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Biomedical subjects

G Crosby

Publications and source records attributed to G Crosby.

At least 19 recordsLinked to original sources
PubMed2001

SCH 57790, a selective muscarinic M(2) receptor antagonist, releases acetylcholine and produces cognitive enhancement in laboratory animals.

The present studies were designed to assess whether the novel muscarinic M(2) receptor antagonist 4-cyclohexyl-alpha-[4[[4-methoxyphenyl]sulphinyl]-phenyl]-1-piperazineacetonitrile (SCH 57790) could increase acetylcholine release in the central nervous system (CNS) and enhance cognitive performance in rodents and nonhuman primates. In vivo microdialysis studies show that SCH 57790 (0.1-10 mg/kg, p.o.) produced dose-related increases in acetylcholine release from rat hippocampus, cortex, and striatum. SCH 57790 (0.003-1.0 mg/kg) increased retention times in young rat passive avoidance responding when given either before or after training. Also, SCH 57790 reversed scopolamine-induced deficits in mice in a passive avoidance task. In a working memory operant task in squirrel monkeys, administration of SCH 57790 (0.01-0.03 mg/kg) improved performance under a schedule of fixed-ratio discrimination with titrating delay. The effects observed with SCH 57790 in behavioral studies were qualitatively similar to the effects produced by the clinically used cholinesterase inhibitor donepezil, suggesting that blockade of muscarinic M(2) receptors is a viable approach to enhancing cognitive performance.

Acetylcholine↗
PubMed2001

Metabolic stabilization of benzylidene ketal M(2) muscarinic receptor antagonists via halonaphthoic acid substitution.

The potential toxicological liabilities of the M(2) muscarinic antagonist 1 were addressed by replacing the methylenedioxyphenyl moiety with a p-methoxyphenyl group, resulting in M(2) selective compounds such as 3. Several halogenated naphthamide derivatives of 3 were studied in order to improve the pharmacokinetic profile via blockage of oxidative metabolism. Compound 4 demonstrated excellent M(2) affinity and selectivity, human microsomal stability, and oral bioavailability in rodents and primates.

Acetylcholine↗
PubMed2001

Facilitation of acetylcholine release and improvement in cognition by a selective M2 muscarinic antagonist, SCH 72788.

Current treatment of Alzheimer's Disease (AD) requires acetylcholinesterase inhibition to increase acetylcholine (ACh) concentrations in the synaptic cleft. Another mechanism by which ACh levels can be increased is blockade of presynaptic M2 muscarinic autoreceptors that regulate ACh release. An antagonist designed for this purpose must be highly selective for M2 receptors to avoid blocking postsynaptic M1 receptors, which mediate the cognitive effects of ACh. Structure-activity studies of substituted methylpiperadines led to the synthesis of 4-[4-[1(S)-[4-[(1,3-benzodioxol-5-yl)sulfonyl]phenyl]ethyl]-3(R)-methyl-1-piperazinyl]-4-methyl-1-(propylsulfonyl)piperidine. This compound, SCH 72788, binds to cloned human M2 receptors expressed in CHO cells with an affinity of 0.5 nM, and its affinity at M1 receptors is 84-fold lower. SCH 72788 is a functional M2 antagonist that competitively inhibits the ability of the agonist oxotremorine-M to inhibit adenylyl cyclase activity. In an in vivo microdialysis paradigm, SCH 72788 increases ACh release from the striatum of conscious rats. The compound is also active in a rodent model of cognition, the young rat passive avoidance response paradigm. The effects of SCH 72788 suggest that M2 receptor antagonists may be useful for treating the cognitive decline observed in AD and other dementias.

Acetylcholine↗
PubMed2000

Benzylidene ketal derivatives as M2 muscarinic receptor antagonists.

Benzylidene ketal derivatives were investigated as selective M2 receptor antagonists for the treatment of Alzheimer's disease. Compound 10 was discovered to have subnanomolar M2 receptor affinity and 100-fold selectivity against other muscarinic receptors. Also, 10 demonstrated in vivo efficacy in rodent models of muscarinic activity and cognition.

Acetylcholine↗
PubMed2000

Diphenyl sulfoxides as selective antagonists of the muscarinic M2 receptor.

Structure activity studies on [4-(phenylsulfonyl)phenyl]methylpiperazine led to the discovery of 4-cyclohexyl-alpha-[4-[[4-methoxyphenyl(S)-sufinyl]phenyl]-1-pi perazineacetonitrile, 1, an M2 selective muscarinic antagonist. Affinity at the cloned human M2 receptor was 2.7 nM; the M1/M2 selectivity is 40-fold.

Acetylcholine↗
PubMed2000

Diphenylsulfone muscarinic antagonists: piperidine derivatives with high M2 selectivity and improved potency.

Piperidine analogues of our previously described piperazine muscarinic antagonists are described. Piperidine analogues show a distinct structure-activity relationship (SAR) that differs from comparable piperazines. Compounds with high selectivity and improved potency for the M2 receptor have been identified. The lead compound, 12b, increases acetylcholine release in vivo. Compounds of this class may be useful for the treatment of cognitive disorders such as Alzheimer's disease (AD).

Acetylcholine↗
PubMed1999

Halothane effect on formalin-induced paw edema and flinching in rat.

The formalin test is a model of injury-produced inflammatory pain. Anesthetics, in clinically relevant concentrations, affect neutrophils and immune suppression. This study was to determine whether halothane reliably inhibits inflammatory reaction and formalin induced pain behavior or does not. Rats were exposed to 100% oxygen (control) or halothane, respectively for 30 min and then 24 hr later five percent formalin test was assessed. The base values of the paw's diameter were obtained earlier, and then formalin induced edema was assessed by measuring diameters of the injected paws at 5 min, 1 hr, 4 hr and 24 hr after the injection. Nociceptive behavior was quantified by counting the number of times with the paw flinched at 5 min intervals for 60 min. The diameters of edema in the halothane group lessened more than those in the oxygen group at 1 and 24 hr in each following of the injection (p<0.05). The rats pre-administered with oxygen or halothane were similar appearances in nociceptive behaviors. It suggests that halothane anesthesia might inhibit slightly the inflammatory reaction with the formalin-induced edema but might not inhibit the formalin-induced pain behavior in the event of pre-administration halothane 24 hr earlier before the formalin test of rat.

Anesthetics, Inhalation↗
PubMed1998

Skin and soft tissue infections: development of a collaborative management plan between community and hospital care.

The commonest indication in the US for referral to an outpatient/home i.v. antibiotic therapy programme is the management of skin and soft tissue infections. In the UK, however, these infections account for 10% or more of admissions to infection units. The main indication for hospitalisation is to receive parenteral antibiotics. A retrospective audit of one year of admissions to a regional infection unit revealed that, although most of these patients do not progress to complications ('low risk'), they occupy a mean time of five days in hospital and for nearly half of that time they receive parenteral antibiotics. This period in hospital reflected 11.4% of the unit's bed occupancy. Even if 75% of these patients were treated in the community with parenteral therapy, this would result in bed savings of 8.55%, nearly one-tenth of the unit's occupied capacity. This type of audit should help key decision makers thinking of developing similar services in their region. Outpatient or home parenteral antimicrobial therapy (OHPAT) should be delivered as part of a complete disease management programme in collaboration with primary care.

Algorithms↗
PubMed1996

Volatile anaesthetics antagonize nitrous oxide and morphine-induced analgesia in the rat.

We reported previously that nitrous oxide induces pre-emptive analgesia that is partially antagonized by naloxone and totally antagonized by halothane. The aims of this study were to determine if halothane and isoflurane are similar in this respect and to examine if volatile anaesthetics antagonize the analgesic effect of exogenous opioids. We found that 75% nitrous oxide prolonged tail-flick latency by 37% and this analgesia was dose-dependently inhibited by halothane and, less effectively, by isoflurane. In contrast, morphine 1.25 mg kg-1 i.v. also prolonged tail-flick latency by 35% but, unlike nitrous oxide-induced analgesia, this effect was attenuated only by high doses of halothane and was unaffected by isoflurane. Neither halothane nor isoflurane alone altered the tail-flick response. We conclude that both halothane and isoflurane dose-dependently antagonized nitrous oxide analgesia but antagonized morphine-induced analgesia to a lesser extent.

Analgesics, Non-Narcotic↗
PubMed1996

Exacerbation or unmasking of focal neurologic deficits by sedatives.

BACKGROUND: Transient focal neurologic deficits have been observed in patients emerging from brain tumor or carotid surgery, and a pharmacologic effect of anesthetic agents has been proposed as the cause of such neurologic dysfunction. Therefore, the effect of sedation with midazolam or fentanyl on motor neurologic function was studied prospectively and preoperatively in patients with carotid disease or mass lesions of the brain. METHODS: Fifty-four unpremedicated adult patients with carotid disease or a brain tumor were given small intravenous doses of either 2.8 +/- 1.3 mg midazolam or 170 +/- 60 micrograms fentanyl in the preoperative period. A thorough motor examination was performed at baseline and after sedation by an individual who was unaware of the details of the patient's disease or symptoms. A mental status examination also was performed to control for the effects of inattentiveness or lack of cooperation during the neurologic examination. RESULTS: Patients were sedated mildly but were fully cooperative. Focal motor deterioration occurred after sedation in 30% of patients, and the incidence was similar in patients in the fentanyl and midazolam groups. Among patients with a focal motor abnormality on baseline examination or a resolved prior motor deficit, 73% had exacerbation or unmasking of these signs by sedation, whereas no patient without a prior history of motor dysfunction had a sedative-induced change. Sedative-induced changes in neurologic function ranged from unilateral mild weakness to complete plegia, but appeared to be transient in nature. CONCLUSIONS: Sedation with midazolam or fentanyl can transiently exacerbate or unmask focal motor deficits in patients with prior motor dysfunction.

Adult↗
PubMed1995

Intact nociception-induced neuroplasticity in transgenic mice deficient in neuronal nitric oxide synthase.

Nitric oxide is thought to play an important role in multiple forms of use-dependent synaptic plasticity, including that which follows noxious peripheral stimulation. This suggests that development of nociception-induced neuroplasticity should be impaired in transgenic animals lacking the neuronal form of nitric oxide synthase. We used the formalin model of nociception to test this hypothesis in wild-type and nitric oxide synthase knockout mice. Formalin-induced nociceptive behavior was intact in the knockout mice. Furthermore, administration of a nitric oxide synthase inhibitor blocked nociception-induced neuroplasticity in wild-type mice but had no effect in the knockouts, whereas inhalation of the gaseous analgesic nitrous oxide attenuated development of neuroplastic changes in both phenotypes. These data indicate that nitric oxide is sufficient but not essential for development of nociception-induced neuroplasticity.

Animals↗
PubMed1995

Identification of the primary muscarinic autoreceptor subtype in rat striatum as m2 through a correlation of in vivo microdialysis and in vitro receptor binding data.

Muscarinic autoreceptors located on cholinergic nerve terminals are involved in the inhibitory feedback regulation of acetylcholine (ACh) release. Establishing the subtype identity of such sites provides a more complete understanding of both normal receptor function and the functional significance of receptor changes associated with various neurodegenerative diseases. In this study, a novel approach was used to identify the muscarinic autoreceptor in rat striatum. It involved the correlation of data from two different sources--in vivo microdialysis and in vitro receptor binding. Four standard muscarinic antagonists with varying binding profiles (scopolamine, pirenzepine, AF-DX116 and himbacine) were infused directly through a microdialysis probe into the striatum of conscious, freely moving rats. The objectives were to find the minimal concentration of each antagonist capable of manifesting a functional autoreceptor response (i.e., increased ACh release) and to compare the relative ability of the antagonists to bring about this effect with their relative abilities to bind to each of the cloned muscarinic receptor subtypes. The conclusion is that the muscarinic receptor mediating ACh release in rat striatum exhibits a pharmacological profile clearly consistent with it being of the m2 subtype.

Acetylcholine↗
PubMed1994

Pentobarbitone, but not propofol, produces pre-emptive analgesia in the rat formalin model.

Injection of formalin into the hindpaw of a rat induces a biphasic response in pain-related behaviours, such that C-fibre activation during phase 1 triggers a state of central sensitization characterized by a longer lasting phase 2. As the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) may participate in processing of nociceptive inputs, we hypothesized that pentobarbitone and propofol, i.v. anaesthetics with known GABAA agonist properties, would interfere with development of central sensitization and thereby modify the phase 2 hyperalgesic response. Pentobarbitone administered i.v. before injection of formalin produced dose-dependent suppression of phase 2, even though animals had recovered from anaesthesia, whereas it had substantially less effect when given after phase 1 had resolved. Picrotoxin, a GABAA antagonist, reversed the effect of pentobarbitone on phase 2 pain behaviour but was itself a mild analgesic. In contrast, propofol had no effect on phase 2 formalin-induced pain behaviour. Thus we conclude that pentobarbitone, but not propofol, produced pre-emptive analgesia in this model, presumably by suppressing noxious stimulation-induced central sensitization via activation of GABAA receptors.

Analgesics↗
PubMed1994

Nitrous oxide induces preemptive analgesia in the rat that is antagonized by halothane.

BACKGROUND: Noxious stimulation-induced sensitization of the central nervous system has been proposed as a key element in the development of subsequent protracted pain. Accordingly, the authors used the formalin model of pain to test the hypothesis that general anesthesia can produce preemptive analgesia and thereby interfere with noxious stimulation-induced central sensitization. METHODS: Rats received 0.9% or 1.8% halothane, 30% or 75% nitrous oxide (N2O), or 75% N2O plus 0.9% halothane (n = 4 or 5 per group). Control rats (n = 5) received only 100% oxygen. Fifteen minutes after the induction of anesthesia, formalin was injected subcutaneously into a hind paw of each rat, and anesthesia was maintained for 5 more min. Because the behavioral pain response to formalin (i.e., flinching of the injected paw) is biphasic, these treatment groups were anesthetized only during phase 1 (acute phase). Another group (n = 5) received 75% N2O only during phase 2 (delayed phase). Reversibility of the N2O effect was tested by the administration of naloxone before phase 1 or naltrexone during phase 2 (n = 5 per group). Finally, additional rats anesthetized as described above (n = 4 or 5 per group) underwent tail-flick testing during anesthesia. RESULTS: All anesthetics reduced phase 1 pain behavior, but only N2O produced antinociception on tail-flick testing. Thirty percent and 75% N2O, administered during phase 1, suppressed phase 2 flinching 29% and 49%, respectively, whereas nitrous oxide administered after phase 1 did not suppress phase 2 pain behavior. This effect of nitrous oxide was reversed by an opioid antagonist given during phase 1 but not phase 2. Halothane administered during phase 1 had no effect on phase 2 flinching, and it antagonized the effect of 75% N2O. CONCLUSIONS: Nitrous oxide induces dose-dependent preemptive analgesia in this model that is reversed partially by naloxone, thus suggesting the involvement of endogenous opioids in this action. In contrast, halothane has no preemptive analgesic properties and even antagonizes the analgesic effect of nitrous oxide. Hence, the hypnotic potency of an anesthetic is a poor indication of its preemptive analgesic potential.

Analgesia↗
PubMed1994

Subarachnoid morphine reduces stimulation-induced but not basal expression of preproenkephalin in rat spinal cord.

BACKGROUND: To evaluate directly the possibility that the potent exogenous opioid analgesic morphine may alter neuronal expression of opioid peptide genes, we assessed the effect of subarachnoid morphine on basal and noxious stimulation-induced expression of preproenkephalin in spinal cord neurons. METHODS: Twenty male Sprague-Dawley rats were prepared 48 h in advance with lumbar subarachnoid catheters. In the first phase, basal expression was evaluated in rats that received morphine 10 micrograms or saline intrathecally (n = 5 per group). Subsequently, the experiment was repeated (n = 5 per group), except that 10 min after morphine or saline administration rats received a hindpaw footpad injection of 50 microliters 5% formalin. Rats were killed during pentobarbital anesthesia 2 h later, and messenger RNA transcribed from preproenkephalin was measured in lumbar spinal cord with quantitative in situ hybridization with a complementary sulfur 35-labeled oligonucleotide probe and emulsion autoradiography. RESULTS: In control (nonstimulated) rats, 20% of the neurons in laminae I-II and 10% of those in laminae III-IV expressed preproenkephalin. Injection of formalin increased the fraction of positive neurons by 34% (P < 0.05) and 20% (P < 0.05) in laminae I-II and V-VI, respectively, but had no effect on expression in laminae III-IV. Subarachnoid morphine did not alter basal expression of preproenkephalin but markedly attenuated the noxious stimulation-induced increase in laminae I-II (P < 0.01) and V-VI (P < 0.05) by preventing the stimulation-evoked recruitment of preproenkephalin-expressing neurons that otherwise would have occurred. CONCLUSIONS: Subarachnoid morphine does not acutely alter basal expression of preproenkephalin in spinal cord neurons but inhibits the increase in preproenkephalin expression that would otherwise occur after noxious stimulation.

Animals↗