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Biomedical subjects

R F Moulds

Publications and source records attributed to R F Moulds.

At least 19 recordsLinked to original sources
PubMed1991

Anticonvulsants in pregnancy.

OBJECTIVE: To review the potential problems and their management associated with the use of anticonvulsant drugs during pregnancy. DATA SOURCES: Studies published between 1968 and 1990 assessing the effect of pregnancy on the pharmacokinetics of anticonvulsant drugs, the teratogenicity of anticonvulsants, breast feeding and anticonvulsants and use of the oral contraceptive pill in patients taking anticonvulsant medication, were reviewed. RESULTS OF DATA SYNTHESIS: In general, plasma levels fall during pregnancy and rise during the puerperium. A number of factors including possible reduced absorption, increased volume of distribution, reduced protein binding, increased clearance and noncompliance, contribute to this fall in plasma concentration. All anticonvulsants are potentially teratogenic. The incidence of fetal malformations is higher in patients treated with multiple anticonvulsant drugs and on higher dosages with higher plasma levels. Anticonvulsants are excreted in low concentrations in breast milk. All anticonvulsants except valproic acid have been associated with failure of the oral contraceptive pill. This is due to liver enzyme induction of these drugs. CONCLUSION: As plasma levels of anticonvulsants fall during pregnancy, concentrations should be monitored regularly. Due to the fall in protein binding, marginally low total plasma levels of highly protein bound drugs may not reflect reduced unbound levels, and hence an increase in dosage may not be required. In order to reduce teratogenicity, one should aim to use a single anticonvulsant drug and the lowest dosage able to achieve seizure control. In general, breast feeding is not contraindicated.

Abnormalities, Drug-Induced↗
PubMed1991

Differences between rat and guinea pig aorta in postreceptor mechanisms of alpha 1-adrenoceptors.

The relative importance of different postreceptor mechanisms associated with alpha 1-adrenoceptor activation in guinea pig aorta and rat aorta was compared. In both tissues, a concentration-dependent correlation was observed between contractile responses produced by high concentrations of norepinephrine (NE) and inositol-1-phosphate (IP1) accumulation. Blockade of Ca2+ entry through voltage-dependent membrane channels by nifedipine had no inhibitory action on NE-induced contractile responses in guinea pig aorta, but significantly inhibited NE-induced contractile responses in rat aorta. Nifedipine had no major effect on NE-induced IP1 accumulation in either tissue. A medium with no Ca2+ inhibited NE-induced contractile responses and IP1 accumulation in guinea pig aorta, but had a more marked effect on contractile responses and IP1 accumulation in rat aorta. The combination of a high concentration of nifedipine and a medium with no Ca2+ almost completely inhibited NE-induced contractile responses and IP1 accumulation in both tissues. Exposure to EGTA also virtually completely inhibited NE-induced contractile response and IP1 accumulation in both tissues. Significant 45Ca2+ entry was stimulated in rat aorta by NE, and this entry was completely blocked by nifedipine. No significant 45Ca2+ entry was stimulated by NE in guinea pig aorta. We conclude that the most important postreceptor event linked to alpha 1-adrenoceptor stimulation in guinea pig aorta is activation of the phosphatidylinositol pathway, whereas in rat aorta Ca2+ entry through voltage-dependent membrane channels is as important as activation of the phosphatidylinositol pathway. We also conclude that activation of the phosphatidylinositol pathway in both tissues is critically dependent on the presence of a small amount of Ca2+, which may enter from the external medium.

Animals↗
PubMed1991

Differing calcium sensitivities of human cerebral and digital arteries, human metatarsal veins, and rat aorta.

1. The effects of the voltage dependent calcium channel blocking agent nifedipine, and of a calcium free bathing medium, on the responses of human blood vessels obtained postmortem to various agonists have been compared with those of the rat aorta. The human vessels studied were digital arteries, basilar arteries and metatarsal veins. 2. Responses to potassium chloride (5-80 mM), noradrenaline (10(-9)-10(-4) M), 5-hydroxytryptamine (10(-8)-10(-4) M) and U46619 (10(-11)-10(-6) M), in the presence and absence of nifedipine (1, 10, and 100 nM) or in a calcium-free bathing medium, were assessed using an area-under-curve analysis. 3. In general, the order of sensitivity of the vessels to inhibition of agonist induced contractures by nifedipine was basilar arteries greater than metatarsal veins = digital arteries = rat aorta. 4. For all the vessels, the order of sensitivity for antagonism of responses to the agonists by nifedipine was potassium chloride greater than 5-hydroxytryptamine = noradrenaline greater than U46619. 5. A calcium free bath inhibited responses of digital arteries to potassium chloride more than noradrenaline, 5-hydroxytryptamine or U46619, and responses of rat aorta to a greater extent than responses of the digital arteries. 6. In the rat aorta, a calcium-free bath inhibited responses to all agonists (except KCl) to a greater degree than did nifedipine. 7. We conclude that inhibition of extracellular calcium entry through voltage dependent calcium channels affects contractile responses of different blood vessels to different extents, and, within the same blood vessel, responses to different contractile agonists to different extents.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1991

Ponalrestat does not cause a protein binding interaction with warfarin in diabetic patients.

Ponalrestat (Statil, ICI; Prodiax, Merck Sharp and Dohme) is an aldose reductase inhibitor which is highly protein bound. Ponalrestat markedly displaced warfarin from its protein binding in vitro at a concentration of 500 micrograms ml-1, but not at a concentration of 50 or 100 micrograms ml-1. Twelve diabetic patients (six males), age range 38-65 years, in receipt of chronic stable warfarin therapy, were given ponalrestat (600 mg daily) for 2 weeks in an open trial. A matching placebo tablet was administered for 1 week before and after the active treatment period. Patients were seen ten times (four times during the ponalrestat phase), and during the ponalrestat phase, plasma samples were also taken before and at 3 h after the daily dose of ponalrestat. At none of the visits was there any significant change in prothrombin ratio (INR), plasma total or unbound warfarin concentrations, or percentage protein binding of warfarin. No clinical complications of combination treatment were detected. The maximum ponalrestat concentration observed in the patients was approximately 100 micrograms ml-1. We conclude that no significant interaction between these drugs occurs at the doses of ponalrestat studied.

Adult↗
PubMed1990

Measurement of cost-effectiveness of drug therapy: a review of the treatment of hypertension.

There is good quantitative epidemiological evidence on the risk of cardiovascular disease posed by hypertension and, from large clinical trials, on the actual benefits gained from treatment of hypertension. Thus, hypertension presents a good model for the performance of cost-effectiveness analysis. From the Framingham study, it can be calculated that hypertensive men (blood pressure, greater than 160/95 mmHg) have a 2.8-fold higher cardiovascular mortality than normotensive men (blood pressure, less than 140/90 mmHg), and hypertensive women have a 2.3-fold higher incidence of cardiovascular mortality than normotensive women. Hypertension presents an equal relative risk to both men and women, but the absolute risk to men is greater. The largest absolute risk from hypertension is of coronary heart disease (144 events per 10,000 men per year); however, the largest relative risk from hypertension is of stroke (approximately 700%). From the Framingham data, it can be calculated that the complete reversal of hypertension for 18 years across a community could reduce the incidence of coronary heart disease by approximately 63%, and of strokes by 87%. Meta-analysis of the large clinical trials on the treatment of hypertension shows that mortality from stroke was reduced as a result of treatment by 38%, and that from coronary heart disease by 8%. Therefore the actual benefits of treatment, while significant, have not matched the theoretical benefits that could have been achieved. One of the reasons for this is that treatment may have adverse effects on other risk factors for coronary artery disease. All these factors, including the incidence of side effects interfering with quality of life, need to be taken into consideration when performing a cost-effectiveness analysis of the treatment of hypertension.

Aged↗
PubMed1990

Lack of effect of granulocyte-macrophage colony stimulating factor on the rat aorta or human saphenous vein.

1. In order to assess whether the observed hypotensive response in some patients given human granulocyte-macrophage colony stimulating factor (GM-CSF) is caused by a direct vascular effect of the GM-CSF, the effects of mouse and human GM-CSF were examined in rat aortic rings and human saphenous veins respectively. 2. No effects of GM-CSF were observed, either in the presence or absence of endothelium, on responses to the alpha-adrenoceptor agonist phenylephrine. 3. These data suggest that GM-CSF does not have direct effects on either vascular endothelium or smooth muscle, and that a direct vascular effect of GM-CSF is not the explanation for the observed clinical response.

Animals↗
PubMed1990

Alpha adrenoceptor activation and postreceptor contractile mechanisms in the human digital artery.

In order to compare postreceptor mechanisms of different alpha adrenoceptors, polyphosphoinositide hydrolysis and extracellular calcium entry stimulated by alpha-1 and alpha-2 adrenoceptor activation has been evaluated in the human digital artery, a tissue which contains both receptors. [3H]Inositol-I-PO4 accumulation during a 60-min exposure to an alpha-1 or alpha-2 agonist in the presence of 5 mM LiCl was used as an index of phosphatidylinositol-4,5-bisphosphate hydrolysis. Norepinephrine (1-30 microM) produced a concentration-related increase in [3H]inositol phosphate formation with an EC50 of 2.3 microM. Equieffective contractile concentrations of TL-99 (1 microM) and methoxamine (100 microM) produced similar increases in [3H]inositol-I-PO4 formation (1.41- and 1.70-fold increases over control, respectively). Norepinephrine EC50 values of 0.54, 1.7 and 1.0 microM were obtained for contractile responses in 1.25 mM Ca++, 0 mM Ca++ and 0 mM Ca++ + 0.1 mM ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid, respectively. Calcium omission (no ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid) produced similar inhibition of alpha-2 and alpha-1 adrenoceptor-mediated responses, assessed as inhibition of the area under the concentration-effect curve. Calcium omission generally produced a slightly greater inhibition of TL-99- or methoxamine-induced contractile responses than did nifedipine (0.1 or 1 microM), but the combination of calcium-omission and nifedipine practically abolished the contractile responses. However, the combination of a calcium omission and nifedipine did not prevent the accumulation of inositol monophosphate stimulated by TL-99 or methoxamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium↗
PubMed1978

Effects of the beta-receptor antagonists propranolol, oxprenolol and labetalol on human vascular smooth-muscle contraction.

1. Spiral strips of human digital arteries have been studied in vitro to investigate whether DL-propranolol, D-propranolol, oxprenolol and labetalol have peripheral vascular effects in man. 2. Labetalol was a potent inhibitor of contractile responses to noradrenaline, but had less effect on responses to 5-hydroxytryptamine and barium chloride. 3. DL-and D-propranolol were equally effective inhibitors of responses to barium chloride. They were only weak antagonists of noradrenaline responses, but stronger, non-competitive antagonists of 5-hydroxytryptamine responses. 4. Oxprenolol was only a weak inhibitor of the responses to both noradrenaline and 5-hydroxytryptamine and had little effect on responses to barium chloride. 5. It is concluded that labetalol has specific alpha-adrenoreceptor-blocking properties, which are probably relevant to its therapeutic action in man. Propranolol has non-specific inhibitory effect on vascular smooth muscle, which might contribute to its hypotensive activity at high concentrations, but oxprenolol has only slight peripheral effects that are probably therapeutically insignificant.

Adrenergic beta-Antagonists↗
PubMed1978

The action of prazosin in human vascular preparations.

To identify the mode of action of prazosin, its effects on isolated human vascular preparations were studied. Isometric tension was recorded from spiral strips of dorsal metacarpal veins, common palmar digital arteries and uterine, splenic and ileocolic arteries. Prazosin was a potent antagonist of noradrenaline, but not 5-hydroxytryptamine or barium chloride in the metacarpal veins. Higher concentrations of prazosin were necessary to antagonize noradrenaline in the visceral arteries. The digital arteries were resistant to its sympatholytic effect. It is concluded that prazosin acts as an alpha-adrenoceptor antagonist of different potency in various vascular beds. It is postulated that the initial cardiovascular side effects of prazosin are due to venous pooling and that the long term antihypertensive effect is the result of reduced peripheral resistance because of interference with arterial sympathetic tone.

Barium↗
PubMed1977

A study of the contractility, biochemistry and morphology of an isolated preparation of human skeletal muscle.

1. A new method of studying isolated human skeletal muscle has been evaluated. This involves the incubation and electrical stimulation of strips of muscle, obtained at surgical biopsy, that are tied at the cut ends of the fibre bundles. 2. Morphological examination showed that the fibres were sealed off at the cut ends. Damage appeared to be restricted to the areas immediately adjacent to the ties. 3. Contractile properties were well maintained for several hours and measurements of tissue metabolites showed that muscle contents of the high-energy phosphate compounds were well preserved. 4. The isolated preparations were found to have the same contractile properties as human quadriceps femoris studied in vivo by the methods described in the preceeding paper. 5. Correlation was found between the relaxation speed of the isolated preparations and their fibre-type composition histochemically determined. 6. It is concluded that this technique is a valid addition to the present methods of studying the physiology and pharmacology of human skeletal muscle.

Adenosine Triphosphate↗
PubMed1977

A comparison of the effects of sodium thiocyanate and dantrolene sodium on a mammalian isolated skeletal muscle.

1 A combination of electrical and pharmacological stimulation has been used to compare the effects of sodium thiocyanate and dantrolene sodium on the excitation-contraction coupling (ECC) mechanism of the mouse soleus muscle. 2 Thiocyanate prolonged the 'active state' after electrical stimulation and increased the response to 8 mM caffeine and 80 mM KCl. Dantrolene had an opposite effect to thiocyanate on all the indices studied. 3 It is concluded that the mechanism of action of dantrolene is by inhibition of the release of the calcium ions involved in the ECC mechanism, probably at the level of the transverse tubules.

Animals↗
PubMed1977

Is malignant hyperpyrexia muscle denervated?

To test the hypothesis that human muscular dystrophies may be secondary to denervation, the responses in vitro of muscle in human malignant hyperpyrexia to electrical and pharmacological stimuli have been compared with those of the denervated mouse soleus muscle. The results suggest that the muscle abnormality in malignant hyperpyrexia is different from that produced by denervation. This must cast doubt on the concept that other human muscular dystrophies are secondary to denervation.

Animals↗