摘要:

AbstractSenile dementia of the Alzheimer type (SDAT) is a degenerative disease of the brain that affects up to 20% or more of individuals who live beyond 80 years of age. A deficiency of cholinergic function is expected to play a major role in the development of SDAT psychopathology. Possible existence of an underactive cholinergic system has led to clinical trials of cholinomimetic drugs to attempt to reverse the deficit in SDAT. Some improvement in memory function has followed the administration of cholinesterase (ChE) inhibitors, but in general the affected individuals have not been returned to normal or mildy impaired mental functions or activities of daily living functioning. This paper is a critical review of results of acute and chronic trials performed with ChE inhibitors in experimental animals and humans. We also review and discuss mechanisms of decvelopment of pharmacological behavioral tolerance to ChE inhibitors. Behavioral changes following ChE inhibition appear to coincide with predicted peak levels of acetulcholine (ACh) concentration in the brain. Yet we find an inconsistent relationship among the degree of ChE inhibition, changes in brain acetylcholine concentrations, and behavioral changes, both therapeutic and adverse effects, following administration of ChE inhibitors. ChE inhibition is associated with distressing adverse effects. The therapeutic effects of increased ACh levels in the brain may be masked by these side effects. We suggest that an adequate test of the efficacy of ChE inhibition may await the use of new and improved ChE inhibitors that produce significantly fewer side effects and greater therapeutic effects than drugs presently being tested for efficacy in the treatment of SDAT patients.

ISSN:0272-4391    

DOI:10.1002/ddr.430120302

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

摘要:

AbstractVarious studies suggest that the 7‐dihydroxypropionyl derivative of forskolin, HP 663, effectively lowers intraocular pressure (IOP) by a novel mechanism. Biochemically, HP 663 stimulates rat striatal adenylate cyclase and displays an affinity for forskolin binding sites similar to that of forskolin. Following topical administration this compound lowers IOP in both New Zealand White (NZW) and Dutch Belt (DB) rabbits. In NZW rabbits, concentrations from 0.05 to 2.0% in a buffered hydroxypropylmethylcellulose (HPMC) vehicle produce significant reductions in outflow pressures of 35–45% for 5–6 hr. Additionally, HP 663 is soluble in this vehicle up to a concentration of 0.25%. As mentioned, HP 663 also reduces IOP in DB rabbits; however, this response is not significant until a concentration of 1% is attained. The effect on aqueous humor inflow was indirectly determined by studying the rate of IOP recovery following rapid i.v. infusion of 20% NaCl. In NZW rabbits, HP 663 significantly reduced aqueous humor inflow as shown by a 40% decrease in the IOP recovery rate compared to control. Tolerance also does not appear to develop to the IOP lowering effects of HP 663 in NZW rabbits. This compound is still capable of significantly lowering IOP following twice daily treatment for 21 consecutive days. Following topical administration of concentrations which effectively lower IOP, HP 663 exhibits no significant effects on heart rate or blood pressure of NZW rabbits. Therefore, this compound does not appear to exhibit a potential for peripheral side effects after topical application. Based on the results of the present study, HP 663 appears to be a potent activator of adenylate cylase and may provide a novel and effective treatment for gla

ISSN:0272-4391    

DOI:10.1002/ddr.430120303

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

摘要:

AbstractThe new potential antipsychotic drug BMY 20661 was subjected to a series of electrophysiological tests to determine its effects on midbrain dopamine (DA) neurons in the rat substantia nigra pars compacta (A9) and ventral tegmental area (A10). Acute intravenous (i.v.) administration of BMY 20661 exerted little effect on the basal spontaneous firing rates of either A9 or A10 DA neurons. Following suppression of DA unit activity by the DA agonist apomorphine (APO), BMY 20661 consistently increased the firing of A10, but not A9, DA cells. However, the rates of A10 DA cells seldom recovered to pre‐APO basal levels following BMY 20661 administration. The ability of BMY 20661 to partially reverse the APO‐induced rate suppression was apparently not due to blockade of DA receptors since pretreatment with BMY 20661 (6.3 mg/kg, i.v.) only slightly (nonsignificantly) reduced the ability of APO to inhibit the firing of A10 cells. Surprisingly, BMY 20661 significantly attenuated the effects of APO on A9 DA cells. These findings suggest that BMY 20661 influences A10 DA neurons by a non‐DA mechanism. Because BMY 20661 has been reported to bind to 5‐HT1A receptors, the acute effects of this compound were compared to those of 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT), a known 5HT1A agonist. These compounds demonstrated similar profiles in their ability to reverse APO‐induced suppression of A10 DA cells but, unlike BMY 20661, 8‐OH‐DPAT was also active on A9 DA cells. Repeated administration of BMY 20661 for 28 days (either 5 or 10 mg/kg/day) failed to alter significantly the number of spontaneously active A10 DA cells but caused a small, but statistically significant, increase in the number of A9 DA cells/track. Because the ability to decrease the number of spontaneously active A10 DA cells has been proposed as a predictive model for antipsychotic drug action, the results obtained following repeated administration of BMY 20661 fail to support a potential antipsychotic pr

ISSN:0272-4391    

DOI:10.1002/ddr.430120304

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

摘要:

AbstractThe cardiostimulatory effects of celiprolol were evaluated in isolated cat cardiac tissue to elucidate the contributions of beta versus alpha adrenoceptor mechanisms. Racemic celiprolol increased the spontaneous rate of cat right atria and the developed tension of paced left hemi‐atria and papillary muscle 44% ± 7%, 36% + 5% and approximately 23% of the maximum response to isoproterenol, respectively. In both left and right atrial preparations, celiprolol (d‐, l‐, and racemic) produced a concentration‐related cardiostimulatory effect. The l‐ and racemic celiprolol were approximately 50 times more potent than the d‐isomer. The cardiostimulatory effects of celiprolol in cat right atria were either not changed, or only slightly reduced, by catecholamine depletion with reserpine or chemical sympathectomy with 6‐hydroxydopamine or by alpha blockade with prazosin (3 × 10−7M) alone or in combination with propranolol. Beta‐1 blockade with atenolol 10−6M alone produced a parallel rightward shift of the celiprolol concentration‐response curve of 1.7 log units. By contrast, beta‐2 blockade with ICI 118, 551 10−6M shifted the celiprolol response curve only 0.6 log units. It is concluded that celiprolol has a limited but significant cardiostimulatory effect in isolated cat cardiac tissue due primarily to a partial agonist action on postsynaptic beta‐1 receptors and does not involve noradrenergic mechanisms

ISSN:0272-4391    

DOI:10.1002/ddr.430120305

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

摘要:

AbstractNonsteroidal antiinflammatory drugs (NSAID) and ethanol can produce gastritis and mucosal hemorrhages in man. We report the potent protective effects of a synthetic prostanoid, Ro 22‐1327, on experimental models of NSAID and ethanol‐induced gastric mucosal injury. Rats were orally administered aspirin (200 mg/kg in 150 mM HCl), indomethacin (80 mg/kg), or absolute ethanol (1 ml) after pretreatment with vehicle or Ro 22‐1327. Oral administration of 10 μg/kg and 100 μg/kg of Ro 22‐1327 significantly (P≤ ·05) protected the gastric mucosa from the corrosive effects of aspirin and ethanol; Ro 22‐1327 protected against indomethacin at a dose of 100 μg/kg. The duration of the protective effect was 90 and 180 min for aspirin and ethanol, respectively. Topical (dermal) application of 100 μg/kg and intraperitoneal injection of 1 μg/kg and 100 μg/kg of Ro 22‐1327 produced significant (P≤ ·01) inhibition of the formation of ethanol‐induced lesions. Orally administered Ro 22‐1327 produced a significant (P≤ ·001) dose‐related (25 μg/kg–225 μg/kg) increase (40–90%) in mean thickness of mucus covering the gastric mucosa. PGE2was less effective than Ro 22‐1327. Ro 22‐1327 produced diarrhea only when administered orally at doses that were 100‐fold greater than the dose required for mucosal protection. The results suggest that this new prostanoid may be useful as adjunctive therapy in rheumatoid arthritic patients susceptible to gastritis and mucosal injury cau

ISSN:0272-4391    

DOI:10.1002/ddr.430120306

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

摘要:

AbstractThe cardiovascular properties of bemarinone (5, 6‐dimethoxy‐4‐methyl‐2‐(1H)‐quinazolinone), a new chemical entity with positive inotropic and vasodilator activity, were investigated. Bemarinone (10−6−10−3M) selectively increased contractile force 144 ± 15% in electrically paced guinea pig left atria while marginally affecting sinus rate (16 ± 13%, peak effect) in spontaneously beating right atria. In anesthetized dogs, bemarinone (0.125–0.875 mg/kg, i.v.) increased myocardial contractile force (21–114%) and left ventricular dP/dtmax(7–45%) in a dose‐related manner. Selective inotropic activity was observed in vivo since no significant change in mean arterial pressure or heart rate occurred at a 50% increase in contractile force (ED50= 0.23 mg/kg). In conscious instrumented dogs, oral administration of bemarinone (2.5–10 mg/kg) produced peak increases in left ventricular dP/dtmaxranging from 28% to 87% (ED50= 3.7 mg/kg). The onset of positive inotropic activity after 10 mg/kg p.o. occurred within 5 min, and the duration exceeded 3 hr. Bemarinone decreased mean arterial blood pressure (0.4–16%) via a reduction in total peripheral resistance. Direct vascular effects were observed in vitro since bemarinone relaxed rabbit aortic strips contracted with phenylephrine or KCl. In an acute model of ischemic left ventricular failure, bemarinone increased cardiac output (41%) and stroke volume (34%) while reducing left ventricular end diastolic pressure (63%) and total peripheral resistance (29%) without significantly changing mean arterial pressure or heart rate. The positive inotropic effect of bemarinone was not antagonized by propranolol and atropine pretreatment. The compound selectively and competitively inhibited cyclic AMP phosphodiesterase fraction III from canine ventricle (Ki= 15.8.μM). In summary, bemari none is an orally active, positive inotropic and vasodilator agent with potential clinical utility in the manage

ISSN:0272-4391    

DOI:10.1002/ddr.430120307

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

摘要:

AbstractThe authors performed a double‐blind study in which 38 inpatients diagnosed as schizophrenic with depressive symptoms were treated with either bupropion and thiothixene or placebo and thiothixene. Of the 36 patients who completed 4 weeks of study treatment, the placebo‐thiothixene treated patients did significantly better than the bupropion‐thiothixene treated patients on BPRS total scores as well as anxiety and depression items. The bupropion‐thiothixene treated patients reported significantly more dry mouth and constipation than the placebo‐thiothixene treated group, whereas the placebo‐thiothixene treated group reported more frequent occurrences of increased appetite, menstrual disturbance, and decreased sex drive. Neither group differed on ratings of pseudoparkinson or dyskinetic signs. The antidepressant bupropion as an adjunct to thiothixene was less effective in the treatment of depressed schizophrenic patients than the antipsychotic alone and appeared to inhibit the therapeutic effects of thiothixene primarily in the depressive symptoms of t

ISSN:0272-4391    

DOI:10.1002/ddr.430120308

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

摘要:

AbstractTwenty patients with primary degenerative dementia participated in a 6‐week, doseranging, double‐blind, placebo‐controlled study of Cl‐911, a cognition activator that enhances performance in animal models of impaired cognition. Cl‐911 was well tolerated in these patients, but it did not result in significant improvement on objective measures of cognition, social functioning, or

ISSN:0272-4391    

DOI:10.1002/ddr.430120309

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

摘要:

AbstractWe gave scopolamine to patients with Alzheimer's disease (AD) and age‐matched control subjects in order to identify which cognitive functions are affected by blocking muscarinic receptors for acetylcholine (ACh). Both subject groups showed dose‐related impairments in verbal learning, and patients with AD exhibited enhanced vulnerability to effects of scopolamine on attentional vigilance. In the same dose range, scopolamine did not alter retrieval from long‐term lexical‐semantic memory or performance on a test of visual discrimination, suggesting that cholinergic neurotransmission is not critical for these cognitive functions. The importance of cholinergic transmission in learning and attention is confirmed by this study, and the results indicate that both these abilities should be measured in investigations of potential cholinergic treatments

ISSN:0272-4391    

DOI:10.1002/ddr.430120310

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

摘要:

AbstractClonidine (0.03–0.06 mg/kg), in a dose‐ and delay‐dependent manner impaired the ability of aged rhesus monkeys to perform a microcomputer‐controlled delayed response test similar to that used previously by Bartus et al. (J. Gerontol.33:858–871, 1978). These doses of clonidine produced overt sedation, increased response latencies and decreased the percentage of correct responses. Continued disruption of delayed response performance was seen during 11 days of repeated daily clonidine (0.04 mg/kg) administration. Performance immediately returned to preexisting baseline levels on the day following cessation of this repeated drug regimen. In addition, repeated clonidine administration did not alter responsivity to acutely administered clonidine, suggesting that tolerance did not develop rapidly to the disruptive effects of this agent. These data indicate that clonidine impairs delayed response performance in aged rhesus monkeys under these testing c

ISSN:0272-4391    

DOI:10.1002/ddr.430120311

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY