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Biomedical subjects

R F Moulds

Publications and source records attributed to R F Moulds.

At least 55 records · Page 3Linked to original sources
PubMed1987

A kinetic study of sulindac in the elderly.

To study the disposition of the anti-inflammatory drug sulindac, its active sulphide metabolite, and the inactive sulphone metabolite, sulindac (200 mg twice daily) was given to eight elderly subjects for at least 14 consecutive days. The drug was then ceased for 72 hours, and suitable samples were collected to study its elimination. The mean steady-state concentration for sulindac was 5.0 micrograms/ml, for sulindac sulphide was 6.5 micrograms/ml, and for sulindac sulphone was 13.2 micrograms/ml. These are approximately twice the reported steady-state levels for the respective redox forms in healthy young adults. The mean half-lives of sulindac, sulindac sulphide, and sulindac sulphone were 18.3 hours, 22.3 hours, and 54.6 hours, respectively. One patient who had mildly abnormal liver function tests developed more severe abnormalities whilst receiving sulindac. These returned towards normal after cessation of treatment. This patient had the highest steady-state plasma concentration of sulindac sulphone. It is concluded that care should be taken with the use of sulindac in the elderly, and control of patients' symptoms should be attempted with lower doses of the drug before the standard dose of 200 mg twice daily is administered.

Age Factors↗
PubMed1987

Changes in clearance of sodium valproate with changes in dose.

The relationship between total sodium valproate concentrations and drug clearance was studied in four patients, by the evaluation of clearance at two different doses. In each patient, the average unbound fraction for a dosing interval increased with increase in sodium valproate dose. Despite this increase in unbound fraction, there was no increase in total drug clearance, and in each patient there was a decrease in clearance of the unbound drug. These findings suggest either that the drug is restrictively cleared and there is a dose-related decline in intrinsic clearance, or, contrary to previous reports, that sodium valproate is cleared nonrestrictively.

Adult↗
PubMed1986

Educational antibiotic advertising.

Antibiotic audits that were conducted within our hospital between 1978 and 1982 showed persisting patterns of inappropriate antibiotic use. A commercial advertising agency was commissioned to plan a campaign to change entrenched prescribing habits. Amoxycillin was chosen as the test drug because previous audits consistently had shown that its intravenous administration was prescribed more frequently than was that of benzylpenicillin in the treatment of primary pneumonia. In addition, amoxycillin given by mouth was prescribed six-hourly rather than eight-hourly in one-third of the patients who were surveyed. A three-month remedial campaign used direct mail (pads and pens), display stands and posters, all of which focused on the booklet Antibiotic guidelines. Educational material was placed wherever staff members congregated. At the end of the campaign, intravenously administered amoxycillin was used in only 8% of 50 patients with primary pneumonia and amoxycillin given by mouth was prescribed six-hourly in only 10% of 99 patients. These changed habits were sustained six months after the campaign but showed some fall-off 18 months after the campaign. The campaign costs of $10,000 were recouped within 12 months by savings on drug costs. It is concluded that educational advertising is an effective means of changing prescribing behaviour in a hospital.

Administration, Oral↗
PubMed1986

Interaction between platelet-released serotonin and thromboxane A2 on human digital arteries.

Synergism between the contractile effects of platelet-derived serotonin (5HT) and thromboxane A2 (TXA2) on a human blood vessel has been investigated by incubating strips of digital arteries in subcontractile concentrations of either 5HT or the TXA2-mimetic agent U46619. Either agonist U46619 or 5HT, in subcontractile concentrations, significantly potentiated the contractile response to the other. The 5HT antagonist ketanserin (10 mumol/l), the Ca2+ antagonist drugs verapamil (3 mumol/l), or nifedipine (10 nmol/l), or a Ca2+-free bathing medium, reduced the contractile responses to 5HT, but had no effect on the potentiation mediated by U46619. The interaction between TXA2 and 5HT derived from platelets was studied by measuring responses to platelets 1 min after aggregation (in the absence or the presence of ketanserin 10 mumol/l), and 20 min after aggregation. The results indicated that the response to platelets mediated by TXA2 and 5HT was greater than the sum of those mediated by TXA2 or 5HT separately. It is concluded that synergism between the contractile effects of 5HT and U46619 occurs in human blood vessels; that this is mediated by enhanced utilization of intracellular, rather than extracellular calcium; and that synergism can also occur when 5HT and TXA2 are released from stimulated human platelets.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1986

Antagonism by nifedipine of alpha-1 and alpha-2 adrenoceptor-mediated responses of human digital arteries.

This study examines the effects of calcium-entry blockade by nifedipine on alpha-1 and alpha-2 adrenoceptor-mediated contractile responses of the human isolated digital artery to exogenous agonists and sympathetic nerve stimulation. Spiral strips of digital artery were mounted for isometric tension recording in physiological salt solution. Contractile responses to TL-99 and to norepinephrine in the presence of prazosin were effectively antagonized by rauwolscine and are therefore presumably mediated by alpha-2 adrenoceptors. Responses to norepinephrine in the presence of rauwolscine were antagonized by prazosin and are therefore mediated predominantly by alpha-1 adrenoceptors. Responses to methoxamine were antagonized by prazosin and, to a lesser extent, by rauwolscine, suggesting that this agonist is also activating alpha-2 adrenoceptors. Nifedipine antagonism of contractile responses was assessed as the percentage of inhibition of the area under the agonist concentration-effect curve or nerve stimulation frequency-effect curve. Nifedipine (10(-9) to 10(-7) M) inhibited responses to TL-99 and methoxamine to similar extents. Nifedipine (10(-8) and 10(-7) M) also had similar effects on the alpha-1 and alpha-2 adrenoceptor-mediated responses (in the presence of rauwolscine and prazosin, respectively) to either exogenous norepinephrine or sympathetic nerve stimulation. At concentrations up to 10(-6) M, nifedipine failed to reduce the efflux of [3H]norepinephrine produced by sympathetic nerve stimulation at either 2 or 8 Hz. We conclude that the alpha-1 and alpha-2 adrenoceptor-mediated contractile responses of the human digital artery are dependent to similar extents on calcium entry through the slow calcium channels of the cell membrane.

Electric Stimulation↗
PubMed1985

Effect of impairment of renal function on the accumulation and disposition of isoxicam.

The accumulation and disposition of the non-steroidal antiinflammatory drug isoxicam were investigated following its oral administration to 6 subjects with normal renal function and 13 patients with diminished renal function. Isoxicam was given daily as a single oral dose for 14-15 consecutive days. Steady-state plasma levels were achieved after 13 days. The effect of differences in renal function on the kinetics of isoxicam appeared to be minimal. Accumulation of isoxicam was similar in both groups of subjects and there was no significant difference between the groups in the plasma clearance or terminal half-life of isoxicam. There were substantial differences between individuals in the apparent plasma clearance and half-life of the drug, and this is reflected in the 7-fold range of steady-state plasma isoxicam concentrations encountered in the subjects.

Adult↗
PubMed1985

Neuronally released norepinephrine does not preferentially activate postjunctional alpha 1-adrenoceptors in human blood vessels in vitro.

Human isolated digital arteries and metatarsal veins, obtained postmortem, have been used to compare the effects of alpha-adrenoceptor antagonists on contractile responses to nerve stimulation. The antagonists used were prazosin, rauwolscine, BE 2254, and yohimbine. Rauwolscine (alpha 2-antagonist), as well as prazosin and BE 2254 (alpha 1-antagonists), in concentrations of 10(-9), 10(-8), and 10(-7) mol/liter, potently antagonized the frequency-response curves to nerve stimulation. Yohimbine (alpha 2-antagonist) was slightly less potent, failing to antagonize responses to nerve stimulation in arteries at the concentration of 10(-9) mol/liter significantly, but producing potent antagonism of responses in both arteries and veins at higher concentrations (10(-8), 10(-7) mol/liter). All antagonists inhibited the contractile responses to nerve stimulation to a greater extent in veins than in arteries. Rauwolscine (10(-9), 10(-8), and 10(-7) mol/liter) and BE 2254 (10(-7) but not 10(-8) mol/liter) significantly enhanced stimulation-induced tritium efflux in arteries and veins. These results suggest that alpha 2-adrenoceptor antagonists, despite their prejunctional effects, are potent antagonists of contractile responses to nerve stimulation. Thus, in these human blood vessels, endogenously released norepinephrine does not preferentially activate postjunctional alpha 1-adrenoceptors, but activates receptors with the properties of both the alpha 1- and alpha 2-adrenoceptor subtypes.

Adrenergic alpha-Antagonists↗
PubMed1984

The potential bronchodilator action of verapamil.

Although calcium antagonists such as verapamil are used primarily in cardiovascular disease, they appear to relax smooth muscle generally. Therefore, the possibility that verapamil might have bronchodilator properties was explored using the guinea-pig tracheal ring technique. Verapamil was found to produce considerable tracheal smooth muscle relaxation from a threshold concentration of 2 X 10(-7) M and with maximum effect at 10(-3) M. The responses to the contractile agonists histamine and prostaglandin F2 alpha and especially methacholine and serotonin were substantially reduced by prior administration of verapamil. Verapamil 2 X 10(-4) M was equally effective as isoprenaline 10(-8) M in producing 50% maximum direct relaxation but was more effective than isoprenaline as an antagonist of the contractile agonists, methacholine, histamine and serotonin, but not prostaglandin F2 alpha. Verapamil abolished the contractile responses to barium chloride. It is concluded that, although verapamil was not very potent as a direct bronchodilator, it could potentially be of prophylactic benefit in asthma because of its efficacy as an antagonist of common contractile agonists.

Animals↗
PubMed1984

The effects of platelet-derived contractile agents on human digital arteries.

The contractile responses of spiral strips of human digital arteries to samples of a suspension of human platelets aggregated by thrombin have been studied at different time intervals after aggregation. Platelets added to the arterial strips 1 min after aggregation of the platelets produced contractile responses which were significantly greater than those produced by corresponding platelets added 20 min after aggregation. When platelets were aggregated in the presence of indomethacin or the thromboxane synthetase antagonist 1-benzylimidazole, contractile responses produced by the platelets 1 min after aggregation were significantly reduced. They were then not significantly different from those produced by addition of the aliquots 20 min after aggregation, which were unaffected. Pretreatment of the arteries with the serotonin antagonist ketanserin nearly abolished the contractile responses produced by addition of the platelets 20 min after aggregation, and significantly reduced those produced by addition of the platelets 1 min after aggregation. Ketanserin did not affect the contractile responses of the arteries to potassium chloride, prostaglandin F2 alpha, or the endoperoxide analogue U-46619, but antagonized the contractile effects of exogenous serotonin. Combination of pretreatment of the arteries with ketanserin and aggregation of the platelets in indomethacin or 1-benzylimidazole virtually abolished contractile responses to platelets added both 1 min and 20 min after aggregation. Tensions developed to different dilutions of platelets added 1 min after aggregation to arteries pretreated with ketanserin were not significantly different from those obtained to the same dilutions added 20 min after aggregation to arteries not pretreated with ketanserin.(ABSTRACT TRUNCATED AT 250 WORDS)

Arteries↗
PubMed1983

Techniques for testing isolated blood vessels.

There are many different techniques described for studying isolated blood vessels, either human or animal. 1. For postsynaptic responses, spiral strip preparations using isometric tension monitoring probably allow the greatest flexibility for drug concentration-effect relationships. Isotonic tension may be monitored if extreme sensitivity is necessary and ring preparations probably better mimic the situation in vivo, but are harder to use. 2. Minor differences in salt solutions, pH, temperature and degree of oxygenation are probably not important except in special situations such as pH alterations when studying cerebral vessels and pO2 alterations when studying pulmonary or umbilical vessels. It is most important that the calcium concentrations remain constant as altered contractile effect may occur with small alterations in the calcium concentration of the physiological salt solution. 3. Electrical stimulation is necessary for studying presynaptic mechanisms. Most commonly, vessels are canulated and perfused through their lumen and superfused to remove the transmitter which has overflowed from the perivascular nerve stimulation. Neurotransmitter is then measured after preloading with tritiated noradrenaline. Electrical stimulation can also be performed on spiral strips which are immersed in small volume tissue baths allowing rapid changes in the bathing fluid, and although this method allows better monitoring of the postsynaptic responses associated with the electrical stimulation, it is more difficult to perform than perfusion and superfusion.

Animals↗
PubMed1983

Facilitatory prejunctional beta-adrenoceptors in human arteries and veins.

The effects of beta-adrenoceptor agonists and antagonists on both the transmitter outflow and the associated pressure response produced by perivascular nerve stimulation have been studied in human digital arteries and metatarsal veins, in which transmitter stores were labelled with [3H]noradrenaline. Both isoprenaline in arteries, and salbutamol in arteries and veins, at concentrations of 10(-8) - 10(-6) mol/l significantly enhanced stimulation-induced tritium outflow. These two agonists were approximately equipotent. Salbutamol also potentiated pressure responses to stimulation, and propranolol prevented the enhancement of stimulation-induced tritium outflow by salbutamol. Adrenaline, at a concentration of 10(-8) mol/l, but not lower concentrations, significantly enhanced stimulation-induced tritium outflow in arteries. Propranolol, however, had no effect on stimulation-induced transmitter outflow, even when the arteries were either perfused throughout the experiment with a low concentration of adrenaline, or when the arteries were preincubated in a high concentration of adrenaline as well as perfused throughout with a low concentration of adrenaline. It is concluded that facilitatory prejunctional beta-adrenoceptors (probably of the beta 2-subtype) are present in human arteries and veins, but that under the conditions of these experiments, neither transmitter noradrenaline, nor adrenaline that has been incorporated into transmitter stores with noradrenaline, activate these prejunctional beta-adrenoceptors. They may, however, be activated under conditions of enhanced adrenomedullary secretion.

Adrenergic beta-Agonists↗