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Biomedical subjects

H J Smith

Publications and source records attributed to H J Smith.

At least 163 records · Page 9Linked to original sources
PubMed1987

Experimental Trichinella infections in ponies.

Light Trichinella infections were established in three ponies given 1000, 5000 and 25000 T. spiralis spiralis infective larvae respectively by stomach tube. A predilection site of infection in all ponies was the tongue. Anti-Trichinella antibodies were detected in all ponies by the enzyme-linked immunosorbent assay using a T. spiralis spiralis excretory-secretory antigen. The ponies given 5000 and 25000 infective larvae reacted positively on days 26 and 24 postinfection, respectively, using a criterion of greater than or equal to 5 X mean optical density readings of preinfection sera as positive. The pony given 1000 larvae did not react positively although antibodies were present as indicated by 3 X to 4 X mean optical density readings of preinfection sera. The results of this limited study indicate that the enzyme-linked immunosorbent assay cannot be used to certify horsemeat free of Trichinella since the presence of detectable antibody levels appears to be related to the magnitude of the infection and duration of the infection when the animal is tested.

Animals↗
PubMed1986

Influence of food and marker length on gastric emptying of indigestible radiopaque markers in healthy humans.

A simple, noninvasive radiographic method was used to investigate the influence of food and of marker length on gastric emptying of indigestible solids. Ten healthy human subjects who had fasted for 12 h exhibited more rapid emptying when solid radiopaque markers were ingested with water than they did when markers were ingested with a 400-kcal solid and liquid meal. Mean (+/- SE) emptying of markers that were 10 mm in length averaged 55% +/- 15%, 97% +/- 3%, and 100% 1, 2, and 4 h after ingestion of the markers with water, compared with 4% +/- 2%, 32% +/- 11%, and 64% +/- 12% emptying 1, 2, and 4 h after ingestion of markers with the meal (p less than 0.05). Ingestion of a second and third test meal significantly prolonged gastric emptying of indigestible markers (p less than 0.05). No significant difference in emptying of the 10- and 2-mm markers from the stomach was detected. These experiments indicate that gastric emptying of indigestible solids in humans is strongly influenced by food intake, but not by the particle lengths studied.

Adult↗
PubMed1986

Synthesis and biochemical evaluation of analogues of aminoglutethimide based on phenylpyrrolidine-2,5-dione.

A series of (aminophenyl)pyrrolidine-2,5-diones has been prepared that bear structural similarities to aminoglutethimide (1, 3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione). The inhibitory activity of these compounds was evaluated toward human placental aromatase and bovine adrenal cholesterol side chain cleavage (CSCC) enzyme assay systems. Selective, competitive inhibition of the aromatase enzyme system was demonstrated by 5 (3-(4-aminophenyl)-1-methyl-pyrrolidine-2,5-dione, Ki = 1.75 microM), 6 (3-(4-aminophenyl)-1,3-dimethylpyrrolidine-2,5-dione, Ki = 1.75 microM), 7 (3-(4-aminophenyl)-3-methylpyrrolidine-2,5-dione, Ki = 0.8 microM), and 8 (3-(4-aminophenyl)-3-ethylpyrrolidine-2,5-dione, Ki = 1.0 microM). Compound 15 (3-(4-aminophenyl)pyrrolidine-2,5-dione) proved unexpectedly difficult to prepare following standard methods and was only moderately inhibitory toward aromatase (IC50 = 20 microM). Compound 16 (3-(4-aminophenyl)-3-ethyl-1-methylpyrrolidine-2,5-dione) was weakly inhibitory toward testosterone aromatization and totally inactive toward androstenedione aromatization. These compounds were either weak or ineffective inhibitors of the CSCC enzyme systems, while 1 gave Ki values toward aromatase and CSCC enzymes of 0.68 and 14 microM, respectively. The unsubstituted phenylpyrrolidinediones were inactive in either system, and the 4-nitrophenyl derivatives exhibited weak, nonselective inhibition, indicating the importance of the primary amine moiety for potent inhibition of aromatase activity.

Aminoglutethimide↗
PubMed1986

Trends in pacemakers which physiologically increase rate: DDD and rate responsive.

Exercise (rate) responsive pacemakers benefit patients by providing increased cardiac output when needed and permitting lower rate during rest. This paper briefly reviews trends in reported studies on rate responsive pacemakers. For patients with reliable atrial rhythms, atrial-triggered pacemakers (DDD) provide physiological ventricular rates unless complications arise. At low rates, A-V synchrony benefits patients with refractory cardiac decompensation; however, in patients with healthy myocardiums, achieving higher pacing rates is more significant than maintaining synchrony. If atrial rhythms are unreliable, an alternative sensor for determining pacing rate is indicated. Pacemakers that respond to changes in right ventricular blood temperature, respiratory rate, QT interval, body vibration (motion), and pH have been implanted in humans. Clinical evaluations have shown that increased pacing rate leads to increased exercise tolerance and cardiac output when needed, independent of the sensor type (DDD, QT, respiratory rate, etc.). The effectiveness of any sensor type to increase pacing rate appropriately requires reliable sensors that respond specifically to the need for increased pacing rate. Sensors for stroke volume, venous oxygen saturation, right atrial or ventricular pressure and catecholamines are also under preclinical investigation. The availability of a reliable, long-term sensor is a key limitation to several techniques including pH, stroke volume, oxygen saturation, pressure, and catecholamines. Sensor technology and clinical effectiveness are the keys to rate responsive pacing.

Blood↗
PubMed1986

Pharmacology of aminoglutethimide: structure/activity relationships and receptor interactions.

The structure/activity relationships for inhibition of aromatase and cholesterol side-chain cleavage enzyme (CSCC) by aminoglutethimide and some of its analogues are reviewed. Although more effective against aromatase than CSCC, aminoglutethimide markedly inhibits both enzymes. Optimal competitive antagonism of aromatase is obtained with a free amino or basic group at the 4' position of the phenyl ring substituent. This is important because two major metabolites of aminoglutethimide where the amino group is conjugated have low or no inhibitory effect on aromatase. Relocation of the free amino group to the nitrogen atom of the piperidinedione ring enhances CSCC inhibition. The piperidinedione ring is not essential for inhibitory activity, several 4'-aminophenyl pyrrolidinediones being as potent as aminoglutethimide for aromatase but less effective against CSCC. In this series 3-(4'-aminophenyl)-pyrrolidine-2,5-dione is a selective aromatase inhibitor. Inactivity of 4'-aminophenyl derivatives of imidazolidinedione and pyrimidinetrione indicate that the 4'-aminophenyl moiety alone is insufficient for antagonist activity against aromatase. Replacement of the aminophenyl group by the stronger basic 4-pyridyl moiety in aminoglutethimide yields a selective aromatase inhibitor. The structure/activity data suggest that there is a critical distance between the basic centre and the dione moiety for effective aromatase inhibition. Aminoglutethimide and its analogues possessing a free basic centre elicit a Type II difference spectrum with various cytochrome P-450 isozymes. The spectrally-determined binding affinity correlates with inhibitory activity of these compounds and indicates binding of the amino group to the iron centre of this haem enzyme. In reviewing the postulated mechanisms for the enzyme-mediated aromatisation of substrates it is seen that the initial oxidative attack is at the C-19 position of the steroid. It is proposed that two binding or association sites on the protohaem moiety of this P-450 enzyme (iron and propionic acid residues respectively) are required for the orientation of the substrate. Crystallographic evidence indicates there is a distance of about 6.3 A between the C-17 oxygen and the C-19 methyl of the aromatase substrates (these points interacting with the association sites). There is a similar distance between the basic function and the C-6 keto group for aminoglutethimide (and the C-5 keto group for the pyrrolidinediones). It is proposed that aminoglutethimide and its active analogues interact with aromatase at these binding sites competitively inhibiting the aromatisation of androstenedione and testosterone.

Aminoglutethimide↗
PubMed1985

Gastrointestinal hemorrhage in paralyzed and neurologically impaired patients: contribution of reflux esophageal disease.

The role of gastroesophageal reflux (GER) and reflux esophagitis in the pathogenesis of gastrointestinal hemorrhage was assessed in 13 male patients with chronic paralysis or neurologic impairment. Nine of the 13 patients initially presented for barium meal examination to evaluate anemia, hematemesis, heme-positive stools, or melena. Six of the 9 had radiographic evidence, confirmed by upper gastrointestinal (GI) endoscopy, of esophagitis with or without stricture without other upper GI tract lesions. Notably absent were antecedent symptoms of GER such as heartburn or dysphagia. Careful examination of the esophagus, although difficult, must be an integral part of the evaluation for anemia and/or gastrointestinal blood loss in paralyzed patients.

Adult↗
PubMed1985

The relative sensitization by acidosis of five calcium blockers in cat papillary muscles.

We have previously reported that the negative inotropic effects of both verapamil and nifedipine on cat papillary muscles are enhanced as pH is lowered from 7.4 to 6.8 and 6.0. These studies have now been extended to compare the relative sensitization by acidosis of verapamil, nifedipine, lidoflazine, perhexilene and diltiazem. Developed tension was recorded in cat papillary muscles and the calcium concentration was adjusted over the range 2 to 10 mM. At pH 7.4, addition of all five drugs moved the dose response curve to the right with pA2 values from 4.82 (lidoflazine) to 9.94 (nifedipine). At pH 6.0, there was eight-fold sensitization by acidosis for verapamil, but four, three, and two-fold sensitization for nifedipine, lidoflazine and perhexilene. Diltiazem, however, was not sensitized by acidosis. The differential effects of acidosis on the negative inotropic properties of the five drugs may reflect their ancillary properties opposite gating of the calcium channel, local anaesthesia, intracellular calcium movement or Na+/Ca2+ exchange, but also suggest that diltiazem may have the property of inhibiting the effects of low pH on cell membranes.

Acidosis↗
PubMed1985

Experimental models of heart failure.

Experimental models of heart failure can be used to address specific questions not easily answered in patients, but no single model can reproduce exactly any of the clinical syndromes of heart failure since these are dominated by fatigue and breathlessness. Heart failure may be induced experimentally by pressure loading, volume loading, myocardial infarction, or by the creation of other disease states within the myocardium. Pressure loading may be especially useful in the study of ventricular hypertrophy, cellular derangements and vascular changes. Volume loading may be useful when examining the pathogenesis of hormone and electrolyte disturbances. Models of myocardial infarction or destruction are likely to be the most suitable for assessing novel therapy provided that peripheral reflexes are maintained. Experimental cardiomyopathy can provide an important means of identifying pathological subcellular mechanisms. They may be of use in the evaluation of vasodilator drugs but caution should be exercised in the study of inotropic agents. Any one model may be useful if it permits study of a single factor or variable in isolation or at a time when information is not obtainable from patients. For greatest clinical relevance, studies should be made in conscious animals with intact reflexes.

Animals↗
PubMed1985

A clinically relevant model of heart failure: effects of ticlopidine.

A clinically relevant model of heart failure has been developed in chronically instrumented mini-pigs by injecting Sephadex beads into the left main or circumflex coronary arteries under fluoroscopic control. In six control animals, left atrial pressure (LAP) increased from 10 +/- 2 to 19 +/- 2 mmHg (p less than 0.01) and remained elevated for 3 days. Heart rate increased by 26 beats X min-1 (p less than 0.05) and diastolic pressure fell after 24 h but recovered over the next 48 h. In six animals treated with ticlopidine (50 mg X kg-1 p.o.) for four days prior to embolisation, the acute haemodynamic changes were less in the first day but similar to control after 3 days. Infarct size was approximately 20% of the left ventricle in control animals and 9.5% in the treated group (p less than 0.01). ADP-induced platelet activity was reduced in the treated animals suggesting that coronary occlusion followed both physical occlusion by the beads and later development of platelet thrombi.

Animals↗
PubMed1985

Intrinsic sympathomimetic activity of cardioselective beta-adrenoceptor blockers and effects on renal function.

The effects of a 21 infusion of isotonic sodium chloride on renal haemodynamics and sodium excretion were measured in nine normotensive volunteers. Changes in these responses to volume expansion induced by cardioselective beta-adrenoceptor blockade by drugs with (epanolol) and without intrinsic sympathomimetic activity (atenolol) were examined. Renal plasma flow was significantly lower before, during and after sodium chloride infusion whilst on treatment with atenolol compared with epanolol. Urinary sodium excretion was lower on atenolol than epanolol. Glomerular filtration rate was unchanged by either drug. Basal urinary kallikrein excretion was diminished by atenolol and both epanolol and atenolol inhibited the rise in urinary kallikrein excretion after sodium chloride infusion. Although some of these findings may be due to a more potent hypotensive effect of atenolol, intrinsic sympathomimetic activity may contribute to the apparent protective effects of epanolol on renal function.

Adrenergic beta-Antagonists↗
PubMed1985

Infectivity of Canadian isolates of Trichinella spiralis nativa for swine, rats and carnivores.

The infectivity of Trichinella spiralis nativa isolates from widely separated geographic areas of Canada was determined by feeding infected musculature to swine, laboratory rats and carnivores (cats, foxes, ferrets). Low infectivity for swine and rats and high infectivity for carnivores were observed. Light infections were established in four of 16 swine examined between 25 and 53 days postinfection. Feeding of infected porcine musculature to ferrets demonstrated that Trichinella spiralis nativa can be passaged through swine even though the infectivity rate is low.

Animals↗
PubMed1984

Preconditioning of Trichinella spiralis nativa larvae in musculature to low temperatures.

Preconditioning of a Trichinella spiralis nativa isolate in ferret and fox musculature was carried out by freezing at -15 degrees C from 0 to 322 days prior to low temperature refrigeration at -32 degrees C. A limited number of preconditioned samples of infected fox musculature was also refrigerated at -45 degrees C. Preconditioned larvae were appreciably more resistant than those subjected to the low temperatures directly. Under the conditions of this investigation, the longer the period of preconditioning, the greater the resistance, (i.e., survival of larvae) observed. The larvae in fox musculature were slightly more resistant than those in ferret musculature. Limited infectivity trials indicated that pre-conditioned larvae surviving low temperature refrigeration of -32 degrees C -45 degrees C retained their infectivity for at least 44 and 37 days, respectively.

Adaptation, Physiological↗
PubMed1984

Facilitation of calcium blocking and membrane effects by intrinsic sympathomimetic activity.

The interactions between ICI 118, 587 (Corwin) a beta 1-selective partial adrenergic agonist, and atenolol (Tenormin), propranolol (Inderal) and verapamil were examined first in anaesthetised dogs pretreated with syrosingopine and vagotomised. ICI 118, 587 was administered iv in cumulative doses of 0.1 to 1000 micrograms X kg-1. In four animals, heart rate increased from 102 +/- 4 to 188 +/- 12 beats X min-1 with a KA of 2.5 +/- 0.9 micrograms X kg-1. ICI 118, 587 was then administered to five groups each of four animals pretreated with atenolol (250 micrograms X kg-1 and 500 micrograms X kg-1iv), propranolol (250 micrograms X kg-1 and 500 micrograms X kg-1) or verapamil (200 micrograms X kg-1 plus 5 micrograms X kg-1 X min-1 iv). Both atenolol and propranolol shifted the dose response curve to the right but verapamil did not. Atenolol did not lower the maximal heart rate response to ICI 118,587. Both propranolol and verapamil slowed heart rate significantly (P less than 0.05) after, but not before, ICI 118,587. Further studies were then carried out in vitro. Cat papillary muscles were superfused with physiological saline at pH 7.4 and with either atenolol or ICI 118,587 at 5 X 10(-5) mol X litre-1. Tension was recorded at Lmax over a [Ca2+] range of 0.5 to 8 X 10(-3)mol X litre-1. The pA2 for verapamil against Ca2+ in the presence of atenolol and ICI 118,587 was 5.25 +/- 0.10 and 6.57 +/- 0.22 respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗