazepam in aging animals has a pharmacokinetic component (prolonged t112 and reduced CL), as well as a pharmacodynamic component: increased CNS depression at any given cortex cIonazepam concentration or degree of receptor occupancy. 5.3 Receptor Number, Affinity and Function The neurochemical mechanism of altered benzodiazepine sensitivity in the elderly has been assessed in a number of laboratories. The usual technique involves in vitro assessment of benzo-

268

Clin. Pharrnacokinet. 21 (4) 1991

diazepine receptor binding and function in brain tissue taken from young and aged rodent species. The results have been consistently negative. No significant age-related differences have been observed in benzodiazepine receptor number or affinity (Barnhill et at. 1990; Heusner & Bosmann 1981; Komiskey & MacFarlan 1983; Memo et at. 1981; Meyers & Komiskey 1985; Pedigo et at. 1981; Tsang et at. 1982; Reeves & Schweizer 1983). Barnhill et at. (1990) also evaluated the effect of age on chloride channel binding and on muscimol-stimulated chloride uptake in cortical synaptoneurosomes. Again, no significant effect was observed. Thus, the neuroreceptor mechanism of altered benzodiazepine sensitivity in aging organisms has not yet been elucidated.

6. Clinical Implications The metabolic clearance of most benzodiazepines metabolised by hepatic microsomal oxidation is impaired in the elderly, leading to higher plasma concentrations and/or prolonged t'hi3' When extended to the steady-state condition, impaired CL predictably implies increased accumulation during multiple dosage. However, no causal link between

increased accumulation in the elderly and an increased incidence of side effects related to central nervous system depression has yet been proven. For benzodiazepines metabolised by glucuronide conjugation or nitroreduction, there appear to be minimal or small age-related changes in clearance. This has led to the theoretical suggestion that conjugated benzodiazepines may be safer or more appropriate than oxidised benzodiazepines for elderly individuals. Again, there is no experimental validation of this theoretical possibility. There is, however, the suggestion from epidemiological studies that short half-life benzodiazepines, regardless of the metabolic pathway, may be relatively safer than long half-life agents with respect to the frequency of adverse events, such as hip fracture, presumed to result from excessive CNS depression, confusion and falls (Ray et at. 1987, 1989). One study suggested that long term dosage with diazepam in healthy elderly volunteers was more likely to produce persistent sedation than long term oxazepam administration (Salzman et at. 1983). Pharmacokinetic-pharmacodynamic studies have indicated that the increased clinical sensitivity to benzodiazepines in the elderly may result from either higher plasma concentrations or increased

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Fig. 7. Relation of rota rod ataxia (y-axis) to cortex c10nazepam concentration and percentage in vivo benzodiazepine receptor occupancy in the 3 groups of animals described in figure 6. The relationships are similar for animals aged 6 weeks and 6 months, but are significantlyshifted for l-year-old animals (from Barnhill et al. 1990, with permission).

Anxiolytics and Hypnotics in the Elderly

intrinsic sensitivity, or a combination of the two. This has been validated in studies of experimental models. However, no neuroreceptor explanation for the change in sensitivity is currently available. It is not yet possible to translate these clinical and scientific observations into specific recommendations on changes in the approach to therapy that are appropriate for treating agitation, anxiety or sleep disorders in the elderly. There is a pressing need for the development of methodology, and for the execution of controlled clinical trials that establish plasma concentration-response relationships for benzodiazepines in the clinical treatment of agitation, anxiety or sleep disorders. Further, these studies must be extended to aging populations, to establish whether changes in the dose-concentration or concentration-response relationships are evident in elderly populations in the clinical therapeutic context. Essentially, no reported studies of anxiolytic treatment in the elderly involve plasma concentration determinations, or direct comparison with young populations with the same target disorder (Salzman 1990). Until such data are available, clinicians have no choice but to revert to the instinctive use of lower doses of benzodiazepines in the elderly, coupled with titration of dosage and monitoring of response.

Acknowledgements The authors are grateful for the collaboration and assistance of Lawrence G. Miller, Joseph M. Scavone, Marcia Divoll, Darrell R. Abernethy, Hermann R. Ochs, Jamie G. Barnhill and many other individuals who have advised and collaborated over the years. This work was supported in part by grants MH-34223, AG-OOI06 and DA-05258 from the Department of Health and Human Services.

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Pharmacology 15: 303-309, 1983d Greenblatt DJ, Divoll M, Abernethy DR, Ochs HR, Shader RI. Benzodiazepine kinetics: implications for therapeutics and pharmacogeriatrics. Drug Metabolism Reviews 14: 251-292, 1983a Greenblatt DJ, Oivoll M, Harmatz JS, MacLaughlin OS, Shader RI. Kinetics and clinical effects of flurazepam in young and elderly noninsomniacs. Clinical Pharmacology and Therapeutics 30: 475-486, 1981 b Greenblatt OJ, Divoll M, Harmatz JS, Shader RI. Oxazepam kinetics: effects of age and sex. Journal of Pharmacology and Experimental Therapeutics 215: 86-91, 1980b Greenblatt OJ, Divoll M, Moschitto U, Shader RI. Electron-capture gas chromatographic analysis of the triazolobenzodiazepines alprazolam and triazolam. Journal of Chromatography 225: 202-207, 1981c Greenblatt OJ, Divoll M, Puri SK, Ho I, Zinny MA, et al. Reduced single-dose clearance of clobazam in elderly men predicts increased multiple-dose accumulation. Clinical Pharmacokinetics 8: 83-94, 1983d Greenblatt OJ, Divoll M, Puri SK, Ho I, Zinny MA, et al. C10bazam kinetics in the elderly. British Journal of Clinical Pharmacology 12: 631-636, 1981 d Greenblatt DJ, Ehrenberg BL, Scavone JM, Harmatz JS, Shader RI. Increased sensitivity to midazolam in the elderly. Abstract. Clinical Pharmacology and Therapeutics 47: 210, 1990 Greenblatt DJ, Harmatz JS, Shapiro L, Engelhardt N, Gouthro T A, et al. Sensitivity to triazolam in the elderly. New England Journal of Medicine 324: 1691-1698, 1991 Greenblatt DJ, Laughren TP, Divoll Allen M, Harmatz JS, Shader RI. Plasma diazepam and desmethyldiazepam concentrations during long-term diazepam therapy. British Journal of Clinical Pharmacology II: 35-40, 1981a Greenblatt DJ, Schillings RT, Kyriakopoulos AA, Shader RI, Sisenwine SF, et al. Clinical pharmacokinetics of lorazepam: I. Absorption and disposition of oral 14C-lorazepam. Clinical Pharmacology and Therapeutics 20: 329-341 , 1976 Greenblatt DJ, Sellers EM, Shader RI. Drug disposition in old age. New England Journal of Medicine 306: 1081-1088, 1982a Greenblatt DJ, Shader RI. Benzodiazepines in clinical practice, Raven Press, New York, 1974 Greenblatt DJ, Shader RI. Pharmacokinetics of antianxiety agents. In Meltzer (Ed.) Psychopharmacology: the third generation of progress, pp. 1377-1386, Raven Press, New York, 1987 Greenblatt DJ, Shader RI. Benzodiazepines in the elderly: pharmacokinetics and drug sensitivity. In Salzman & Lebowitz (Eds) Anxiety in the elderly: treatment and research, pp. 131-145, Springer, New York, 1990 Greenblatt DJ, Shader RI, Abernethy DR. Current status of benzodiazepines. New England Journal of Medicine 309: 354-358, 410-416, 1983b Greenblatt DJ, Shader RI , Harmatz JS. Implications of altered drug disposition in the elderly: studies of benzodiazepines. Journal of Clinical Pharmacology 29: 866-872, 1989a Greenblatt DJ, Shader RI, Koch-Weser J. Psychotropic drug use in the Boston area. Archives of General Psychiatry 32: 5 I 8521, 1975 Greenblatt DJ, Shader RI, MacLeod SM, Sellers EM. Clinical pharmacokinetics of chlordiazepoxide. Clinical Pharmacokinetics 3: 381-394, 1978 Gurian BS, Miner JH. Clinical presentation of anxiety in the elderly. In Salzman & Lebowitz (Eds) Anxiety in the elderly: treatment and research, pp. 31-44, Springer, New York, 1990 Guthrie S, Cooper RL, Thurman R, Linnoila M. Pharmacodynamics and pharmacokinetics of ethanol, diazepam and pentobarbital in young and aged rats. Pharmacology and Toxicology 61: 308-312, 1987 Heusner JE, Bosmann HB. GABA stimulation of 3H-diazepam binding in aged mice. Life Sciences 29: 971-974, 1981

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Correspondence and reprints: Dr David J. Greenblatt, Division of Clinical Pharmacology, Box 1007, Tufts-New England Medical Center, 171 Harrison Avenue, Boston, MA 02111, USA.

International Symposium of Immuno- Rheumatology Physiological and Therapeutical Immunomodulation in Rheumatic Disease

Date: 13-15 May, 1992 Venue: Montpellier, France For further information, please contact: Prof. Jacques any Service d'lmmuno-Rheumatologie Hopital Gui-de-Chauliac 34059 Montpellier FRANCE