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Biomedical subjects

A E Fletcher

Publications and source records attributed to A E Fletcher.

At least 37 records · Page 2Linked to original sources
PubMed2000

Bisoprolol and nifedipine retard in elderly hypertensive patients: effect on quality of life.

Subjects over the age 60 with sustained sitting diastolic pressures of 95-115 mm Hg were randomised to a regime based on bisoprolol (n = 368) or nifedipine retard (n = 379) for 24 weeks. The goal diastolic pressure was < or =90 mm Hg and to achieve this, double-blind medication could be doubled (5/10 mg bisoprolol, 40/80 mg nifedipine retard) or hydrochlorothiazide 25 mg (unblinded) could be added to the higher dose. In an intention-to-treat analysis, 309 subjects in both the bisoprolol and nifedipine retard treated group provided at least a baseline and a second quality of life assessment (82%). An excess of symptoms was observed in the nifedipine group for oedema of the legs, nocturia, constipation, racing heart and heart thumping. Fewer patients reported wheeze in the nifedipine group. For quality of life, there were no statistically significant differences between the two groups after 8 weeks. However, when analysing the results of the last available assessment (usually at 24 weeks) there were significant (P < 0.05) improvements in tension/anxiety, anger/ hostility, vigour/activity, and confusion/bewilderment, assessed by the Profile of Mood States (POMS) in patients receiving bisoprolol in comparison to those receiving nifedipine retard. The Sickness Impact Profile and objective tests of cognitive function did not differ statistically between the two groups. Quality of life was maintained at a good level on both treatments with advantages for bisoprolol in certain areas. Journal of Human Hypertension (2000) 14, 205-212.

Adrenergic beta-Agonists↗
PubMed1999

1-(3-Cyanobenzylpiperidin-4-yl)-5-methyl-4-phenyl-1, 3-dihydroimidazol-2-one: a selective high-affinity antagonist for the human dopamine D(4) receptor with excellent selectivity over ion channels.

After the requirement of pseudocycle formation in the ureas 3 and 7 for hD(4) binding and selectivity was confirmed, structural hybridization with the known hD(4) ligand 2 led to the design and identification of the lead 4-(2-oxo-1, 3-dihydroimidazol-2-yl)piperidine 8. Optimization studies were carried out on 8 with the aim of achieving 1000-fold selectivity for hD(4) over all other receptors while retaining the good pharmacokinetic properties of the lead. After initial preparation of 8 as a minor component in a low-yielding reaction, a novel and regioselective "four-step/one-pot" procedure was developed which proved to be applicable to rapid investigation of the SAR of the 1, 3-dihydroimidazol-2-one ring. Various changes to substituents attached to the 3-, 4-, or 5-position of the 1, 3-dihydroimidazol-2-one core of 8 did not significantly improve selectivity for hD(4) over hD(2) and hD(3). Greater selectivity (>1000-fold) was ultimately achieved by meta substitution of the benzyl group of 8 with various substituents. Compounds 28, 31, and 32 all possess the required selectivity for hD(4) over the other dopamine subtypes, but only 32 has >1000-fold selectivity over all the key counterscreens we tested against. Compound 32 is an antagonist at hD(4) and has a good pharmacokinetic profile in the rat, with excellent estimated in vivo receptor occupancy, thus making it a potentially useful pharmacological tool to investigate the role of the D(4) receptor.

Animals↗
PubMed1999

Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. Systolic Hypertension in Europe Trial Investigators.

BACKGROUND: Recent reports suggest that calcium-channel blockers may be harmful in patients with diabetes and hypertension. We previously reported that antihypertensive treatment with the calcium-channel blocker nitrendipine reduced the risk of cardiovascular events. In this post hoc analysis, we compared the outcome of treatment with nitrendipine in diabetic and nondiabetic patients. METHODS: After stratification according to center, sex, and presence or absence of previous cardiovascular complications, 4695 patients (age, > or =60 years) with systolic blood pressure of 160 to 219 mm Hg and diastolic pressure below 95 mm Hg were randomly assigned to receive active treatment or placebo. Active treatment consisted of nitrendipine (10 to 40 mg per day) with the possible addition or substitution of enalapril (5 to 20 mg per day) or hydrochlorothiazide (12.5 to 25 mg per day) or both, titrated to reduce the systolic blood pressure by at least 20 mm Hg and to less than 150 mm Hg. In the control group, matching placebo tablets were administered similarly. RESULTS: At randomization, 492 patients (10.5 percent) had diabetes. After a median follow-up of two years, the systolic and diastolic blood pressures in the placebo and active-treatment groups differed by 8.6 and 3.9 mm Hg, respectively, among the diabetic patients. Among the 4203 patients without diabetes, systolic and diastolic pressures differed by 10.3 and 4.5 mm Hg, respectively, in the two groups. After adjustment for possible confounders, active treatment was found to have reduced overall mortality by 55 percent (from 45.1 deaths per 1000 patients to 26.4 deaths per 1000 patients), mortality from cardiovascular disease by 76 percent, all cardiovascular events combined by 69 percent, fatal and nonfatal strokes by 73 percent, and all cardiac events combined by 63 percent in the group of patients with diabetes. Among the nondiabetic patients, active treatment decreased all cardiovascular events combined by 26 percent and fatal and nonfatal strokes by 38 percent. In the group of patients receiving active treatment, reductions in overall mortality, mortality from cardiovascular disease, and all cardiovascular events were significantly larger among the diabetic patients than among the nondiabetic patients (P=0.04, P=0.02, and P=0.01, respectively). CONCLUSIONS: Nitrendipine-based antihypertensive therapy is particularly beneficial in older patients with diabetes and isolated systolic hypertension. Thus, our findings do not support the hypothesis that the use of long-acting calcium-channel blockers may be harmful in diabetic patients.

Aged↗
PubMed1999

Low uptake of eye services in rural India: a challenge for programs of blindness prevention.

OBJECTIVES: To investigate service uptake in a rural Indian population served by outreach eye camps and to identify barriers to uptake. PARTICIPANTS AND METHODS: A routine eye camp was conducted within 5 km of each of 48 randomly selected villages of typically Hindu, backward-caste communities. Subsequently, participatory rural appraisal-community mapping, focus groups, matrix ranking, and semistructured interviews-was undertaken to explore community views of eye problems. An eye examination was conducted on persons with eye problems who did not attend the eye camp. Predictors of attendance were identified by multilevel regression analysis. RESULTS: Of 749 adults with an eye problem, 51 (6.8%) attended the eye camp. Independent predictors of attendance were being male (odds ratio = 2.3; 95% confidence interval, 1.2-4.5) and living within 3 km of the camp (odds ratio = 4.5; 95% confidence interval, 1.7-12.5). Of the 552 persons who did not attend the eye camps and had an eye examination, 242 (43.8%) had low vision (visual acuity <6/18 to > or =3/60 in presenting better eye) and 38 (6.9%) were blind in both eyes. Cataract surgery was recommended for 197 (35.8%) of the persons who did not attend the eye camps. Of 109 persons with a previous cataract operation, 42 (38.5%) had low vision and 11 (10.1%) were blind. Fear (principally of eye damage), cost (direct and indirect), family responsibilities, ageism, fatalism, and an attitude of being able to cope (with low or no vision) were the principal barriers to attending the eye camps. CONCLUSIONS: A high proportion of people who could have benefited from eye treatment were not using available services. Poor visual outcomes were observed in surgically treated persons.

Attitude to Health↗
PubMed1999

Systolic Hypertension in Europe (Syst-Eur) trial phase 2: objectives, protocol, and initial progress. Systolic Hypertension in Europe Investigators.

The Systolic Hypertension in Europe (Syst-Eur) trial proved that blood pressure (BP) lowering therapy starting with nitrendipine reduces the risk of cardiovascular complications in older (> or = 60 years) patients with isolated systolic hypertension (systolic BP > or = 160 mm Hg and diastolic BP < 95 mm Hg). After the completion of the Syst-Eur trial on 14 February 1997, 3506 consenting patients (93.0% of those eligible) were enrolled in phase 2 of the Syst-Eur trial. This open follow-up study aims to confirm the safety of long-term antihypertensive therapy based on a dihydropyridine. To lower the sitting systolic BP below 150 mm Hg (target BP), the first-line agent nitrendipine (10-40 mg/day) may be associated with enalapril (5-20 mg/day), hydrochlorothiazide (12.5-25 mg/day), both add-on study drugs, or if required any other antihypertensive agent. On 1 November 1998, 3248 patients were still being followed, 86 patients had proceeded to non-supervised follow-up, and 43 had died. The median follow-up in Syst-Eur 2 was 14.3 months. At the last available visit, systolic/diastolic BP in the patients formerly randomised to placebo (n = 1682) or active treatment (n = 1824), had decreased by 13.2/5.2 mm Hg and by 4.6/1.6 mm Hg, respectively, so that the between-group BP difference was 1.7 mm Hg systolic (95% Ci: 0.8 to 2.6 mm Hg; P < 0.001) and 0.9 mm Hg diastolic (95% Cl: 0.4 to 1.5 mm mm Hg; P < 0.001). At the beginning of Syst-Eur 2, the goal BP was reached by 25.4% and 50.6% of the former placebo and active-treatment groups; at the last visit these proportions were 55.9% and 63.1%, respectively. At that moment, 45.9% of the patients were on monotherapy with nitrendipine, 29.3% took nitrendipine in combination with other study drugs. Until the end of 2001, BP control of the Syst-Eur 2 patients will be further improved. Cardiovascular complications and adverse events, such as cancer or gastro-intestinal bleeding, will be monitored and validated by blinded experts.

Aged↗
PubMed1999

Symptoms reported by elderly patients with isolated systolic hypertension: baseline data from the SYST-EUR trial. Systolic Hypertension in Europe.

OBJECTIVES: To determine the symptomatic well-being of elderly persons with isolated systolic hypertension. DESIGN AND SETTING: Well-being determined during the placebo run-in period prior to entry to the Systolic Hypertension in Europe (SYST-EUR) trial. SUBJECTS: 641 People, 60 years or older with an average sitting blood pressure of 173/86 mm Hg. OUTCOME MEASURES: 33 Symptomatic complaints determined by a standard interview. RESULTS: The 437 women complained of 25% of the symptoms and the 204 men 21% (P<0.001). A markedly higher prevalence was observed in women compared with men for: pain in the joints of the hands (35% of women complained of this against 22% of men); 'racing heart' (33% against 17%); dry eyes (16% against 6%); blurring of vision (35% against 23%); cramps in the legs (43% against 31%); and a sore throat (15% against 7%). Nocturia was the most frequent complaint (68% in both sexes). Eight symptoms increased with age and one (rash) tended to decline. With increasing systolic pressure women also reported more headaches, unsteadiness, blurring of vision, irregular heart beat and 'racing heart' but, of these, only headaches increased with diastolic pressure. These observations were made after adjusting for age, blood sugar and body mass index (BMI) and were not observed in men. Higher blood sugars were associated with mouth ulcers, 'racing heart', blurring of vision and cramps in the legs. A higher BMI was associated with six symptoms, and a lower age of leaving education with eight. In men, alcohol consumption was related to 'racing heart', and smoking to wheezing and having a dry cough. CONCLUSIONS: A high level of complaint was associated with female gender, increasing age, blood sugar and BMI and a low age of leaving education.

Aged↗
PubMed1998

Visual acuity and quality of life outcomes in patients with cataract in Shunyi County, China.

PURPOSE: To measure visual acuity and vision-related quality of life in individuals in rural China operated on for cataract. METHODS: Five thousand fifty-two persons age 50 years and older, 90.9% (5,052/5,555) of a randomly selected population in Shunyi County, were examined in the fall of 1996. Visual functioning and quality of life questionnaires were administered to those with presenting visual acuity less than 6/60 in either eye and to those who were aphakic or pseudophakic. RESULTS: Of the 87 individuals operated on for cataract, 12% (10/87) had presenting visual acuity of 6/18 or more in both eyes, and 24.1% (21/87) had less than 6/60. Twenty-five percent (29/116) of the 116 eyes operated on for cataract had presenting visual acuity of 6/18 or more, and 44.8% (52/116) had less than 6/60. Aphakic cases without glasses and uncorrectable aphakia attributable to surgical complications were common. In a multivariate regression model, including time period of surgery, hospital type, and surgical procedure, only pseudophakia was associated with better outcomes (P = .05). On a scale from 0 (maximum problems) to 100 (no problems), the mean visual functioning score (+/-SD) for the operated-on population was 61.9 +/- 30.0, and 71.0 +/- 31.8 for the quality of life questionnaire. These scores were comparable to those of the unoperated-on population with moderate bilateral blindness (<6/60 to > or =3/60 in the better eye). Visual functioning and quality of life scores were closely correlated with visual acuity in operated-on (r = 0.64 and r = 0.61, respectively) and unoperated-on populations (r = 0.68 and r = 0.59, respectively). CONCLUSIONS: Both clinical and patient-reported cataract surgery outcomes are below what should be achievable. Improvement in outcomes must be given greater emphasis if the potential of cataract surgery in restoring sight is to be realized.

Aged↗
PubMed1998

Substituted pyrazoles as novel selective ligands for the human dopamine D4 receptor.

Two novel series of 3-(heterocyclylmethyl)pyrazoles have been synthesised and evaluated as ligands for the human dopamine D4 receptor. Compounds in series I (exemplified by 8k) have a phenyl ring joined to the 4-position of the pyrazole while those in series II (exemplified by 15j) have a 5-phenyl ring linked by a saturated chain to the 4-position of the pyrazole. Both series supplied compounds with excellent affinity for the human D4 and good selectivity over other dopamine receptors. Excellent selectivity over calcium, sodium, and potassium ion channels was also achieved.

Antipsychotic Agents↗
PubMed1998

Quality of life of elderly patients with isolated systolic hypertension: baseline data from the Syst-Eur trial. Syst-Eur Trial Investigators.

OBJECTIVE: To describe measures of quality of life of elderly patients with isolated systolic hypertension at entry to a placebo-controlled randomized trial of antihypertensive treatment and to investigate factors associated with these. DESIGN: Cross-sectional analyses at entry to a randomized controlled trial. SETTING: Patients attending hypertension clinics or general practitioners' surgeries at 30 centres in 10 European countries. PATIENTS: Six hundred and thirty-one patients aged 60 years or more, with a sitting systolic blood pressure during the run-in phase of 160-219 mmHg, a sitting diastolic blood pressure below 95 mmHg and a standing systolic blood pressure of 140 mmHg or more. MAIN OUTCOME MEASURES: Cognitive function tests (Reitan Trail Making A and B), Brief Assessment Index (a measure of depressed mood) and four subscales from the Sickness Impact Profile (Ambulation, Social Interaction, Sleep and Rest and Housework). RESULTS: Poor quality of life was generally associated with increasing age, previous treatment with antihypertensive drugs, presence of cardiovascular complications and, among women, high diastolic blood pressure, higher consumption of alcohol and high body mass index. CONCLUSIONS: At entry to the trial there was considerable heterogeneity of patients in terms of measures of quality of life and cognitive performance. It remains to be determined whether these influence subsequent quality of life during randomized treatment.

Age Factors↗
PubMed1998

Quality of life in chronic heart failure: cilazapril and captopril versus placebo. Cilazapril-Captopril Multicentre Group.

OBJECTIVE: To measure quality of life (QOL) in patients with mild to moderate heart failure treated with angiotensin converting enzyme (ACE) inhibitors cilazapril or captopril. DESIGN: Randomised, double blind, placebo controlled, parallel groups trial. SUBJECTS: 367 patients with New York Heart Association (NYHA) heart failure class II (62%), III (36%) or IV (1%). METHODS: Patients were randomised to receive cilazapril 1 mg daily (n = 191) or captopril 25 mg three times daily (n = 90) for 24 weeks, or placebo for 12 weeks followed by cilazapril 1 mg daily for a further 12 weeks (n = 86). If patients had not responded after four weeks cilazapril was increased to 2.5 mg daily and captopril to 50 mg three times daily. QOL was assessed at baseline, 12, and 24 weeks using the sickness impact profile (SIP), the profile of mood states (POMS), the Mahler index of dyspnoea-fatigue, and a health status index (HSI). RESULTS: The physical dimension of the SIP averaged 7 units at baseline and improved after 12 weeks by 2.24 units in the cilazapril group, 2.38 units in the captopril group, and 1.51 units in the placebo group. The difference between drug and placebo was therefore 0.73 units (95% CI -0.86 to 2.32) for cilazapril, and 0.87 units (95% CI -0.96 to 2.70) for captopril, with small non-significant effect sizes (a statistical method for estimating the importance of a treatment related change) of 0.12 and 0.14. Similar results were observed for the total POMS and HSI scores. Although QOL improved more on the ACE inhibitors than on placebo, the effect sizes were not significant (< or = 0.26). CONCLUSIONS: Improvements in QOL in mild to moderate heart failure were small when treated with cilazapril or captopril compared with placebo.

Adult↗
PubMed1998

Calcium channel blockade and cardiovascular prognosis in the European trial on isolated systolic hypertension.

In the double-blind Systolic Hypertension in Europe (Syst-Eur) Trial, active treatment was initiated with nitrendipine (10 to 40 mg/d) with the possible addition of enalapril (5 to 20 mg/d) and/or hydrochlorothiazide (12.5 to 25 mg/d) titrated or combined to reduce sitting systolic blood pressure by at least 20 mm Hg to <150 mm Hg. In the control group, matching placebos were used similarly. In view of persistent concerns about the use of calcium channel blockers as first-line antihypertensive drugs, this report explored to what extent nitrendipine, administered alone, prevented cardiovascular complications. Age at randomization averaged 70.2 years and systolic/diastolic blood pressure 173.8/85.5 mm Hg. Of 2398 actively treated patients, 1327 took only nitrendipine (average dose, 23.4 mg/d), and 1042 progressed to other treatments including nitrendipine (n=757; 35.7 mg/d), enalapril (n=783; 13.4 mg/d), and/or hydrochlorothiazide (n=294; 21.0 mg/d). Compared with the whole placebo group (n=2297), patients receiving monotherapy with nitrendipine had 25% (P=0.05) fewer cardiovascular end points, and those progressing to other active treatments showed decreases (P</=0. 01) in total mortality (40%), stroke (59%), and all cardiovascular end points (39%). Among the control patients, 863 used only the first-line placebo. Compared with this subgroup, patients receiving monotherapy with nitrendipine showed a nearly 50% (P</=0.004) reduction of all types of end points, including total and cardiovascular mortality. The full relative benefit from nitrendipine was seen as early as 6 months after randomization. To ascertain that the benefit conferred by the dihydropyridine was not due to selection bias, the 1327 patients remaining on monotherapy with nitrendipine were matched by gender, age, previous cardiovascular complications, and systolic blood pressure at entry with an equal number of placebo patients. In this analysis, nitrendipine reduced (P</=0.05) cardiovascular mortality by 41%, all cardiovascular end points by 33%, and fatal and nonfatal cardiac end points by 33%. Despite the limitations inherent in post hoc analyses, the present findings suggest that the calcium channel blocker nitrendipine, given as a single antihypertensive medication, prevents cardiovascular complications in older patients with isolated systolic hypertension.

Aged↗
PubMed1998

Association of symptoms of type 2 diabetic patients with severity of disease, obesity, and blood pressure.

OBJECTIVE: The symptoms of 430 type 2 diabetic patients were determined by a self-administered questionnaire before entry into the U.K. Prospective Diabetes Study. RESEARCH DESIGN AND METHODS: Entry into the trial followed 2 months of dietary treatment for newly diagnosed patients with type 2 diabetes. Forty symptoms with five levels of severity were included in the questionnaire. A complaint rate was computed as the sum of symptom scores divided by the number of symptom questions answered. RESULTS: The complaint rate was independently and positively related to BMI, fasting plasma glucose (FPG), and being a woman. Three symptoms--presence of dry mouth (P < 0.001), thirst (P < 0.01), and stomach pain (P = 0.02)--were related to FPG independent of sex, age, BMI, or blood pressure. Only dry mouth was related to HbA1c (P = 0.05). Complaints of shortness of breath, swollen ankles, headaches, heartburn, sweating, wheezing, nocturia, thirst, and diarrhea increased with BMI independently of other variables. A complaint of cold extremities decreased with BMI. Heartburn, weakness of limbs, and hot flushes were positively related to blood pressure, and unsteadiness was negatively related. CONCLUSIONS: The symptoms reported by patients with type 2 diabetes increased with FPG and markedly with BMI. The symptoms associated with obesity have been underestimated in the past.

Age Factors↗
PubMed1997

Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators.

BACKGROUND: Isolated systolic hypertension occurs in about 15% of people aged 60 years or older. In 1989, the European Working Party on High Blood Pressure in the Elderly investigated whether active treatment could reduce cardiovascular complications of isolated systolic hypertension. Fatal and non-fatal stroke combined was the primary endpoint. METHODS: All patients (> 60 years) were initially started on masked placebo. At three run-in visits 1 month apart, their average sitting systolic blood pressure was 160-219 mm Hg with a diastolic blood pressure lower than 95 mm Hg. After stratification for centre, sex, and previous cardiovascular complications, 4695 patients were randomly assigned to nitrendipine 10-40 mg daily, with the possible addition of enalapril 5-20 mg daily and hydrochlorothiazide 12.5-25.0 mg daily, or matching placebos. Patients withdrawing from double-blind treatment were still followed up. We compared occurrence of major endpoints by intention to treat. FINDINGS: At a median of 2 years' follow-up, sitting systolic and diastolic blood pressures had fallen by 13 mm Hg and 2 mm Hg in the placebo group (n = 2297) and by 23 mm Hg and 7 mm Hg in the active treatment group (n = 2398). The between-group differences were systolic 10.1 mm Hg (95% CI 8.8-11.4) and diastolic, 4.5 mm Hg (3.9-5.1). Active treatment reduced the total rate of stroke from 13.7 to 7.9 endpoints per 1000 patient-years (42% reduction; p = 0.003). Non-fatal stroke decreased by 44% (p = 0.007). In the active treatment group, all fatal and non-fatal cardiac endpoints, including sudden death, declined by 26% (p = 0.03). Non-fatal cardiac endpoints decreased by 33% (p = 0.03) and all fatal and non-fatal cardiovascular endpoints by 31% (p < 0.001). Cardiovascular mortality was slightly lower on active treatment (-27%, p = 0.07), but all-cause mortality was not influenced (-14%; p = 0.22). INTERPRETATION: Among elderly patients with isolated systolic hypertension, antihypertensive drug treatment starting with nitrendipine reduces the rate of cardiovascular complications. Treatment of 1000 patients for 5 years with this type of regimen may prevent 29 strokes or 53 major cardiovascular endpoints.

Aged↗
PubMed1997

Measurements of vision function and quality of life in patients with cataracts in southern India. Report of instrument development.

OBJECTIVE: To develop and validate vision function (VF) and quality of life (QOL) instruments in patients with cataracts in the context of large volume surgery in a developing country. MATERIALS AND METHODS: The instruments were developed using a consensus approach. One hundred patients who were undergoing cataract surgery at Aravind Eye Hospital, Madurai, India, were interviewed preoperatively and 3 and 12 months postoperatively. Standard clinical procedures were followed, including measurement of visual acuity. Between-interviewer reproducibility was measured by repeated administration of the preoperative questionnaire. Within-interviewer reproducibility was measured preoperatively in a separate study of 50 patients. RESULTS: Preoperative scores from the VF and QOL instruments were significantly associated with visual acuity (r = 0.4). Internal reliability (Cronbach alpha) was greater than .9. Both instruments showed large changes after surgery, with effect sizes of 3 or greater for most VF scales (range, 1.8-3.7) and 1 or greater for QOL scales (range, 1.0-2.2). Changes in visual acuity after surgery were correlated with changes in the VF (r = 0.44) and QOL (r = 0.41) scale scores. Between-interviewer reproducibility was acceptable (total VF scale, Spearman r = 0.7; total QOL scale; r = 0.74). The kappa values were lower for within-interviewer reproducibility. CONCLUSIONS: The study provided strong evidence for the validity, reproducibility, and responsiveness of the instruments, and for the feasibility of using them in the setting of a large volume of cataract surgery in a developing country.

Cataract↗
PubMed1997

Biological profile of L-745,870, a selective antagonist with high affinity for the dopamine D4 receptor.

L-745,870,(3-([4-(4-chlorophenyl)piperazin-1-yl]methyl)-1H- pyrollo[2,3-b] pyridine, was identified as a selective dopamine D4 receptor antagonist with excellent oral bioavailability and brain penetration. L-745,870 displaced specific binding of 0.2 nM [3H] spiperone to cloned human dopamine D4 receptors with a binding affinity (Ki) of 0. 43 nM which was 5- and 20-fold higher than that of the standard antipsychotics haloperidol and clozapine, respectively. L-745,870 exhibited high selectivity for the dopamine D4 receptor (>2000 fold) compared to other dopamine receptor subtypes and had moderate affinity for 5HT2, sigma and alpha adrenergic receptors(IC50 < 300 nM). In vitro, L-745,870 (0.1-1 microM) exhibited D4 receptor antagonist activity, reversing dopamine (1 microM) mediated 1) inhibition of adenylate cyclase in hD4HEK and hD4CHO cells; 2) stimulation of [35S] GTPgammaS binding and 3) stimulation of extracellular acidification rate, but did not exhibit any significant intrinsic activity in these assays. Although standard antipsychotics increase dopamine metabolism or plasma prolactin levels in rodents, L-745,870 (</=30 mg/kg p.o.) had no effect in these assays. The lack of a suitable in vivo assay for D4 receptor activation prompted the use of in vivo surrogate marker assays which confirmed that doses of 5-60 microg/kg L-745,870 would be sufficient to occupy 50% D4 receptors in the brain. These results show that dopamine D4 receptor antagonism in the brain does not result in the same neurochemical consequences (increased dopamine metabolism or hyperprolactinemia) observed with typical neuroleptics.

Animals↗
PubMed1996

Controlled modification of acidity in cholecystokinin B receptor antagonists: N-(1,4-benzodiazepin-3-yl)-N'-[3-(tetrazol-5-ylamino) phenyl]ureas.

The design, synthesis, and biological activity of a novel series of CCK-B receptor antagonists (1) which incorporate a tetrazol-5-ylamino functionality attached to the phenyl ring of the arylurea moiety of L-365,260 are described. In these compounds, the acidity of the tetrazole was gradually modified by utilization of simple conformational constraints, and X-ray crystallographic data were obtained to support the conformational depenence of the pK(a) of the aminotetrazoles. Compounds to emerge from the present work such as 1f and 2c,d are among the highest affinity and, in the case of 1f, most selective (CCK-A/CCK-B, 37 000) antagonists so far reported for this receptor. The C(5)-cyclohexyl compound 2c (L-736,380) dose-dependently inhibited gastric acid secretion in anesthetized rats (ID(50), 0.064 mg/kg) and ex vivo binding of [(125)I]CCK-8S in BKTO mice brain membranes (ED(50), 1.7 mg/kg) and is one of the most potent acidic CCK-B receptor antagonists yet described.

Animals↗
PubMed1996

The relationship between plasma cholesterol concentration and minor psychiatric disturbance in the Department of the Environment Study.

We examined the hypothesis that low plasma cholesterol concentration was associated with minor psychiatric disturbance in a cross-sectional study of 410 male and 138 female civil servants. Psychiatric disturbance was measured using the 30-item General Health Questionnaire (GHQ). Mean GHQ score did not vary significantly with quartile of total cholesterol concentration. After adjustment for confounding variables a significant trend of increasing mean GHQ with increasing cholesterol concentration emerged. In a logistic regression analysis subjects in the highest quartile of cholesterol concentration had an adjusted odds ratio for being a "psychiatric case" of 2.0 (95% confidence interval, 1.1-2.5) compared with those in the lowest quartile. This relationship reversed when using a higher cutoff point to define more severe cases, although the trend was not statistically significant.

Adult↗