Über die Wirkung einiger herzwirksamer Bisguanylhydrazone auf den Veratrineffekt am Frosch-Sartoriusmuskel

Zusammenfassung Die Wirkung einiger Guanylhydrazone sowie von Tyramin auf die Veratrine-Response des Froschsartoriusmuskels wurden untersucht. Von den drei herzglykosidartigen Bisguanylhydrazonen zeigten BG 60 und BG 31 den unspezifischen Veratrinantagonismus des Chinidins. BG 85 hingegen beeinflußte die VR herzglykosidartig. Von den drei tyraminartigen Substanzen BG 81, MG 41 und Tyramin wirkten die letzten zwei chinidinartig, während BG 81 trotz seiner tyraminartigen Wirkung die VR herzglykosidartig beeinflußte.

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Summary A series of guanylhydrazones was synthesized, some of the substances had a cardiac glycoside-like activity on the mammalian heart whereas other ones acted tyramine-like. The effect of some guanylhydrazones of each kind of action on the veratrine response (VR) of the frog's sartorius muscle should be investigated. Following substances were synthesized: 1. with cardiac glycoside-like activity 3,3-dimethyl-4,4-diacetyldiphenylbisguanylhydrazone (BG 60), progesteronebisguanylhydrazone (BG 31), p-aceto-m-methyl-phenyl-acetonyl-ether-bisguanylhydrazone (BG 85) 2. with sympathomimetic activity: p-aceto-phenyl-acetonyl-ether-bisguanylhydrazone (BG 81) and p-hydroxybenzaldehyd-monoguanylhydrazone (MG 41). The characteristic influence of the cardiac glycosides on the VR was only to be seen with BG 85 and BG 81. BG 60, BG 31 and BG 41 showed a quinidine-like effect on the VR. That means that from 3 guanylhydrazones with cardiac glycoside-like activity on the mammalian heart two of them had a quinidine-like effect on the VR and only one of them showed the typical cardiac glycoside-like effect on the VR. On the other hand among the guanylhydrazones with tyramine-like activity on the mammalian heart there is one, BG 81, which influenced the VR like a cardiac glycoside.

     

Drug,doctor warmth,and clinic setting in the symptomatic response to minor tranquilizers

An NIMH-PRB collaborative double-blind clinical trial, concerned with the importance of the doctor variable for drug treatment outcome, was conducted with 485 anxious neurotic outpatients receiving either chlordiazepoxide, meprobamate, or placebo. The participating clinics were located at the Johns Hopkins Hospital, Philadelphia General Hospital, and the Hospital of the University of Pennsylvania. The doctor variable selected for presentation was doctor warmth. Data on the 169 patients completing the 4 week study according to protocol were analyzed using a factorial analysis of covariance procedure, and the main findings were as follows: 1. several main drug effects, present only at 2 weeks, indicated chlordiazepoxide to produce significantly more improvement than either meprobamate or placebo; 2. several main warmth effects, present only at 4 weeks, showed patients rating their physicians at the initial visit as warm to improve significantly more than patients rating their physicians as non-warm; and 3. several significant drug X clinic interaction effects at 4 weeks reflected the fact that while hardly any drug differences were seen in 2 clinics, at Philadelphia General Hospital, patients strongly favored chlordiazepoxide. Drug and warmth effects were particularly marked in initially sicker patients, and warmth appeared especially important in the improvement of initially sicker placebo patients.     

Reversal of tumor-induced immunosuppression by TGF-beta inhibitors

The immune system is responsible for the early detection and destruction of newly transformed malignant cells. Some transformed cells become immunologically invisible by passive avoidance of immune surveillance (i.e., when tumor cells are immunologically indistinguishable from normal cells). Other transformed cells actively secrete cytokines that effectively blind the immune system to the presence of abnormal antigens on the tumor cell surface. Transforming growth factor- (TGF-), which is expressed by a majority of malignant tumors, is the most potent immunosuppressor and therefore, the most likely cytokine to be responsible for the latter phenomenon. In addition to playing a key role in tumor-induced immunosuppression, TGF- stimulates angiogenesis. Interestingly, tumor cells eventually become refractory to TGF--mediated growth arrest, either due to loss of TGF- receptors or due to dysregulation in TGF- signaling pathways. Neutralization of TGF- or inhibition of its production is an effective method of cancer treatment in variety of animal models. Several agents targeting TGF- are in the early stages of development and include anti-TGF- antibodies, small molecule inhibitors of TGF-, Smad inhibitors and antisense gene therapy. Since tumors may express more than one isoform of TGF-, these new drugs should target all three TGF- isoforms produced by human tumors. The effects of therapies targeting TGF- are likely to be synergistic with cytotoxic chemotherapy and immunotherapy. Reversal of TGF--induced immunosuppression is a new and promising approach to cancer therapy, with potential applications in other diseases such as AIDS.     

Quantification of communication processes, is it possible?

The PAS^® system (ProblemAnalysisSolutionsystem) is developed to quantify oral communication processes during counselling in pharmacy practice. The pharmacist translates the patients' drugrelated questions into a Pcode, the analysis of the question into an Acode and finally the given solution upon the question into a Scode. The PAS^® system has been developed for two goals. First, for the registation of drugrelated questions from patients which gives the pharmacist insight in the most common issues addressed by patients. Second, it might help the pharmacist to structure the communication with the patient during the consultation. Fortyone pharmacists participated in the evaluation of the PAS^® system. The validation of the PAS^® system consisted of two phases: the external validation and the internal validation. Kappa values were calculated as a measure of agreement in the coding by the pharmacists. The kappavalue of the external validation for the P , A and Scodes for the total set of questions indicate a moderate to poor agreement. This means that pharmacists categorize drugrelated questions from patients in a different way. Therefore we conclude that the PAS system is less reliable for research purpose. The kappavalue of the internal validation for the Pcode varies from 0.42 to 0.91. For the Acode it varies from 0.07 to 0.35 and for the Scode from zero to 0.68. Internal reproducibility is good for Pcode but not for the Acode and Scode This implies that the pharmacist can use the Pcodes for registration of patients' questions in his own pharmacy. Moreover, the usage of the PAS^® system during counselling in pharmacy practice can structure the consultation.     

A comparison of the analgetic potency of some analgesics as measured by the “flinch-jump” procedure

Summary The effects of various doses of morphine, dl-methadone, nalorphine, codeine, meperidine and saline on the flinch-jump thresholds of rats were measured by a procedure described previously. While none of the drugs influenced the flinch threshold, the group slopes of elevation of jump thresholds were significant for all drugs studied. In order of potency as revealed by this method, nalorphine ranked with morphine and methadone, while codeine and meperidine were less potent, suggesting that the procedure may be useful as a screening test for analgesic drugs.     

Effect of Cyclodextrins on Protein Binding of Drugs: The Diflunisal/Hydroxypropyl-β-Cyclodextrin Model Case

The binding of diflunisal to hydroxypropyl--cyclodextrin (HPCD), bovine serum albumin (BSA), human serum albumin (HSA), normal human plasma, and mixed solutions of HPCD/ protein was studied at 25°C, pH 7.4, by potentiometry using an electrode selective to diflunisal. The experimental data for diflunisal/ HPCD fit well to the 1:1 binding model. The binding of diflunisal with each of the studied proteins was compatible with a model having two independent classes of binding sites. The binding of diflunisal in mixed solutions HPCD/BSA, HPCD/HSA, and HPCD/plasma increased considerably when the HPCD concentration was increased. The binding behavior of the two biomolecules in the mixed solutions of HPCD/BSA or HPCD/ HSA was described with an additive model formulated on the basis of the estimates of the binding parameters of diflunisal derived from the separate experiments with each one of the binders tested. The lower than theoretical binding observed in HPCD/plasma solutions was ascribed to the competitive displacement of diflunisal from the HPCD cavity by plasma cholesterol.     

Clockwise hysteresis or proteresis

The authors propose the word proteresis to designate the clockwise hysteresis, i.e., when an effect increases more rapidly than the observed drug concentrations. Such a phenomenon has been recently described for aspirin and nicotine. Indeed hysteresis means which comes after, while proteresis, the greek symmetrical word, means which comes earlier, a more appropriate term for the described situation.     

Enhancement of Solubility and Bioavailability of β-Lapachone Using Cyclodextrin Inclusion Complexes

Purpose. To explore the use of cyclodextrins (CD) to form inclusion complexes with -lapachone (-lap) to overcome solubility and bioavailability problems previously noted with this drug. Methods. Inclusion complexes between -lap and four cyclodextrins (-, -, -, and HP-CD) in aqueous solution were investigated by phase solubility studies, fluorescence, and ¹H-NMR spectroscopy. Biologic activity and bioavailability of -lap inclusion complexes were investigated by in vitro cytotoxicity studies with MCF-7 cells and by in vivo lethality studies with C57Blk/6 mice (18-20 g). Results. Phase solubility studies showed that -lap solubility increased in a linear fashion as a function of -, -, or HP-CD concentrations but not -CD. Maximum solubility of -lap was achieved at 16.0 mg/ml or 66.0 mM with HP-CD. Fluorescence and ¹H-NMR spectroscopy proved the formation of 1:1 inclusion complexes between -CD and HP-CD with -lap. Cytotoxicity assays with MCF-7 cells showed similar biologic activities of -lap in -CD or HP-CD inclusion complexes (TD₅₀ = 2.1 M). Animal studies in mice showed that the LD₅₀ value of -lap in an HP-CD inclusion complex is between 50 and 60 mg/kg. Conclusions. Complexation of -lap with HP-CD offers a major improvement in drug solubility and bioavailability.     

Presynaptic dopamine DA2-receptors in rabbit jejunal arteries

Summary Excitatory junction potentials (e.j.ps) evoked by nerve stimulation with 15 pulses at 1 Hz were recorded from muscle cells of rabbit isolated jejunal arteries. LY 171555 1 mol/l, SKF 38393 10 mol/l, dopamine 10 ol/l and clonidine 0.1 mol/l depressed all e j.ps in the train. The percentage inhibition was inversely related to the number of pulses. S- and R-sulpiride, 10 mol/l, domperidone 1 mol/l, SCH 23390 1 mol/l and rauwolscine 1 mol/l did not change, or even depressed the first e j.ps. Of these compounds only S- and R-sulpiride, 10 mol/l and rauwolscine 1 mol/l facilitated the late e.j.ps. The percentage facilitation increased with the number of pulses until a maximum was reached; rauwolscine 1 ol/l had the largest effect. S- and R-sulpiride, 10 mol/l, as well as domperidone 1 ol/l antagonized the action of LY 171555 1 mol/l. S-Sulpiride was more potent than its R-isomer. SCH 23390 1 mol/l and rauwolscine 1 mol/l blunted the effect of SKF 38393 10 mol/l. Rauwolscine 1 mol/l slightly reduced the inhibition by dopamine 10 mol/l; S-sulpiride 10 mol/l was antagonistic only in the presence of rauwolscine 1 mol/l. When rauwolscine 1 mol/l, prazosin 0.1 mol/l, propranolol 1 mol/l and cocaine 10 mol/l was added to the medium, dopamine 10 mol/l continued to produce the same depression of e j.ps, as in the absence of these compounds. Under such conditions S-sulpiride 10 mol/l also counteracted dopamine 10 gmol/l. Rauwolscine 1 mol/l prevented the effect of clonidine 0.1 mol/l. The antagonists were not absolutely selective against only one type of agonist. We suggest that both presynaptic DA₂- and postsynaptic DA₁-receptors are present in rabbit jejunal arteries. The activation of either receptor-type may depress the e j.ps. Dopamine interferes with neuroeffector transmission due to ₂-adrenoceptor agonist properties; its DA₂-effect is unmasked only after ₂-adrenoceptor blockade. There was no evidence for a co-transmitter function of dopamine. Send offprint requests to P. Illes at the above address     

Plasma insulin levels and β-adrenoceptor antagonists

Summary The effect of -adrenoceptor antagonists on the intravenous glucose tolerance test was investigated in conscious dogs. dl-Celiprolol (cardioselective with ISA=intrinsic sympathomimetic activity) 200 and 1000 g/kg i.v., dl-metoprolol (cardio-selective without ISA) 200 and 1000 g/kg i.v., dl-pindolol (non-selective with ISA) 5 and 25 g i.v. and l-bupranolol (non-selective without ISA) 10 and 50 g/kg i.v. were used in the study. The influence of -adrenoceptor antagonists on the plasma glucose and immunoreactive insulin following the intravenous glucose tolerance test were evaluated by calculating the respective areas under the plasma curve.The present investigtion clearly demonstrates the marked difference between the various -adrenoceptor antagonists on heart rate and, especially on metabolic parameters. dl-Metoprolol, a -adrenoceptor antagonist with cardioselectivity and without ISA can be assumed not to alter plasma insulin level and glucose assimilation. l-Bupranolol, a non-selective -adrenoceptor antagonist without ISA reduces plasma insulin level and probably enhances peripheral glucose uptake, resulting in an unchanged glucose tolerance. dl-Celiprolol or dl-pindolol, -adrenoceptor antagonists with ISA, but cardioselective or non-selective enhance both, basal insulin level and insulin level after glucose stimulation but must be assumed to decrease peripheral glucose uptake since here too glucose tolerance was unchanged.     

The effect of nicotine on the swimming speed of pre-trained rats through a water alley

Summary In sessions of ten runs each, swimming time of rats through a 4 m long water alley was measured. Four doses of nicotine (0.05; 0.1; 0.2; 0.4 mg/kg given intraperitoneally 30 minutes before testing) were tested in sessions with a braking load on the tails of the animals either in all 10 runs of a session, or in every second run, or in none of the 10 runs. Regardless of the swimming condition, nicotine produced a considerable, and at doses of 0.1 mg/kg and over, significant decrease of performance in the first two runs. From the third to the 10th run, the changes caused by nicotine were smaller and differed depending on the swimming conditions.A dose of 0.1 mg nicotine/kg improved performance in the without-load-sessions and the without-load-runs of the alternating sessions, while both 0.1 and 0.2 mg/kg improved performance of the with-load-runs of the alternating sessions. Performance in the without-load-sessions and the without-load-runs was depressed by 0.4 mg/kg and that in the with-load-sessions by 0.2 and 0.4 mg/kg.     

Enhancement of the Antiinflammatory Effect of Ethyl 4-Biphenylyl Acetate in Ointment by β-Cyclodextrin Derivatives: Increased Absorption and Localized Activation of the Prodrug in Rats

Ethyl 4-biphenylyl acetate (EBA) is a prodrug of the antiinflammatory 4-biphenylyl acetic acid (BPAA). The inclusion complexes of EBA with -cyclodextrin (-CyD), heptakis(2,6-di-O-methyl)--cyclodextrin (DM--CyD), and 2-hydroxypropyl--cyclodextrin (HP--CyD) at a molar ratio of 1:2 (EBA:cyclodextrin) were prepared and used to make hydrophilic antiinflammatory ointments. The in vitro release of EBA from the ointments was enhanced by complexation in the order of -CyD < DM--CyD HP--CyD. The improvement correlated with the improved solubility and not with the decreased diffusibility observed to occur upon the complexation of EBA. In vivo the complexation with cyclodextrin derivatives increased both the release of EBA from the vehicle and its conversion in the underlying tissue to BPAA, but the total of EBA and BPAA in the tissue was decreased. In vitro studies confirmed that the effects of cyclodextrin derivatives on the conversion were exerted indirectly. The combination of the enhanced release and of the enhanced prodrug hydrolysis by esterases in the site where the antiinflammatory action is required resulted in increased therapeutic effects. In the model of carrageenan-induced acute edema in rat paw, the complexation improved the therapeutic effects over those of EBA alone in the order of -CyD < DM--CyD < HP--CyD. HP--CyD may be a particularly useful cyclodextrin derivative since it improves the topical availability and does not irritate tissues.     

A three-state model of the benzodiazepine receptor explains the interactions between the benzodiazepine antagonist Ro 15-1788, benzodiazepine tranquilizers, β-carbolines,and phenobarbitone

Summary The potent benzodiazepine receptor ligands -carboline-3-carboxylic acid ethyl ester (-CCM) and the corresponding methylester (-CCM) administered i.v. depressed segmental dorsal root potentials in spinal cats, reversed the prolongation of dorsal root potentials by phenobarbitone, and abolished the depression of a motor performance task induced by phenobarbitone in mice; -CCE enhanced the low-frequency facilitation of pyramidal population spikes in the hippocampus of anaesthetized rats. These effects of -carbolines reflect a depression of GABAergic synaptic transmission and, thus, are diametrically opposed to the enhancing action of benzodiazepine tranquilizers. The specific benzodiazepine antagonist, Ro 15-1788, while not affecting dorsal root potentials, hippocampal population spikes or phenobarbitone-induced motor performance depression, abolished the effects of -CCE on the three parameters and similar effects of -CCM on the spinal cord and motor performance.A three-state model of the benzodiazepine receptor is proposed in which benzodiazepine tranquilizers act as agonists enhancing the function of the benzodiazepine receptor as a coupling unit between GABA receptor and chloride channel, -carbolines act as inverse agonists reducing this coupling function, and Ro 15-1788 represents a competitive antagonist blocking both the enhancing effect of agonists and the depressant effect of inverse agonists on GABAergic synaptic transmission.     

The influence of learning on morphine analgesia and tolerance development in rats tested on the hot plate

The influence of learning on the development of tolerance to the analgesic effect of morphine in rats was examined employing the hot plate procedure. A tested-reinforced (Tr) group and its yoked-control, a tested-non-reinforced (Tnr) group, received identical exposure to the testing procedure; the Tr group was reinforced daily for its behavior on the heated plate whereas the Tnr group was reinforced only on the last day of the experiment. Paired statistical comparisons between these two groups on the last day of the experiment revealed that: 1. premorphine control reaction times on the heated plate were significantly lower in Tr than in Tnr animals; and 2. post-morphine increases in reaction time did not differ between Tr and Tnr animals. It was concluded that whereas some learning does occur in this testing procedure, learning does not influence the behavioral tolerance to morphine which develops in this analgesiometric method. An hypothesis which accommodates this behavioral tolerance and a mechanistic scheme is offered.     

Pharmacological characterization of central α-adrenoceptors which mediate clonidine-induced locomotor hypoactivity in the developing rat

Summary The present experiment was designed to pharmacologically characterize receptors which mediate the clonidine-induced locomotor change in the developing rat. A subcutaneous injection of clonidine (0.78 mol/kg) produced locomotor hyperactivity in 7-day-old rats but hypoactivity in 20-day-old rats. Phenoxybenzamine (1.5 mol/kg, 5.9 mol/kg and 15 mol/kg) decreased spontaneous activity in a dosedependent manner but did not antagonize clonidineinduced hypoactivity in 20-day-old rats. By contrast, the significant reversal of the clonidine-induced hypoactivity by pretreatment with phentolamine (1.6 mol/kg and 6.3 mol/kg), yohimbine (1.3 mol/kg and 5.1 mol/kg) and piperoxan (7.4 mol/kg) was observed at such doses when the blockers did not cause and hypoactivity by themselves. It is suggested that clonidine could induce locomotor hypoactivity by activating presynaptic (₁-type) -adrenoceptors in the CNS of 20-day-old rat.     

The Molecular Basis of β-Lactamase Catalysis and Inhibition

The -lactamases catalyze the hydrolysis of the lactam bond in -lactams, thus rendering the -lactam ineffective as an antibiotic. The increasing spread of resistance to -lactam antibiotics is largely due to this class of enzyme. Mechanistically these enzymes appear to be related to the transpeptidases and carboxypeptidases involved in the synthesis of the bacterial cell wall. Interest in the basic mechanism of action of the -lactamases has been spurred by the potential for mechanism-based drug design. The past seven years have seen a significant increase in our knowledge of the catalysis and inhibition of the -lactamases. The presence of an essential, conserved, serine residue which participates in the formation of a covalent acyl-enzyme intermediate in catalysis, inhibition and inactivation by -lactams has been established. Unfortunately, few additional details regarding the catalytic mechanism are well established. A generalized reaction pathway can be formulated for most -lactam inhibitors (reversible or irreversible). This scheme involves partitioning of the initially-formed acyl-enzyme by three pathways: 1) hydrolysis leading to turnover, 2) transient inhibition probably involving formation of an imine or enamine acyl-enzyme, or possibly involving a substantial conformational change in some cases, and 3) imine formation followed by additional covalent modification of the enzyme leading to irreversible inactivation. The flux through each of these pathways varies with the nature of the substrate and the particular -lactamase.     

Role of brain amines in learning associated with “amphetamine-state”

Conditional avoidance responses acquired under amphetamine were recalled without deficit only when tested under amphetamine (amphetaminestate dependent learning). Hydroxyamphetamine was devoid of this property. Dihydroxyphenylalanine (DOPA) but not 5-hydroxytryptophan (5-HTP) substituted for amphetamine while reserpine but not syrosingopine eliminated the amphetamine-state. DOPA and 5-HTP, only when given together, restored the amphetamine-state in reserpinized animals. DOPA alleviated the deficit in retention which was caused by methyl-p-tyrosine. 5-HTP alleviated the similar deficit caused by p-chlorophenylalanine. Chlorpromazine or cyproheptadine antagonized the amphetamine-state. It is suggested that amphetamine, but not hydroxyamphetamine is capable of producing an asymmetric behavior-controlling state. The amphetamine-state is related to the stimulation of central and not peripheral amine-receptors and depends on newly synthesized catecholamines which stimulate central catecholamine receptors through serotonin modulation in this case.     

Retrospective study on the reliability of an “approximate LD50” determined with a small number of animals

Based on 364 LD₅₀ determinations in mice and rats after intravenous and oral administration of drugs, the reliability of an approximate LD₅₀ was retrospectively tested.The difference between approximate LD₅₀ and LD₅₀ is — independent of species and route of administration — not greater than ± 20% of the LD₅₀ in 90% of the cases.Four to five doses — uniformly distributed over the dose-mortality range can suffice in reliably determining the approximate LD₅₀.The probability is 10% that an approximate LD₅₀ and LD₅₀ are significantly different from each other.152 parallel studies on male and female animals show that the LD₅₀ or approximate LD₅₀ must not be determined for both sexes. It is sufficient to test a dose near the LD₅₀ in the opposite sex. A 50–75% reduction of expenditure in animal material is possible in most of LD₅₀ determinations.     

The role of neuronal uptake atα- andβ-adrenoceptor sites in subcutaneous adipose tissue

Summary Intravascular noradrenaline infusion may cause vasodilatation or vasoconstriction in subcutaneous adipose tissue, whereas sympathetic nerve activity causes vasoconstriction only. This discrepancy may be due to a differential distribution of - and -adrenoceptors in relation to adrenergic nerve terminals in the adipose tissue vessels. In order to test this hypothesis the extent of prejunctional supersensitivity to noradrenaline was studied after blockade the neuronal uptake of noradrenaline with cocaine.In the autoperfused, isolated inguinal canine adipose tissue pretreatment with cocaine (200–600 g close i.a.) increased lipolysis following sympathetic nerve stimulation or close i.a. injection of noradrenaline. Cocaine also potentiated the vasoconstriction induced by nerve stimulation (1–3 Hz) or intra-arterial noradrenaline (0.2–2 nmoles) as well as the vasodilatation induced by sympathetic nerve stimulation (1–3 Hz) after -receptor blockade. However, the vasodilatation following close i.a. injection of noradrenaline after -receptor blockade was not changed by cocaine.The results indicate that the functionally important vascular -adrenoceptors in adipose tissue are in close contact with adrenergic nerve terminals, whereas most vascular -adrenoceptors seem to be unrelated to the nerve terminals. Thus, the -adrenoceptors in the adipose tissue vessels may be classified as innervated receptors, in contrast to the vascular -adrenoceptors which may be more acessible to circulating catecholamines and may be classified as humoral receptors. Furthermore at least some of the -receptors on the adipocytes seem to be located close to sympathetic nerve terminals.     

Low-dose oral lorazepam administration in Alzheimer subjects and age-matched controls

Ten patients with Alzheimer's disease and ten age-matched normal controls were studied in a double-blind, placebo-controlled acute trial of 1 mg PO lorazepam to test the effects of low-dose benzodiazepine on memory and behavior in a mostly older population. Cognitive effects differed somewhat between Alzheimer patients and normal controls, with Alzheimer patients revealing predominantly attentional impairments and age-matched controls showing possible disinhibition. Specifically, Alzheimer patients made more omission errors on a continuous performance task, whereas controls made more commission and intrusion errors with lorazepam versus placebo. This low dose of lorazepam (1 mg), which was associated with mild but statistically significant sedation in both groups, also produced no significant decrease in recent memory or in access to semantic memory. These cognitive findings contrast markedly to the reported effects of scopolamine on recent memory; therefore, supporting the idea that cholinergic interruption has a more specific effect on human memory and on learning than that of low-dose benzodiazepines. Further studies with a wider dose range of benzodiazepines are necessary to evaluate the possibility of differential sensitivity between Alzheimer patients and normal elderly controls.