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Biomedical subjects

S McLean

Publications and source records attributed to S McLean.

At least 55 records · Page 3Linked to original sources
PubMed1997

The effect of CP-99994 on the responses to provocative motion in the cat.

1. The NK1 receptor antagonist CP-99994 has been shown to prevent vomiting elicited by both peripherally and centrally acting emetogens in ferrets and dogs. These results have now been extended to another stimulus, provocative motion, and another species, the cat. 2. CP-99994 displaced [3H]-substance P from cat cortex with IC50 of 0.52 +/- 0.08 nM. Following s.c. administration, peak plasma drug levels were achieved at 30 min. The plasma drug half life was 1.4 h. 3. Subcutaneous administration of CP-99994 inhibited motion-induced vomiting in the cat with an ED50 of 144 micrograms kg-1 but did not change the epiphenomena associated with provocative motion in the cat over the dose range of 30 to 300 micrograms kg-1. The antiemetic effect of CP-99994 can be attributed to antagonism of the NK1 receptor because its enantiomer, CP-100,263, which is 900 fold weaker as an NK1 antagonist, had no effects on any response to provocative motion. 4. The inhibitory effect of CP-99994 on motion-induced retching and vomiting is consistent with a central site of antiemetic action, potentially at the level of the motor nuclei responsible for these behaviours. 5. An investigation into whether the failure of CP-99994 to alter the epiphenomena will also predict a lack of anti-nausea effects in man will provide critical information on the neural organization of the emetic reflex.

Animals↗
PubMed1997

Effect of cardiopulmonary bypass on the plasma concentrations of fentanyl and alcuronium.

This study was conducted to examine the effect of cardiopulmonary bypass surgery on the total and unbound plasma concentrations of fentanyl and the total plasma concentrations of alcuronium. Total fentanyl concentrations were measured by gas chromatography, the plasma protein binding of fentanyl by ultrafiltration, and alcuronium concentrations by high-performance liquid chromatography. Sixteen patients were studied. On initiation of cardiopulmonary bypass (CPB), there were mean decreases of 58.8 +/- 7.1% and 47 +/- 3.2% for total concentrations of fentanyl in plasma and haemoglobin in blood, respectively. The magnitude of these reductions in individual patients was significantly related (Spearman p = 0.65, P < 0.05). The unbound fraction of fentanyl rose from 0.23 to 0.34 after the start of CPB. The total fentanyl concentration remained relatively stable during bypass until near the end of CPB when the mean total concentration increased, coinciding with rewarming. The size of the increase was related to the body mass index (BMI) of the patient (Spearman p = 0.85, P < 0.01). The estimated elimination half-life of fentanyl using the grouped data was 4.7 h. The total alcuronium concentration in plasma fell by 29% on initiation of CPB and there was no increase on rewarming. The estimated elimination half-life of alcuronium using the grouped data was 234 min. Despite marked declines in the plasma concentrations of both drugs on initiation of CPB, suitable levels of anaesthesia were maintained throughout the procedure.

Adjuvants, Anesthesia↗
PubMed1997

Practice guideline for arterial blood gas measurement in the intensive care unit decreases numbers and increases appropriateness of tests.

OBJECTIVE: To test the hypothesis that implementation of a practice guideline for blood gas measurement would decrease numbers and increase appropriateness of tests (according to criteria in the guideline) for up to 1 yr after introduction of the guideline. DESIGN: Numbers of tests and appropriateness of each test were measured retrospectively during each of five periods: two baseline periods 2 yrs and 1 yr before introduction of the guideline and three follow-up periods 2 to 3 months, 6 to 7 months, and 12 to 13 months after introduction of the guideline. SETTING: A ten-bed multidisciplinary intensive care unit (ICU) within a 500-bed tertiary teaching hospital. PATIENTS: A random sample of 30 patients admitted to the ICU during each of the periods specified above. INTERVENTIONS: The nominal group process was used to develop a new guideline and a multipronged educational approach was used to facilitate implementation of the guideline. MEASUREMENTS AND MAIN RESULTS: At 2 to 3 months, test numbers decreased from 4.9 +/- 1.6 to 3.1 +/- 1.8 (SD) tests/patient/day and to 2.4 +/- 1.2 tests/patient/day at 12 to 13 months. Appropriateness increased from a mean of 44% at baseline to 78% at 2 to 3 months and 79% at 12 to 13 months. There were no differences in Acute Physiology and Chronic Health Evaluation scores or ICU mortality among the patient groups and no differences in number of ventilator days or time to wean from ventilation. Cost-minimization analysis showed that the incremental cost-saving 1 yr after introduction of the guideline was $19.18 per patient per day. CONCLUSIONS: Implementation of this guideline for arterial blood gas measurement increases efficiency of test utilization without prolonging mechanical ventilation or affecting outcome.

APACHE↗
PubMed1997

Investigation of urinary levels of salbutamol in asthmatic patients receiving inhaled therapy.

AIM: Some studies have indicated that over-reliance on inhaled bronchodilator (beta 2-agonist) therapy may worsen asthma control and increase morbidity. The aim of this study was to measure urinary concentrations of salbutamol, the most commonly used bronchodilator, in a relatively large sample of asthmatic patients and examine the potential value of the concentration as an indicator of over-use of salbutamol. METHOD: The urinary concentrations of the drug were measured in 'spot' urine samples from 102 asthmatic patients (64 community patients and 38 hospital inpatients). A solid-phase extraction technique, using a phenyl-bonded phase and a reversed-phase ion-pair high-performance liquid chromatography assay with UV-detection were developed and used to measure both unchanged salbutamol concentrations and total salbutamol concentrations after enzymatic hydrolysis of the metabolite. In addition, salbutamol concentrations were corrected for urine dilution, with the measured drug expressed per gram of urinary creatinine. RESULTS: The hospital patients were generally older, had greater disease severity, were more likely to be receiving prophylactic therapy and had received more salbutamol in the past 24 h. The urinary concentrations of salbutamol varied enormously between patients. The median concentrations of unchanged and total drug were 0.38 microgram/ml (range 0-34.4 micrograms/ml) and 2.55 micrograms/ml (range 0-49.8 micrograms/ml), respectively. Even when controlling for dosage in the preceding 24 h, there was a 262-fold and 810-fold variation in the urinary concentrations for unchanged and total salbutamol, respectively, among the community patients. Modest correlations were found between salbutamol concentrations and dosage administered in the preceding 24 h (Spearman's r = 0.67 and 0.54 for unchanged and total drug, respectively; P < 0.001). The correlations improved only slightly with correction for urine dilution (Spearman's r = 0.69 and 0.57 for unchanged and total drug, respectively; P < 0.001). CONCLUSION: This enormous inter-patient variability, which may be largely due to differences in the pharmacokinetics of salbutamol and inhaler technique, may play a role in the observed worsening of asthma control with the regular use of inhaled bronchodilator drugs and warrants further investigation. Measuring urinary concentrations of salbutamol in spot samples provides only a relatively crude indication of the extent of use of inhaled salbutamol in the preceding 24 h.

Administration, Inhalation↗
PubMed1997

Cardiovascular effects of cholecystokinin-4 are mediated by the cholecystokinin-B receptor subtype in the conscious guinea pig and dog.

Panicogenic effects in humans of the selective cholecystokinin (CCK(B)) receptor agonist, cholecystokinin tetrapeptide (CCK4), have been reported to correlate with increases in heart rate (HR) and mean arterial pressure (MAP). Previous investigators have demonstrated that the nonselective CCK(A) and CCK(B) receptor agonist, sulfated cholecystokinin octapeptide, also produces increases in HR and mean arterial pressure. The purpose of our study is to determine if the cardiovascular changes induced by CCK4 are mediated by the CCK(A) or CCK(B) receptor subtype using selective CCK antagonists for both receptor subtypes. The rank order of potency of the CCK receptor antagonists affecting CCK4-induced HR and mean arterial pressure changes in the guinea pig corresponded to the rank order of potency for blockade of the CCK(B) receptor binding in rat cortex, phosphatidyl inositol turnover in AR 4-2J rat pancreatoma cells and inhibition of pentagastrin-induced acid secretion in the rat. The changes induced by CCK4 on HR, but not mean arterial pressure, appear to be species dependent as reflected by a decrease in the HR in the guinea pig and an increase in the dog. Nonetheless, the results from the antagonist studies indicate that the cardiovascular responses to CCK4 in both the guinea pig and dog are mediated by the CCK(B) receptor subtype.

Animals↗
PubMed1996

Design of novel cholecystokinin-B receptor ligands based on the 'double-ring system' approach.

A structurally novel series of cholecystokinin-B (CCK-B) receptor ligands has been designed and synthesized based on the 'double ring system' theory of receptor recognition. Compounds 2b-cis and 2g-cis from this 1-amino-2-benzyltetralin series show modest CCK-B receptor affinity, with IC50 values of 48.5 nM and 39.0 nM, respectively. The results are discussed in the context of ongoing efforts to identify the CCK-B receptor binding site for nonpeptide ligands.

Binding Sites↗
PubMed1996

Use of the respiratory stimulant doxapram in southern elephant seals (Mirounga leonina).

The use of doxapram to stimulate breathing was examined in southern elephant seals chemically restrained with ketamine and xylazine. Animals which were breathing spontaneously received doxapram (approximately 0.5, 1, 2, or 4 mg/kg) or saline into the extradural intravertebral vein. Doxapram caused a dose-dependent increase in the depth and rate of respiration which began within one minute, peaked after two minutes and lasted for up to five minutes. A dose of 2 mg/kg appeared to be safe and effective for the stimulation of respiration, while 4 mg/kg caused arousal and shaking. Doxapram (2 mg/kg) was tested on 14 occasions in animals which had developed apnoea during chemical restraint. Doxapram had no effect when administered into the extradural intravertebral vein and appeared to be of more benefit when administered directly into the lungs via an endotracheal tube, but it was not effective in all cases. There was evidence to suggest that the endotracheal tube prevented some of the animals from breathing. The effect of intubation and endotracheal doxapram administration was therefore examined in 19 apnoeic and 31 spontaneously breathing seals. Intubation induced apnoea in animals at low levels of chemical restraint and endotracheal doxapram was unreliable for the stimulation of breathing.

Animals↗
PubMed1996

Cancer incidence in the rural community of Tecumseh, Michigan: a pattern of increased lymphopoietic neoplasms.

BACKGROUND: The Tecumseh Community Health Study (TCHS), initiated in 1959 at the University of Michigan School of Public Health, has provided a resource for long term prospective studies of the incidence of cancer in the setting of a midwestern rural farming community. METHODS: A survey of total and site specific cancer incidence among 7016 male and female adult residents from 1959-1987 was conducted, and the observed number compared with the expected number, based on the age-sex-race-calendar period-and site-specific cancer incidence rates reported by the Connecticut tumor registry. Based on the results of this survey, a hypothesis was advanced concerning the potential risks of exposures to insecticides and herbicides. This was pursued by analyzing for each county in Michigan the comparative annual number of acres and percentage of acreage treated with agricultural chemicals in 1978 and for the period 1982-1987. Finally, because of the availability of information on lifestyle risk factors that had been collected in the 1960s on all participants, a nested case-control study was implemented. RESULTS: The standardized incidence ratio (SIR), based on the observed number divided by the expected number of invasive cancer cases (all sites combined [excluding nonmelanoma skin cancer]), was not significant in females (SIR, 0.95; 95% confidence interval [CI], 0.86-1.05) nor males (SIR, 0.91; 95% CI, 0.81-1.01). A significant increase was demonstrated for males and females combined in the incidence of lymphopoietic neoplasms, namely non-Hodgkin's lymphoma, Hodgkin's disease, and chronic lymphocytic leukemia; the combined SIR was 1.40 (95% CI, 1.03-1.86; P = 0.03). In the Department of Commerce surveys of counties in Michigan, the Tecumseh area (Lenawee County) was ranked highest with respect to the average annual number of acres (240,000 or more) and the percent of acreage (40%) sprayed with herbicides and insecticides. A comparison of temporal trends for cancer incidence since 1973 was reviewed for the Wayne-Oakland-Macomb tricounty area, in which the survey estimated that less than 80,000 acres per year, or less than 8% of acreage, were treated with pesticides. The comparison of the Tecumseh cohort, for all sites combined, was not significantly different from expectation in females (SIR, 1.01; 95% CI, 0.89-1.14), and was decreased by more than 10% in males (SIR, 0.88; 95% CI, 0.77-1.00). However, the SIR for non-Hodgkin's lymphoma in females was significantly elevated (SIR, 1.92; 95% CI, 1.07-3.11, P = 0.02); the trend for increased risks of lymphomas and leukemias was also evident in males. In the nested case-control study, based on risk factor information documented prior to diagnosis, the relative risk of a family history of lymphoma, leukemia, or multiple myeloma was significantly increased among patients with lymphoproliferative neoplasms (odds ratio, 3.81; 95% CI, 1.49-9.79; P = 0.005). CONCLUSIONS: This prospective epidemiologic study conducted in a rural farming community in Michigan has found significant increases in the incidence dence of lymphoproliferative cancers. A plausible hypothesis, consistent with the preliminary findings, is that the reported cancer pattern is an expression of risk resulting from sustained environmental exposures to agricultural chemicals, perhaps in conjunction with familial or genetic factors.

Adult↗
PubMed1996

Quantitative urinary excretion of unmetabolised N tau-[Me-14C] methylhistidine by the common ringtail possum (Pseudocheirus peregrinus) marsupialia.

Six common ringtail possums (Pseudocheirus peregrinus) were intravenously injected with a standard dose of radioactive 3-Methylhistidine (N tau-[Me-14C]MeH). The dose was rapidly and quantitatively excreted by the possums. More than 90% of radioactivity was recovered within 3 days. Thin layer chromatography and mass spectroscopy showed that 97% of recovered radioactivity was associated with unmetabolised N tau-[Me-14C]MeH. These data satisfy two key requirements for the validity of urinary 3-Methylhistidine (N tau-3MeH) excretion as an index of muscle protein catabolism, in P. peregrinus.

Animals↗
PubMed1996

Chemical restraint of southern elephant seals (Mirounga Leonina); use of medetomidine, ketamine and atipamezole and comparison with other cyclohexamine-based combinations.

A study was conducted to assess the effectiveness of the alpha-2 agonist medetomidine for sedation of pre-moulting, mature female southern elephant seals (Mirounga leonina). Two animals were sedated with a single intramuscular dose of medetomidine (0.013 and 0.027 mg kg-1). A further two groups of five animals received medetomidine (0.017 mg kg-1) combined with ketamine (1.90 mg kg-1) and, 20 min later, either saline or the alpha-2 antagonist atipamezole (0.04 mg kg-1) intravenously. Medetomidine alone did not give sufficient restraint to permit intravenous access. The response appeared to be similar to previous findings with ketamine and xylazine. Administration of atipamezole had little effect upon the level and timecourse of restraint. Ketamine and medetomidine seem to offer few advantages over ketamine and xylazine or other cyclohexamine-drug combinations for routine chemical restraint of southern elephant seals.

Anesthetics, Dissociative↗
PubMed1996

Cardioprotection of rat heart myocytes with amifostine (Ethyol) and its free thiol, WR-1065, in vitro.

Cultured neonatal rat heart myocytes form a synchronously-contracting cell syncytium from one to two days after isolation, plating on plastic and incubation at 37 degrees C. On day 3 after plating, myocytes were exposed to the anthracycline doxorubicin, 0.1-10 micrograms/ml, for 1 h with or without a 15-min pretreatment with the thiophosphate compound amifostine (WR-2721, Ethyol) or its dephosphorylated metabolite, WR-1065. The concentration of each WR-compound was limited to 2 micrograms/ml or 10% of the maximal achievable plasma concentration of amifostine after an intravenous dose of 740 mg/m2. Both amifostine and the free thiol significantly reduced doxorubicin-induced heart-cell toxicity, measured by adenosine triphosphate content normalised to total cellular protein. A concurrent 1-h exposure to these compounds and doxorubicin was also cardioprotective, but neither compound was effective when administered after doxorubicin. Although both amifostine and WR-1065 were approximately equipotent in preventing doxorubicin-induced cardiotoxicity, only amifostine significantly increased glutathione levels in the myocytes. These results complement prior in vitro and in vivo studies in rodents showing cardioprotectant activity for amifostine and its free thiol, WR-1065, when administered prior to doxurubicin.

Amifostine↗
PubMed1996

A comparison of the psychosocial aspects of AIDS and cancer-related bereavement.

OBJECTIVE: This study compares the psychological symptoms and bereavement distress of individuals bereaved by AIDS with a group bereaved by a cancer death, and addresses the question of whether an AIDS death is associated with a higher rate of adverse psychosocial factors that may increase risk of psychological morbidity in the bereaved individuals. METHOD: AIDS (n = 28) and cancer (n = 30) bereaved individuals (all within 3 months of the bereavement) completed measures of psychological morbidity and measures addressing a range of other adverse factors, e.g., number of losses, levels of social support and stigma. RESULTS: The cancer and AIDS bereaved were essentially similar on all psychological symptom measures. The AIDS group reported lower levels of social support in response to the bereavement than cancer bereaved individuals; a greater number of bereavements, were more likely to conceal the cause of death from significant others including their own family and perceived, in some instances, a greater level of rejection from others. The AIDS group reported higher levels of social support from friends than from family. CONCLUSIONS: At three months following bereavement, AIDS and cancer bereaved were similar in levels of distress. While this may change with the progress of grief over time, it suggests essentially similar early bereavement responses. Those bereaved by AIDS reported a range of other adverse factors such as a greater number of losses, lower social support, stigma, and less open disclosure of the cause of death.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Characterization of CP-122,721; a nonpeptide antagonist of the neurokinin NK1 receptor.

CP-122,721 [(+)-(2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2 -phenylpiperidine] interacts with high affinity (pIC50 = 9.8) at the human NK1 receptor expressed in IM-9 cells. In the presence of CP-122,721, there was a reduction in Bmax of [125I]BH-SP binding with no change in affinity suggesting that CP-122,721 does not interact with the NK1 receptor in competitive manner. In an in vitro functional assay. CP-122,721 blocked SP-induced excitation of locus ceruleus cells in guinea pig brain slices with a IC50 value of 7 nM. In vivo, CP-122,721 potently blocked plasma extravasation in guinea pig lung elicited by aerosolized capsaicin (1 mM) with an ID50 = 0.01 mg/kg, p.o. Orally administered CP-122,721 antagonized Sar9, Met (O2)11-SP-induced locomotor activity in guinea pigs with an ID50 = 0.2 mg/kg suggesting good entry into the central nervous system. In addition, consistent with insurmountable blockade observed in vitro, CP-122,721 (0.01, 0.03 0.3 mg/kg, p.o.) produced a rightward shift in the dose response curve for SP-induced hypotension in the awake dog that was accompanied by a decrease in the maximal response. Thus, in vitro and in vivo CP-122,721 appears to behave functionally as a non-competitive antagonist producing an insurmountable blockade of the actions of SP.

Animals↗
PubMed1995

One for the road: on the utility of citation data for identifying problem hotels.

Drink drivers arrested in Tasmania are routinely asked by police where they had last been drinking, and these data were examined for 716 drivers arrested in Southern Tasmania during a 4-month period in 1992. Nearly half (43%) of arrested drink drivers cited individual hotels as the place where they had last been drinking. This enabled a citation score to be assigned to each of the 82 hotels in metropolitan Hobart. The distribution of citation scores was highly skewed, with eight hotels accounting for 45% of hotel citations, and two accounting for 20%. The hotels' citation scores were compared in relation to the rank order of their licence fees, since better measures of patronage proved unobtainable. Some hotels with small total alcohol sales did appear to have an unexpectedly large number of citations, suggesting less than responsible serving practices. Hoteliers' comments were sought on the interpretation of citation scores, and incorporated into a discussion of the limitations of the data in determining the extent of individual hotel responsibility for drink drivers. Important questions remaining include (1) what is the validity of citations made by drink drivers at the time of arrest; (2) what appropriate and quantifiable denominator can be used to adjust the number of citations to the level of patronage; and (3) what level of citations is too high and requires action?

Journal Article↗
PubMed1995

Trends in hotel patronage and drink driving in Hobart, Tasmania.

From 1990 to 1991 in the Hobart region there was a marked fall in both hotel patronage and the proportion of patrons subsequently driving with their blood alcohol concentration above the legal limit. This was associated with smaller falls in the number of drink drivers charged and alcohol-related road accidents, which continued in the following year. It appears that the pattern of drinking and driving is changing, presumably in response to random breath testing and tougher penalties for offences.

Journal Article↗