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Biomedical subjects

S McLean

Publications and source records attributed to S McLean.

At least 73 records · Page 4Linked to original sources
PubMed1995

Monitoring plasma levels of fluphenazine during chronic therapy with fluphenazine decanoate.

This study was conducted to examine the interpatient variability in steady-state plasma concentrations of fluphenazine by repeat depot intramuscular administration, and to determine the relationship between these concentrations and clinical state. Steady-state pre-dose concentrations of fluphenazine in plasma were measured using a sensitive and specific gas chromatography/mass spectrometry (GC/MS) assay in 24 patients with schizophrenia who were receiving continuous treatment with depot intramuscular fluphenazine decanoate. Clinical response was measured using the Andreasen Scale for positive and negative symptoms. Steady-state plasma concentrations of fluphenazine ranged from undetectable (< 0.1 ng/ml) to 27.9 ng/ml, with a median of 0.5 ng/ml. No significant associations were found between plasma concentration and dosage, or age and sex of the patient. Steady-state plasma concentrations in patients taking anticholinergic agents were significantly higher than in patients not receiving such drugs (P < 0.05 by Mann-Whitney U-test). Poorer control, expressed as the sum of the negative symptom scores or the sum of the positive and negative symptom scores, was related to higher log transformed plasma concentration of fluphenazine and higher fluphenazine decanoate dosage. The log transformed plasma concentrations of fluphenazine and the fluphenazine decanoate dosages were weakly related. Patients receiving another antipsychotic drug in addition to fluphenazine decanoate tended to have poorer clinical control and higher dosages of fluphenazine decanoate. These results indicate the useful role that plasma level monitoring can fulfil in identifying patients who are therapy-resistant despite high plasma levels.

Adult↗
PubMed1995

The anti-emetic effects of CP-99,994 in the ferret and the dog: role of the NK1 receptor.

1. The selective NK1 receptor antagonist, CP-99,994, produced dose-related (0.1-1.0 mg kg-1, s.c.) inhibition of vomiting and retching in ferrets challenged with central (loperamide and apomorphine), peripheral (CuSO4) and mixed central and peripheral (ipecac, cisplatin) emetic stimuli. 2. Parallel studies with the enantiomer, CP-100,263 (1 mg kg-1, s.c.), which is > 1,000 fold less potent as a NK1 antagonist, indicated that it was without significant effect against CuSO4, loperamide, cisplatin and apomorphine-induced emesis. Against ipecac, it inhibited both retching and vomiting, expressing approximately 1/10th the potency of CP-99,994. 3. The 5-HT3 receptor antagonist, tropisetron (1 mg kg-1, s.c.) inhibited retching and vomiting to cisplatin and ipecac, but not CuSO4 or loperamide. 4. CP-99,994 (1 mg kg-1, i.v.) blocked retching induced by electrical stimulation of the ventral abdominal vagus without affecting the cardiovascular response, the apnoeic response to central vagal stimulation or the guarding and hypertensive response to stimulation of the greater splanchnic nerves. CP-99,994 (1 mg kg-1, i.v.) did not alter baseline cardiovascular and respiratory parameters and it failed to block the characteristic heart rate, blood pressure and respiratory rate/depth changes in response to i.v. 2-methyl-5-HT challenge (von Bezold-Jarisch reflex). 5. Using in vitro autoradiography, [3H]-substance P was shown to bind to several regions of the ferret brainstem with the density of binding in the nucleus tractus solitarius being much greater than in the area postrema. This binding was displaced by CP-99,994 in a concentration-related manner. 6. In dogs, CP-99,994 (40 micrograms kg-1 bolus and 300 micrograms kg-1 h-1, i.v.) produced statistically significant reductions in vomiting to CuSO4 and apomorphine as well as retching to CuSO4. 7. Together, these studies support the hypothesis that the NK1 receptor antagonist properties of CP-99,994 are responsible for its broad spectrum anti-emetic effects. They also suggest that CP-99,994 acts within the brainstem, most probably within the nucleus tractus solitarius although the involvement of the area postrema could not be excluded.

Animals↗
PubMed1995

Antagonism of some cyclohexamine-based drug combinations used for chemical restraint of southern elephant seals (Mirounga leonina).

This study examined the use of 4 antagonists of chemical restraint in mature female southern elephant seals (Mirounga leonina) that were restrained with ketamine and diazepam, ketamine and xylazine, or tiletamine and zolazepam. The antagonists were: 4-aminopyridine, yohimbine, doxapram and sarmazenil. The effects of the antagonists on the animal's time to first movement forward and recovery, heart rate, respiratory rate and venous blood gas and pH values, and level of chemical restraint were recorded. Sarmazenil (1.0 mg/kg) and doxapram (5.0 mg/kg) partially antagonised 50:1 ketamine: diazepam (ketamine = 3.0 mg/kg, diazepam = 0.06 mg/kg) and tiletamine and zolazepam (tiletamine = 0.5 mg/kg, zolazepam = 0.5 mg/kg). However, the rapid recovery after low doses of anaesthetics means that antagonism is usually unnecessary, and it may increase the likelihood of shaking. Routine antagonism of ketamine and xylazine (ketamine = 3.0 mg/kg, xylazine = 0.5 mg/kg) is more useful given its usually delayed recovery time and potential for thermoregulatory problems. For this purpose yohimbine (0.06 mg/kg) offered advantages over doxapram in giving a smoother recovery with less aggression. 4-aminopyridine (0.2 mg/kg) prolonged chemical restraint by 100:1 ketamine:diazepam (ketamine = 3.0 mg/kg, diazepam = 0.03 mg/kg) and ketamine and xylazine, and should be contraindicated. Doxapram (5.0 mg/kg) was the most useful general antagonist for all groups of drugs but shaking was seen and a lower dose is recommended.

4-Aminopyridine↗
PubMed1995

Ziprasidone (CP-88,059): a new antipsychotic with combined dopamine and serotonin receptor antagonist activity.

Ziprasidone (CP-88,059) is a combined 5-HT (serotonin) and dopamine receptor antagonist which exhibits potent effects in preclinical assays predictive of antipsychotic activity. Whereas the compound is a dopamine antagonist in vitro and in vivo, its most potent action is antagonism of 5-HT2A receptors, where its affinity is an order of magnitude greater than that observed for dopamine D2 sites. Laboratory and clinical findings have led to a hypothesis that antagonism of 5-HT2A receptors in the brain limits the undesirable motor side effects associated with dopamine receptor blockade and improves efficacy against the negative symptoms of schizophrenia. Ziprasidone possesses an in vitro 5-HT2A/dopamine D2 receptor affinity ratio higher than any clinically available antipsychotic agent. In vivo, ziprasidone antagonizes 5-HT2A receptor-induced head twitch with 6-fold higher potency than for blockade of d-amphetamine-induced hyperactivity, a measure of central dopamine D2 receptor antagonism. Ziprasidone also has high affinity for the 5-HT1A, 5-HT1D and 5-HT2C receptor subtypes, which may further enhance its therapeutic potential. The prediction of antipsychotic efficacy without severe motor side effects is supported by the relatively weak potency of ziprasidone to produce catalepsy in animals, contrasted with its potent antagonism of conditioned avoidance responding and dopamine agonist-induced locomotor activation and stereotypy. The compound is well tolerated in animals at doses producing effective dopamine antagonism in the brain. Ziprasidone should be a valuable addition to the treatment of psychotic disorders.

Adenylyl Cyclases↗
PubMed1995

Plasma concentrations of fentanyl with subcutaneous infusion in palliative care patients.

1. Plasma concentrations of fentanyl were measured by g.c. in 20 patients (median age: 75 years and range: 54-86 years; eight females) in palliative care receiving the drug by continuous s.c. infusion (median rate: 1200 micrograms day-1 and range: 100-5000 micrograms day-1). 2. The infusion rate was significantly related to the duration of therapy (Spearman rho = 0.56, P < 0.05). The total steady-state plasma concentrations of fentanyl ranged between 0.1 and 9 ng ml-1, with a median of 1 ng ml-1. The unbound fraction of fentanyl in the plasma ranged from 17.8 to 44.4%, with a median value of 33.6%. Infusion rates and both total and unbound plasma concentrations of fentanyl were correlated (Spearman rho = 0.92, P < 0.05 in each case). Even with standardization for dosage, there was an eightfold variation in total plasma concentrations and 3.5-fold variation in unbound plasma concentrations of fentanyl. 3. There is considerable inter-patient variability in the pharmacokinetics of fentanyl with s.c. infusion in the palliative care setting, which necessitates careful titration of dosage according to individual clinical response.

Aged↗
PubMed1994

Use of midazolam, pethidine, ketamine and thiopentone for the restraint of southern elephant seals (Mirounga leonina).

Thirty-two pre-moulting female southern elephant seals (Mirounga leonina) were heavily sedated with midazolam (0.04 mg/kg) combined with pethidine (4 mg/kg). This combination made it possible to give the seals intravenous injections and was rapidly antagonised by naloxone. After sedation with midazolam and pethidine, 2 to 3 mg/kg intravenous thiopentone or ketamine induced light immobilisation for approximately five minutes and allowed the animals to be intubated. Prolonged deep levels of restraint were achieved after sedation with midazolam and pethidine by repeated intravenous doses of approximately 1.5 mg ketamine/kg at 10 minute intervals, to maintain restraint for 60 minutes.

Animals↗
PubMed1994

5-Phenyl-3-ureidobenzazepin-2-ones as cholecystokinin-B receptor antagonists.

A series of 5-phenyl-3-ureidobenzazepin-2-one cholecystokinin-B (CCK-B) receptor antagonists was synthesized using Beckmann ring expansion of a suitable 4-phenyl-1-tetralone as a key step. Structure-activity relationship studies revealed the importance of the 5-phenyl group for potent and selective CCK-B affinity. Addition of an 8-methyl substituent and resolution provided the potent (CCK-B IC50 = 0.48 nM) CCK-B antagonist 4. The role of the 5-phenyl group as part of a "privileged structure" for high-affinity receptor antagonism is discussed.

Animals↗
PubMed1994

Aza-tricyclic substance P antagonists.

The synthesis and structure-activity relationships of a series of aza-tricyclic analogs of the quinuclidine substance P (SP) antagonist 1 are described. The SP receptor affinity of these compounds was found to vary according to the size of the new ring fused to the quinuclidine and the mode of fusion. Correlations between receptor affinity and (1) the steric bulk of the newly introduced ring fusion and (2) the dihedral angle between the benzhydryl and benzylamino substituents of these aza-tricyclic compounds were explored.

Animals↗
PubMed1994

Promotion of responsible drinking in hotels.

This study reports on an intervention programme to promote responsible drinking in hotels. The licensees of eight hotels agreed to participate in a trial of measures designed to assist patrons to avoid drink-driving, and seven other hotels were used as controls. The interventions acceptable to licensees comprised commercial-quality promotional material with the theme "0.05 Know Your Limits", and a breath analysis machine and poster on its use. Patrons leaving the hotels on Thursday, Friday and Saturday nights were interviewed and breath-tested. Although the intervention material had been seen by one-third of patrons in the intervention hotels, there was no significant difference between them and control hotel patrons in either median BAC or the proportion who were going to drive with BAC over the legal limit. There was poor compliance by hotels with the intervention procedures, indicating that a major impediment to the implementation and evaluation of programmes to promote responsible drinking is a lack of motivation by many licensees, despite support by some licensees and the Australian Hotels Association.

Journal Article↗
PubMed1993

Synthesis, in vitro binding profile, and autoradiographic analysis of [3H]-cis-3-[(2-methoxybenzyl)amino]-2-phenylpiperidine, a highly potent and selective nonpeptide substance P receptor antagonist radioligand.

The synthesis of a highly potent and selective NK1 receptor antagonist radioligand, [3H]-cis-3-[(2-methoxybenzyl)amino]-2-phenylpiperidine (6a) is described. The in vitro binding pharmacology and autoradiographic distribution of 6a in guinea pig brain following peripheral administration are also reported.

Amino Acid Sequence↗
PubMed1993

Discovery of CP-96,345 and its characterization in disease models involving substance P.

Studies with CP-96,345, a potent, selective, orally active, nonpeptide NK1 receptor antagonist, have provided considerable insight into SP pharmacology. Rather than being a primary neurotransmitter, SP prolongs the nociception produced by other neurotransmitters. By controlling endothelial permeability, SP plays a major role in inflammation and inflammatory aspects of asthma, possibly by regulating the access of neutrophils to an inflammatory site. These results indicate potential therapeutic applications for SP antagonists in the treatment of chronic pain, inflammation, and inflammatory aspects of asthma, and signal a new era in the clinical management of these important diseases.

Analgesics↗
PubMed1993

Dose dependent effects of alcohol on visual evoked potentials.

The effects of various alcohol doses on components of the visual evoked potential were investigated. Using a repeated measures, Latin square design, five alcohol dose conditions were administered to ten male subjects: 0.00 (placebo); 0.28; 0.36; 0.54 and 0.72 g/kg total body weight. EEG responses to a reversing checker board stimulus were measured in a standard oddball paradigm. In the alcohol conditions, latencies of the P1 and P2 components of the VEP were unaffected. However, reaction time, and the latencies of N2 and P3 displayed significant dose related increases with increasing blood alcohol levels. Further, RMS power of the P3 complex was reduced by higher alcohol doses, as was the N2-P3 amplitude difference at central and parietal sites. It is concluded that the latency and power of the endogenous components of the VEP are altered by alcohol, without effects being seen in earlier components.

Adolescent↗
PubMed1993

Alcohol consumption and driving intentions amongst hotel patrons.

To examine the extent to which hotel patrons drink in excess of current health recommendations, and to identify risk factors for excessive drinking, hotel patrons were invited to participate in a survey of social drinking, which included a free breath test. Patrons were approached at 15 min. intervals, and 1000 subjects were studied. Amongst this group of hotel patrons interviewed, 1 in 2 had consumed alcohol in excess of the daily limit recommended by the National Health & Medical Research Council. One in 10 intending drivers had a BAC over the legal limit. Excessive drinking and drink driving appear to be prevalent amongst hotel patrons, and hotels should be targets for interventions designed to reduce these problems. For example, the National Guidelines for the Responsible Serving of Alcohol should be more widely practised.

Journal Article↗
PubMed1993

Pharmacology of CP-99,994; a nonpeptide antagonist of the tachykinin neurokinin-1 receptor.

(+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994) binds selectively and with high affinity (Ki = 0.25 nM) to neurokinin (NK)-1 tachykinin receptors in a human cell line and in guinea pigs where it acts as an antagonist as evidenced by its blockade of substance P-induced excitation of locus coeruleus neurons in vitro. Subcutaneously administered CP-99,994 antagonized locomotor activity in guinea pigs induced by intraventricular infusion of [Sar9,Met(O2)11]-substance P (50 micrograms) with an ID50 = 0.59 mg/kg, indicating that CP-99,994 penetrates into the central nervous system. Orally administered CP-99,994 potently blocked (ID50 = 4 mg/kg) the leakage of Evans blue dye into trachea and bronchi elicited by exposure of guinea pigs to aerosol capsaicin (1 mM). CP-99,994 has reduced affinity (IC50 = 3 microM) for the L-type calcium channel in contrast to CP-96,345 (IC50 = 27 nM) an earlier nonpeptide antagonist. Thus, CP-99,994 represents an important pharmacological tool for investigating the physiological role of substance P and a potentially novel therapeutic agent for treating a variety of diseases.

Animals↗
PubMed1992

The substance P receptor antagonist CP-96,345 interacts with Ca2+ channels.

The nonpeptide substance P receptor antagonist CP-96,345 was found to displace binding to Ca2+ channel binding sites labelled with either [3H]desmethoxyverapamil or [3H]diltiazem and to enhance [3H]nitrendipine binding. Unlike the substance P receptor antagonist activity of CP-96,345, these effects on Ca2+ channel binding sites were neither stereoselective nor species-dependent. It is concluded that CP-96,345 may act as an antagonist of L-type Ca2+ channels in addition to being a potent NK1 receptor (substance P) antagonist.

Animals↗
PubMed1992

The discovery of (2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)methyl]-1- azabicyclo[2.2.2]-octan-3-amine as a novel, nonpeptide substance P antagonisst.

We describe the structure-activity relationship development of a series of quinuclidines which culminated in the first potent, selective, nonpeptide substance P (SP) antagonist, (2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxy-phenyl)methyl]-1- azabicyclo[2.2.2]octan-3-amine, 3 (CP-96,345). Compound 3 is a potent displacer of [3H]SP binding in human IM-9 cells and blocks SP-induced and capsaicin-induced plasma extravasation, as well as SP-induced salivation in the rat in vivo. This compound may both help to further our understanding of the interactions of small molecules with peptide receptors and serve to evaluate the therapeutic potential of a SP antagonist.

Amino Acid Sequence↗