Cholinergic Side Effects Research Articles

The Effects of Donepezil and Neostigmine in a Patient with Unusual Pseudocholinesterase Activity

The Effects of Donepezil and Neostigmine in a Patient with Unusual Pseudocholinesterase Activity

Muscarinic agonists with antipsychotic-like activity: structure-activity relationships of 1,2,5-thiadiazole analogues with functional dopamine antagonist activity.

Muscarinic agonists were tested in two models indicative of clinical antipsychotic activity: conditioned avoidance responding (CAR) in rats and inhibition of apomorphine-induced climbing in mice. The standard muscarinic agonists oxotremorine and pilocarpine were both active in these tests but showed little separation between efficacy and cholinergic side effects. Structure-activity relationships of the alkylthio-1,2,5-thiadiazole azacyclic type muscarinic partial agonists are shown, revealing the exo-6-(3-propyl/butylthio-1,2, 5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane analogues (4a,b and 9a, b) to be the most potent antipsychotic agents with large separation between efficacy and cholinergic side effects. The lack of enantiomeric selectivity suggests the pharmacophoric elements are in the mirror plane of the compounds. A model explaining the potency differences of closely related compounds is offered. The data suggest that muscarinic agonists act as functional dopamine antagonists and that they could become a novel treatment of psychotic patients.

Xanomeline compared to other muscarinic agents on stimulation of phosphoinositide hydrolysis in vivo and other cholinomimetic effects

Activation of muscarinic m1 receptors which are coupled to the phosphoinositide (PI) second messenger transduction system is the initial objective of cholinergic replacement therapy in Alzheimer's disease. Thus, we evaluated the ability of the selective muscarinic receptor agonist (SMRA) xanomeline to stimulate in vivo phosphoinositide (PI) hydrolysis and compared it to a number of direct acting muscarinic agonists, two cholinesterase inhibitors and a putative m1 agonist/muscarinic m2 antagonist. Using a radiometric technique, it was determined that administration of xanomeline robustly stimulated in vivo PI hydrolysis and the effect was blocked by muscarinic antagonists, demonstrating mediation by muscarinic receptors. The non-selective muscarinic agonists pilocarpine, oxotremorine, RS-86, S-aceclidine, but not the less active isomer R-aceclidine, also effectively stimulated PI hydrolysis in mice. Amongst the putative m1 agonists, thiopilocarpine, hexylthio-TZTP as well as xanomeline effectively stimulated PI hydrolysis, but milameline, WAL 2014, SKB 202026 and PD 142505 did not significantly alter PI hydrolysis. Furthermore, WAL 2014 and SKB 202026 inhibited agonist-induced PI stimulation, suggesting that they act as antagonists at PI-coupled receptors in vivo. The cholinesterase inhibitors, tacrine and physostigmine, and the mixed muscarinic m1 agonist/m2 antagonist LU25-109 did not activate in vivo PI hydrolysis. Xanomeline, hexylthio-TZTP and thiopilocarpine were relatively free of cholinergic side effects, whereas milameline, WAL 2014 and SKB 202026 produced non-selective effects. Therefore, these data demonstrate that xanomeline selectively activates in vivo PI hydrolysis, consistent with activation of biochemical processes involved in memory and cognition and xanomeline's beneficial clinical effects on cognition in Alzheimers patients.

Milnacipran, a new specific serotonin and noradrenaline reuptake inhibitor.

Milnacipran is a new antidepressant which inhibits equipotently the reuptake of serotonin and noradrenaline both in vitro and in vivo with no effect on dopamine reuptake. Microdialysis studies have shown increased extracellular levels of both serotonin and noradrenaline after acute administration. Milnacipran is devoid of interactions at any known neurotransmitter receptor. In particular, and unlike tricyclic antidepressants (TCAs), it has no activity at noradrenergic, muscarinic or histaminergic receptors. Contrary to TCAs, chronic administration of milnacipran does not modify beta-adrenoceptor binding or second messenger function. Milnacipran is active on various animal models of depression such as the forced swimming test in the mouse, learned helplessness in the rat and the olfactory bulbectomized rat model. Milnacipran has a high bioavailability, low plasma protein binding, and is largely eliminated in the urine as the parent drug or as a glucuronide. These features suggest that interactions with other drugs given concurrently are unlikely. Studies in patients with liver dysfunction and in the elderly suggest that dose adjustment is not necessary. In patients with renal impairment, decreased elimination of milnacipran is correlated to the degree of renal impairment allowing an easy dosage adjustment. An intermediate half-life of approximately 8 h is compatible with twice-daily administration. Clinical studies comparing milnacipran, placebo and other antidepressants provide evidence of its efficacy in moderate to severe depression in both hospitalized and outpatient settings. Meta-analyses of the original data of controlled trials comparing milnacipran with imipramine or selective serotonin reuptake inhibitors (SSRIs) show that milnacipran provides antidepressant efficacy similar to that of TCAs and significantly superior to that of SSRIs. An analysis of a database of over 3300 patients shows that both the general and cardiovascular tolerability of milnacipran are superior to those of TCAs with notably less cholinergic side effects. The tolerance of milnacipran was comparable to that of SSRIs with a higher incidence of dysuria with milnacipran but a higher frequency of nausea and anxiety with the SSRIs. Milnacipran represents an interesting new therapeutic option in depression, being as well tolerated as the SSRIs but offering clinical efficacy similar to the TCAs.

Enhanced performance of spatial and visual recognition memory tasks by the selective acetylcholinesterase inhibitor E2020 in rhesus monkeys

Hepatotoxicity limits the clinical utility of the cholinesterase inhibitor tacrine as a palliative therapy for Alzheimer's disease. The present studies examined the effects of E2020, a selective acetylcholinesterase inhibitor not associated with liver toxicity in man, on cognitive performance in rhesus monkeys using tasks employed previously to evaluate tacrine and other cholinomimetic agents. The ability of E2020 to prevent the induction of a cognitive impairment by the muscarinic receptor antagonist scopolamine was assessed using an automated spatial delayed response task. Coadministration of E2020 (0.5-1.75 mg/kg) caused a dose-dependent reversal of the scopolamine (0.03 mg/kg) induced impairment observed after retention intervals of 10 and 20 s. At the highest dose of E2020 examined (1.75 mg/kg), choice accuracy approached normal control levels. In this dose range, E2020 was well tolerated, but at the higher dose of 2 mg/kg, cholinergic side-effects were apparent. The effect of E2020 on choice accuracy in a visual recognition task was also assessed as this task does not require the use of scopolamine to disrupt performance and beneficial effects of cholinomimetics can therefore be detected at lower doses than in the spatial memory paradigm. In this task, administration of E2020 increased choice accuracy from 59 +/- 1% correct to up to 71 +/- 2% at doses of 0.03 and 0.05 mg/kg. No observable adverse effects were induced by E2020 in this dose range. The ability of E2020 to improve performance in these cognitive tasks resembles the profile of other cholinesterase inhibitors, including tacrine, that also improve cognitive function in Alzheimer's disease patients. Because of its more favourable clinical safety profile, E2020 may provide a significantly improved palliative therapy for dementia.

Milnacipran, a new serotonin and noradrenaline reuptake inhibitor: an overview of its antidepressant activity and clinical tolerability.

Milnacipran (Ixel) is a new antidepressant with essentially equal potency for inhibiting the reuptake of both serotonin and noradrenaline, with no affinity for any neurotransmitter receptor studied. A review of the studies comparing milnacipran, placebo and active comparator antidepressants provides clear-cut evidence of its efficacy in both severe and moderate depression in hospitalized and community settings. Meta-analyses of the original data of controlled trials involving 1032 patients, comparing milnacipran with imipramine or selective serotonin reuptake inhibitors (SSRIs), show that milnacipran provides antidepressant efficacy similar to that of imipramine and significantly superior to that of the SSRIs. An analysis of a database of over 3300 patients shows that both the general and cardiovascular tolerability of milnacipran are superior to those of the tricyclic antidepressants (TCAs) with fewer cholinergic side-effects. The tolerability of milnacipran was comparable to that of the SSRIs, with a higher incidence of dysuria with milnacipran, and a higher frequency of nausea and anxiety with the SSRIs. Milnacipran is a new therapeutic option in depression, which offers a clinical efficacy in the range of the TCAs combined with a tolerability equivalent to that of the SSRIs.

Behavioural evaluation of cholinergic drugs.

Alzheimer's disease involves progressive degeneration of the cortex and the limbic system. Loss of afferent forebrain neurochemical modulatory systems is also seen, most significantly of the basal forebrain cholinergic system. Drug discovery programmes have pursued enhancement of forebrain muscarinic function as a therapeutic target. The most promising muscarinic agonists described achieve functional selectivity as agonists as the M1/M3 receptors in the CNS and M2 antagonists. These compounds have fewer cardiac and other cholinergic side effects. In rodent and monkey models of reference and working memory, these compounds reverse the cognitive impairment induced with plopolamine. Acetylcholinesterase inhibitors are even more efficacious in these models.

Xanomeline: A selective muscarinic agonist for the treatment of Alzheimer's disease

Xanomeline is a novel muscarinic receptor agonist relatively devoid of parasympathomimetic side effects. Xanomeline had high affinity for muscarinic receptors and much lower affinity for a variety of other neuronal receptors in radioligand binding assays. Functional studies in cell lines transfected with the muscarinic receptor subtypes demonstrated that xanomeline had higher potency and efficacy for m1 and m4 receptors than m2, m3, and m5 receptor subtypes. Similarly, in isolated tissue studies, xanomeline had higher potency and efficacy for M1 receptors in rabbit vas deferens than at M2 receptors in guinea pig atria or M3 receptors in guinea pig bladder. Secretion of soluble amyloid precursor protein from m1 cell lines was potently stimulated by xanomeline. In vivo, xanomeline robustly stimulated phosphoinositide hydrolysis in brain, consistent with m1 agonism. Xanomeline produced modest increases in brain acetylcholine levels and did not produce bradycardia, suggesting little, if any, m2 agonist activity in vivo. Additionally, xanomeline did not induce nonselective cholinergic agonist side effects such as tremor, hypothermia and salivation. In animal behavior studies, xanomeline reduced locomotion and blocked memory deficits that were induced by a muscarinic antagonist in a passive avoidance paradigm. Xanomeline was found to be safe and reasonably well tolerated in safety studies in humans. In a placebo controlled double blind clinical trial of 6 months duration, xanomeline halted cognitive decline in patients with Alzheimer's disease. Furthermore, behavioral symptoms associated with Alzheimer's disease such as hallucinations, delusions and vocal outbursts were significantly decreased by xanomeline treatment. Additional clinical trials are under way to assess the novel therapeutic effects of xanomeline. Drug Dev. Res. 40:158–170, 1997. © 1997 Wiley-Liss, Inc.

Development of a pharmacological target profile for muscarinic agonists

The purpose of these studies was to determine the levels of intrinsic activity in vitro at muscarinic receptor pharmacological subtypes (M1, M2, and M3) that would optimize cognitive activity while minimizing acute adverse cholinergic effects in vivo. These levels of intrinsic efficacy at M1, M2, and M3 receptor subtypes, the target profile, could then be used to assess novel compounds for antidementia potential. To accomplish this, a series of muscarinic agonists (spirofuranone analogues) was prepared, and compounds with variable intrinsic activity at M1, M2, and M3 receptor subtypes were selected for characterization in a series of in vivo tests (reversal of scopolamine-induced memory impairment, and agonist-induced salivation, lacrimation, diarrhea, hypothermia, and bradycardia). Memory enhancement was found to correspond best to M1 activity with an apparent threshold of intrinsic activity of approximately 50% in human M1-transfected CHO cells. Surprisingly, a preferential M3 agonist (ARL 16037) produced a partial reversal of scopolamine-induced memory impairment, but only at high doses that resulted in severe diarrhea. However, it was unclear whether this memory effect was due to the weak M1 or strong M3 agonist activity of this compound. Three muscarinic agonists (ARL 14995, ARL 15467, and ARL 15424) reversed the scopolamine-induced memory deficits, as well as the cholinesterase inhibitor tacrine, suggesting that muscarinic agonists may be at least as clinically effective as cholinesterase inhibitors. Acute cholinergic side effects (diarrhea, salivation, lacrimation) corresponded best to M3 activity (contraction of guinea pig trachea) and were greatly diminished with in vitro intrinsic M3 activity of 50% or less. Agonist-induced heart rate reduction corresponded best to M2 receptor efficacy (inhibition of rat heart adenylyl cyclase). Identification of compounds without detectable in vitro intrinsic activity but with measurable heart rate effects suggested that signal amplification at M2 receptors in vitro limited detection of weak partial agonists. Development of the target profile has proven useful in rapid evaluation of compounds for optimization of muscarinic pharmacological properties. Drug Dev. Res. 40:117–132, 1997. © 1997 Wiley-Liss, Inc.

Double-blind placebo-controlled study of velnacrine in Alzheimer's disease

The present study assessed the safety and efficacy of the cholinesterase inhibitor, velnacrine, for treating the cognitive symptoms of Alzheimer's disease. Patients (N = 236) meeting NINCDS-ADRDA criteria for Alzheimer's disease entered a double-blind, placebo-controlled dose-ranging protocol (30, 75, 150, 225 mg/day each for one week) to identify velnacrine responders (≥ four point improvement on the cognitive subscale of the Alzheimer's Disease Assessment Scale [ADAScog]). After a two week drug washout, velnacrine responders were randomly assigned to their best velnacrine dose or placebo in a six week dose-replication protocol employing the ADAScog and the Clinical Global Improvement scale as primary outcome measures. During dose-replication, intent-to-treat analysis revealed that velnacrine patients scored significantly better than placebo patients on the ADAScog after two (p < 0.004), four (p < 0.025) and six (p < 0.001) weeks of treatment. No significant treatment effect on Clinical Global Improvement scores was observed. The primary adverse event was an asymptomatic elevation of liver transaminases found among 28% of the 236 treated patients. Cholinergic side effects including diarrhea (14%), nausea (11%) and vomiting (5%) were observed and 8% of patients experienced skin rash. The present study identified a subgroup of Alzheimer's patients who demonstrated a significant, but modest, improvement during velnacrine treatment on structured cognitive testing.

Arecoline reverses dexamethasone suppression of cortisol in normal males: A pilot study

Six normal controls participated in two or three individual, intravenous challenges (each separated by 1 week) of saline or one of two doses of arecoline at 8 AM following ingestion of 1 mg dexamethasone at 12 midnight the previous evening. Individuals differed in their subjective and neuroendocrine responses to arecoline. At 2.1 micrograms/kg (n = 4) or 2.8 micrograms/kg (n = 1), four of five subjects evidenced dexamethone suppression test (DST) nonsuppression, which followed the rise in prolactin. Cholinergic side effects and nausea were minimal. At a dose of 4.2 micrograms/kg, four of five subjects evidenced cortisol escape from dexamethasone suppression, which was associated with a substantial rise in prolactin, some subjective cholinergic symptoms, and little to modest nausea. These data are consistent with the notion that cholinergic mechanisms are involved in the escape from dexamethasone suppression. Further, arecoline may be preferable to physostigmine as a cholinergic agonist, since it appears less likely to cause marked cholinergic side effects and significant nausea.

Effect of MDL 73,745 on acetylcholine and biogenic amine levels in rat cortex

We postulate that the effect of cholinesterase inhibitors to ameliorate the cholinergic deficit in Alzheimer's disease is related to their ability to maintain long-lasting, non-toxic steady-state levels of acetylcholine in cortex. We investigated the effect of the cholinesterase inhibitor, MDL 73,745 (2,2,2-trifluoro-1-(3-trimethylsilylphenyl)ethanone), on the extracellular levels of acetylcholine, norepinephrine, dopamine and 5-hydroxytryptamine in the cerebral cortex of the rat by high-performance liquid chromatography coupled with electrochemical detection. The drug significantly increased acetylcholine levels above the baseline at 2 and 10 mg/kg s.c., but not at the 1 mg/kg dose. At both 2 and 10 mg/kg, there was a good correlation between cholinesterase inhibition and acetylcholine increase in cortex. At the 2 and 10 mg/kg doses, the maximal cholinesterase inhibition was 64% and 77%, respectively, and the increase in acetylcholine release was 481% and 1016%, respectively. Norepinephrine and dopamine, but not 5-hydroxytryptamine levels, were also significantly increased by the 10 mg/kg dose. The increases of norepinephrine and dopamine levels reached a maximum of 124% and 370%, respectively, and continued for a period of at least 8 h. Cholinergic side-effects were most marked at the 10 mg/kg dose but were also noticeable at the 2 mg/kg dose in the form of fasciculations, tremor and splay.

Intravesical oxybutynin in patients with posterior rhizotomies and sacral anterior root stimulators.

This report investigates the use of intravesical oxybutynin in spinal injury patients, who have had dorsal rhizotomies to abolish reflex detrusor activity and void with S2, S3, and S4 stimulation, done with the Brindley anterior root stimulator. Six male patients (age range 27 to 56, mean 36 years) who have had Brindley anterior root stimulators implanted were included in this study. Video urodynamic assessment was done and 10 mg of oxybutynin hydrochloride was instilled through the urethral catheter. This was left in the bladder for 60 minutes and video urodynamics were repeated. Voiding, both pre and post oxybutynin, was achieved with sacral root stimulation. Peak detrusor pressure (Pves) during voiding in the 6 patients before oxybutynin instillation was 89, 154, 90, 60, 56, and 80 (mean 88.2) cm of water. Post oxybutynin the pressures were 83, 163, 95, 40, 30, and 68 (mean 79.8) cm of water. The peak flow rate (Qmax) pre oxybutynin was 32, 24, 20, 20, 12, and 28 (mean 22.7) ml per second and this changed to 28, 31, 18, 24, 10, and 32 (mean 23.8) ml per second. This shows no difference in the detrusor pressure (P = 0.2) and flow rate (P = 0.54) pre and post oxybutynin instillation into the bladder. Effectiveness of oxybutynin is attributed to a combination of M3 receptor antagonism in the smooth muscle and direct spasmolytic, local anaesthetic and calcium channel blocking action. Its therapeutic benefit is limited by the anti cholinergic side effects (40-80%) and recent studies have shown the intravesical route to be effective and better tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)

Bioisosteres of arecoline: 1,2,3,6-tetrahydro-5-pyridyl-substituted and 3-piperidyl-substituted derivatives of tetrazoles and 1,2,3-triazoles. Synthesis and muscarinic activity.

A series of arecoline bioisosteres, where the ester group is replaced by a 1,2,3-triazole-4-yl or a tetrazole-5-yl group, was synthesized and evaluated in vitro for affinity and efficacy at muscarinic receptors and in vivo for cholinergic side effects. The corresponding piperidine derivatives were also studied. In the 1,2,3,6-tetrahydropyridyl-1,2,3-triazole series, only derivatives with 2-substituents in the 1,2,3-triazole ring exert muscarinic agonist activity. The same trend is seen in the corresponding tetrazole series, where only 2-substituted derivatives display muscarinic agonist activity. The methyl derivatives in both series are full agonists, whereas the derivatives with longer side chains are partial agonists. Introduction of methyl substituents in the 1,2,3,6-tetrahydropyridine ring generally lowers affinity considerably except for the 3-substituted derivatives, where some activity is retained. In both the 1,2,3-triazole and tetrazole series, derivatives without substituents at the basic nitrogen in the 1,2,3,6-tetrahydropyridine ring are unselective full agonists, whereas the methyl-substituted derivatives generally are more M1 selective compared to M2. Larger substituents than methyl abolish activity. The 4-(3-piperidyl)-1,2,3-triazole and 5-(3-piperidyl)-2H-tetrazole derivatives are generally less active than the corresponding 1,2,3,6-tetrahydropyridine derivatives, and only the 2-allyl- and 2-propargyl-1,2,3-triazole derivatives display activities comparable to the most active compounds in the 1,2,3,6-tetrahydropyridine series. The propargyl derivative is an unselective full agonist, and resolution did not reveal any stereoselectivity The allyl derivative is a partial agonist with some selectivity for the M1 receptor, and testing of the enantiomers showed that the (+)-enantiomer is an unselective partial agonist, whereas the (-)-enantiomer is a partial agonist with preference for the M1 receptor. Generally, the structure-activity relationships of the 1,2,3-triazole and tetrazole series are very similar, and two compounds, 2-ethyl-4-(1-methyl-1,2,3,6-tetrahydro-5-pyridyl)-1,2,3-triazole and 2-ethyl-5-(1-methyl-1,2,3,6-tetrahydro-5-pyridyl)-2H-tetrazole, are M1 agonists/M2 antagonists. Muscarinic compounds with this profile are of particular interest as drugs for the treatment of Alzheimer's disease.

Pyridostigmine potentiates growth hormone (GH)-releasing hormone-induced GH release in both men and women.

It has been recently reported that pyridostigmine (PD), an indirect cholinergic agonist, probably acting via inhibition of hypothalamic somatostatin, potentiates the GH-releasing hormone (GHRH)-induced GH rise in men, but not in women. The aim of this study was to verify the sex-related, if any, GH response to GHRH (1 microgram/kg, i.v., as a bolus) both alone and preceded by two different doses of PD (120 mg, group A, and 60 mg, group B, given orally 60 min before GHRH) in a large group of volunteers (36 women, aged 18-35 yr, and 48 men, aged 18-35 yrs). In group A, 120 mg oral PD potentiated the GH response to GHRH in both men [area under the curve (AUC), 2579.3 +/- 264.5 vs. 806.2 +/- 99.7 micrograms/L.h; P < 0.00001] and women (AUC, 2273.2 +/- 248.7 vs. 792.6 +/- 72.7 micrograms/L.h; P < 0.00001). Similarly, in the group B, 60 mg oral PD potentiated the GH response to GHRH in both men (AUC, 1929.6 +/- 157.2 vs. 568.2 +/- 81.3 micrograms/L.h; P < 0.01) and in women (AUC, 1655.9 +/- 146.9 vs. 738.2 +/- 105.7 micrograms/L.h; P < 0.01). The GH responses to GHRH, both alone and after 120 and 60 mg oral PD, did not significantly differ in men and women. No sex-related difference was observed in the cholinergic side-effects (mild abdominal pain and muscle fasciculations) that occurred in nearly 30% of the subjects. In conclusion, our results clearly show that there is no sex-related difference in the potentiating effect of PD on GHRH-induced GH release, ruling out the suggestion that women have increased cholinergic activity, leading to reduced somatostatinergic tone.

An evaluation of the efficacy and safety of tetrahydroaminoacridine (THA) without lecithin in the treatment of Alzheimer's disease.

Seventy-nine patients with probable Alzheimer's disease were enrolled into a double-blind, placebo-controlled cross-over study to assess the therapeutic effect and safety of THA (tetrahydroaminoacridine; tacrine) without concomitant lecithin administration. Forty-one patients completed the trial which consisted of two 12-week treatment phases separated by a 4-week wash-out period. Twenty-six subjects were withdrawn during the active treatment phase, mostly because of elevated transaminases or cholinergic side-effects, and ten during treatment with placebo. Statistical analyses were conducted on two groups of patients; those completing the cross-over and those with at least one evaluation in the first treatment period. This latter analysis, using the last observation carried forward was used to approximate an intention-to-treat analysis. THA was favoured over placebo in all three primary outcome measures (MMSE, ADAS Non-cognitive Scale, and the Functional Life Scale), but the results did not reach statistical significance. THA was favoured over placebo in five of the seven secondary outcome measures, but for only two of these was statistical significance attained. In terms of a three-point or greater increase in MMSE score, three to four times as many subjects improved on THA as on placebo.

Pharmacological and Biochemical Assessment of SM-10888, a Novel Cholinesterase Inhibitor

The effects of the compound SM-10888 (9-amino-8-fluoro-1,2,3,4,-tetrahydro-2,4-methanoacridine citrate) in a number of pharmacological and biochemical tests were studied and compared to those of tacrine (THA), amiridin, HP-029 and physostigmine. SM-10888 inhibited cholinesterase activity (IC50: 2.3×10-7 M) in rat cortical P2 fraction with almost the same potency as THA, while SM-10888 was 2-4 times more potent than amiridin and HP-029, but about 10 times less potent than physostigmine. When given to mice p.o., SM-10888 induced central (hypothermia) and peripheral (salivation) cholinergic effects. When the ratio of the ED50 value for hypothermia to that for salivation was regarded as the index of the selectivity to the central nervous system (CNS), SM-10888 was shown to be about 3 times more selective to the CNS than the other four drugs in mice. The minimum effective dose of SM-10888 for its increasing effect on acetylcholine (ACh) content in the mouse cerebral cortex was about 10 times higher than that of physostigmine, but 5-10 times lower than those of THA, amiridin and HP-029. These results suggest that SM-10888 is an adequate drug for increasing the brain ACh content with less peripheral cholinergic side effects than THA, amiridin, HP-029 and physostigmine.

Cholinomimetic activities of minaprine.

The cholinomimetic activities of the antidepressant drug minaprine have been investigated, in vitro and in vivo, in rodents. Minaprine, and its metabolite SR 95070B [3-(2-morpholinoethylamino)-4-methyl-6-(2-hydroxyphenyl) pyridazine hydrochloride] selectively displaced [3H]-pirenzepine from its cortical and hippocampal binding sites, and only weakly inhibited the binding of [3H]-N-methylscopolamine in either the rat cerebellum, heart and salivary glands, or the guinea-pig ileum. In mice, none of these drugs induced the typical cholinergic side-effects up to lethal doses. Minaprine and SR 95070B antagonized rotations induced by an intrastriatal injection of pirenzepine in mice, after intraperitoneal and/or oral administration. Minaprine also antagonized atropine-induced mydriasis in mice. Both minaprine and SR 95070B potentiated the tremorigenic effect of oxotremorine without inducing tremor when injected alone. Finally, minaprine and SR 95070B, after parenteral and/or oral injection, antagonized the scopolamine-induced deficit in passive avoidance learning, and enhanced short-term retention in the social memory test, in rats. The muscarinic agonists arecoline, oxotremorine and RS 86 [2-ethyl-8-methyl-2,8 diazaspiro-4,5 decan-1,3 dion hydrobromide], as well as the acetylcholine esterase inhibitors physostigmine and tacrine were active in most of these models. These results indicate that minaprine, and its metabolite SR 95070B, have cholinomimetic activities which could be, at least in part, mediated by their selective affinity for M1 muscarinic receptors. Thus minaprine could represent a potential useful drug for the treatment of senile dementias and cognitive impairments occurring in elderly people.

Clinical experience with and side-effects of tacrine hydrochloride in Alzheimer's disease: a pilot study.

Pharmacological manipulation of central cholinergic neurotransmission may prove beneficial in the treatment of Alzheimer's disease (AD). Tacrine hydrochloride is a central anticholinesterase which has been said to improve intellectual function in patients with AD. We report here our clinical experience with this drug in eight patients with AD, diagnosed according to DSM III and NINCDS-ADRDA criteria. Cholinergic side-effects occurred in five patients, three of whom tolerated a reduced dose. Liver function tests rose within the normal range in all patients and became abnormal in one.

The Tensilon test using a three-way stopcock and double syringe.

The use of Tensilon (edrophonium chloride) is important in the diagnostic evaluation of many ptosis patients. A three-way stopcock with double syringe allows concomitant administration of atropine to counteract the cholinergic side effects of edrophonium.