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Biomedical subjects

I Henderson

Publications and source records attributed to I Henderson.

13 recordsLinked to original sources
PubMed1995

A paradigm for drug discovery employing encoded combinatorial libraries.

Very large combinatorial libraries of small molecules on solid supports can now be synthesized and each library element can be identified after synthesis by using chemical tags. These tag-encoded libraries are potentially useful in drug discovery, and, to test this utility directly, we have targeted carbonic anhydrase (carbonate dehydratase; carbonate hydro-lyase, EC 4.2.1.1) as a model. Two libraries consisting of a total of 7870 members were synthesized, and structure-activity relationships based on the structures predicted by the tags were derived. Subsequently, an active representative of each library was resynthesized (2-[N-(4-sulfamoylbenzoyl)-4'-aminocyclohexanespiro]-4-oxo-7 -hydroxy- 2,3-dihydrobenzopyran and [N-(4-sulfamoylbenzoyl)-L-leucyl]piperidine-3-carboxylic acid) and these compounds were shown to have nanomolar dissociation constants (15 and 4 nM, respectively). In addition, a focused sublibrary of 217 sulfamoylbenzamides was synthesized and revealed a clear, testable structure-activity relationship describing isozyme-selective carbonic anhydrase inhibitors.

Benzopyrans↗
PubMed1992

Mechanism of inhibition of the calcium pump of sarcoplasmic reticulum by thapsigargin.

The steady-state ATPase activity of sarcoplasmic-reticulum (Ca(2+)-Mg2+)-ATPase is inhibited by thapsigargin at a molar ratio of 1:1, with a dissociation constant for thapsigargin estimated to be in the sub-nanomolar range. In the presence of thapsigargin, only a single Ca2+ ion binds to the ATPase. Similarly, addition of thapsigargin to the ATPase incubated in the presence of Ca2+ results in the release of one of the two originally bound Ca2+ ions. As monitored by the fluorescence of nitrobenzo-2-oxa-1,3-diazole-labelled ATPase, thapsigargin appears to shift the transition between E1 and E2 conformations towards E2. Addition of thapsigargin prevents phosphorylation of the ATPase by P(i) and results in a very low steady-state level of phosphorylation of the ATPase by ATP, as observed previously for nonylphenol.

Animals↗
PubMed1992

Objective clinical evaluation of physical impairment in chronic low back pain.

The aim of this study was to investigate physical impairment in patients with chronic low back pain, to develop a method of clinical evaluation suitable for routine use, and to consider the relationship between pain, disability, and physical impairment. Twenty-seven physical tests were investigated. Permanent anatomic and structural impairments of spinal deformities, spinal fractures, surgical scarring, and neurologic deficits were excluded as not relevant to the patient with low back pain in the absence of nerve root involvement or previous surgery. Three consecutive 20-patient reproducibility studies were used to develop reliable methods of examination for 23 of the tests. Only four tests were excluded as unreliable: sacral angle, pelvic tilt, and separate lumbar and pelvic extension, none of which are part of routine clinical examination or have any proven relationship to disability. The remaining 23 physical tests were evaluated in 70 asymptomatic subjects and 120 patients with chronic low back pain. Passive knee flexion, passive hip flexion, hip flexion strength, hip abduction strength, pain reproduction on each of these tests, and the prone extension strength test were excluded because they were too closely related to nonorganic and behavioral responses to examination. Eight tests successfully discriminated patients with low back pain from normal subjects and were significantly related to self-report disability in activities of daily living: pelvic flexion, total flexion, total extension, lateral flexion, straight leg raising, spinal tenderness, bilateral active straight leg raising, and sit-up. Factor analysis failed to demonstrate an underlying statistical dimension of physical impairment. However, an empirical combination of total flexion, total extension, average lateral flexion, average straight leg raising, spinal tenderness, bilateral active straight leg raising, and sit-up provided an equally satisfactory alternative. Simple cut-offs from normal subjects made the scale simple and quick to use. This final scale successfully discriminated 78% of patients and normal subjects and explained 25% of the variance of disability, with a specificity of 86% and sensitivity of 76%. This scale provides an objective clinical evaluation that meets the criteria for evaluating physical impairment, yet is simple, reliable, and suitable for routine clinical use. It should, however, be emphasized that all the tests included in the final scale are measures of current functional limitation rather than of permanent anatomic or structural impairment. This raises questions about the physical basis of permanent disability due to chronic low back pain.

Activities of Daily Living↗
PubMed1987

Pharmacokinetics of clavulanic acid-potentiated ticarcillin in renal failure.

The serum kinetics of an intravenous bolus of a combination of ticarcillin (TIC) (3 g) and clavulanic acid (CLAV) (0.2 g) have been determined in a number of patients with different degrees of renal failure as characterized by creatinine clearance. The volume of distribution for both drugs was unaffected by renal failure. Indices of serum and renal drug clearance were related to the degree of renal failure. TIC was cleared more slowly than CLAV. Anephric patients may have a higher serum clearance of CLAV than patients categorized by creatinine clearance as having severe renal failure; this could be due to an increase in metabolic clearance. Haemodialysis effectively clears both drugs. "Rebound" serum concentrations were consistently observed for TIC, but were observed in only one patient for CLAV. Continuous ambulatory peritoneal dialysis results in significant recovery of both drugs. The dosing requirements for the combination of TIC and CLAV in patients with renal failure are considered.

Adolescent↗
PubMed1983

Morphologic alterations in the Purkinje neuron of the rat induced by lysergic acid diethylamide and fixation.

The effect of lysergic acid diethylamide (LSD) on the morphology of the cerebellar cortex of the rat was studied with electron microscopy. Hippocampal electrical activity was used as an objective measure of drug efficacy. At a dose of 1700 micrograms/kg, the amplitude from the hippocampus was diminished (in 2 to 5 min) and this effect lasted for about 65 to 165 min. A morphologic alteration consisting of cisternal stacks occurred in the dendrites of Purkinje neurons of rats treated with this dose of LSD, with the perfusion carried out correctly. These stacks of smooth endoplasmic reticulum were seen 2 h after injection and persisted for at least 8 h. A reduction in the volume of perfused fluid to less than 500 ml caused similar changes in the dendrites of the Purkinje neuron of untreated rats; this was one way to experimentally induce a faulty perfusion. With LSD and faulty perfusion (reduced volume) more severe changes occurred in the dendrites and small stacks of smooth endoplasmic reticulum were seen in the Purkinje soma; similar changes were also seen when the perfusion of a control animal was mismanaged during the initial 3 min. The Purkinje neuron seems to manifest morphologic alterations, generally of two types, with exposure to a variety of noxious agents. The LSD caused some perturbation of this neuron, and this was found under properly controlled conditions of fixation. The results are interpreted as indicating that LSD is causing a metabolic alteration which could disrupt the synaptic activity over several hours.

Animals↗
PubMed1983

Prospective study of the psychiatric disorders of childbirth by self report questionnaire.

Two self report questionnaires, the Anxiety and Depression scales of Bedford and Foulds (SAD), and 10 visual analogue scales were each administered on several occasions during pregnancy and the puerperium to a representative sample of 425 childbearing women. Those women who each completed the analogue scales during pregnancy at 12 and 23 weeks and at 1 week and 5 months after childbirth (N = 230) showed no association between depression or anxiety and either the gravidity or method of delivery on any of the four occasions. Depression, anxiety and tearfulness on the visual analogue scales increased significantly 1 week after delivery, when compared with the other 3 occasions. The SAD failed to detect an increase in depression or anxiety at this time and its validity during pregnancy was also not satisfactory. Only 3 women were referred to a psychiatrist during the study, none of whom had an affective illness.

Adult↗
PubMed1981

Minoxidil in the management of intractable hypertension.

Eighty-seven patients with intractable hypertension received minoxidil for a mean duration of 27 months (range three months to five years). A significant reduction in mean outpatient blood pressure from 206/129 to 158/98 mmHg (p less than 0.001 for both systolic and diastolic values) was recorded after one month's treatment. In 26 patients who received minoxidil for four or more years a further reduction in mean blood pressure to 147/89 mmHg was achieved. The mean daily dose of minoxidil was 23 mg (range 2.5 to 60 mg). In all patients a beta adrenergic neurone blocker and a diuretic were prescribed with minoxidil to counteract tachycardia and fluid retention. Thirteen patients required the addition of a fourth hypotensive agent. The use of minoxidil led to simpler drug regimens with the majority of patients well controlled on twice daily or once daily schedules. Most patients commented spontaneously on a feeling of improved wellbeing while taking minoxidil which also appeared to be relatively free from side effects commonly encountered with other hypotensive drugs, particularly drowsiness, dizziness and impotence. Fluid retention of 7 kg or more occurred in 18 patients, more commonly in those with renal impairment, but could be controlled by increasing the dose or potency of diuretics. Four patients with end stage renal failure and one patient with normal renal function developed pericardial effusions. Hirsutism was universal and limited the usefulness of the drug in women. We currently recommend minoxidil for hypertensive men who diastolic blood pressure remains greater than or equal to 110 mmHg despite an adequate trial of a beta adrenergic neurone blocker, diuretic and an additional drug, or for patients who find the side effects of such therapy intolerable.

Adolescent↗