Search PubMed⌕ Search

Biomedical subjects

W J Louis

Publications and source records attributed to W J Louis.

At least 127 records · Page 7Linked to original sources
PubMed1987

The pharmacokinetics of captopril and captopril disulfide conjugates in uraemic patients on maintenance dialysis: comparison with patients with normal renal function.

We have measured the plasma concentrations of captopril and total disulfide conjugates of captopril after a 50 mg oral dose in 6 uraemic patients on maintenance dialysis and in 8 hypertensive subjects with normal renal function. The mean peak plasma concentration of captopril was 2.5 times higher (0.447 micrograms X ml-1 vs 0.181 micrograms X ml-1) and the concentrations of the disulfides 4 times higher (3.62 micrograms X ml-1 vs 0.924 micrograms X ml-1) in the uraemic patients. Moreover captopril disulfide conjugates in the uraemic subjects reached peak concentrations at 8 h after the dose and subsequently felt. The apparent plasma half-time was 46 +/- 19 h. Only 15% of these conjugates were removed by dialysis. This marked accumulation of captopril conjugates was associated with a sustained fall in both systolic and diastolic blood pressures. In uraemic patients the mean maximum reduction in systolic and diastolic blood pressures were 37 +/- 7 mmHg and 24 +/- 9 mmHg respectively, occurring 6 h after the dose, compared with 8 +/- 7 and 8 +/- 1 mmHg respectively at 30 min in normal renal function patients. These results are consistent with the results of animal experiments, which show that captopril disulfides can be converted back to free captopril and can contribute to the antihypertensive effect of the drug. They provide a reationale for reducing the dose and frequency of administration of captopril in patients with significant renal impairment.

Adult↗
PubMed1987

The N-methyl-D-aspartate (NMDA) receptor antagonist MK-801, attenuates the Bezold-Jarisch reflex in the anaesthetized rat.

The effects of MK-801, an N-methyl-D-aspartate (NMDA) receptor antagonist, on the Bezold-Jarisch reflex elicited by i.v. doses of 5-hydroxytryptamine (5-HT) was investigated in urethane-anaesthetized rats. Activation of the Bezold-Jarisch reflex with 5-HT (0.5-16 microgram/kg) produced pronounced dose-dependent hypotensive and bradycardic responses which were attenuated by MK-801 (1 mg/kg, i.v.) but not by saline. The data suggests that activation of the Bezold-Jarisch reflex by 5-HT involves a glutamatergic synapse presumably located within the brainstem vagal reflex arc.

Anesthesia↗
PubMed1987

Clopamide: plasma concentrations and diuretic effect in humans.

Clopamide pharmacokinetics were determined after oral doses of 5, 10, and 20 mg in normal volunteers. Maximum plasma concentrations occurred within 2 hours and were followed by a monoexponential decline with an elimination half-life of approximately 10 hours. There was an approximately linear relationship between dose and the AUC. Urinary sodium, chloride, and potassium excretion rates indicated that the peak diuretic activity corresponded with peak plasma drug concentrations and probably continued for 12 to 24 hours. There was little difference between the total sodium and chloride output after each dose of clopamide, suggesting that 5 mg may have been close to the top of the dose-response curve. Chlorothiazide, 500 mg, caused less sodium and chloride output with similar potassium loss. During chronic administration to patients with hypertension, hypokalemia was more marked with clopamide, 10 mg daily, than with clopamide, 5 mg, or chlorothiazide, 500 mg daily.

Administration, Oral↗
PubMed1987

Effect of age on pharmacokinetics of and blood pressure responses to prazosin and terazosin.

Prazosin and terazosin are two alpha 1-adrenoceptor blocking agents, their principal difference being the longer half-life of terazosin. The present study was carried out to determine if elderly subjects are different from the young in their pharmacokinetic handling of these two drugs and if age influences the blood pressure response to each drug. Ten young healthy subjects (aged 19-30 years) and five older healthy subjects (aged 54-62 years) received 1 or 2 mg terazosin, 1 or 2 mg prazosin, or placebo 1 week apart according to a 5 X 5 Latin square design. Concentrations of prazosin and terazosin were measured using a high-performance liquid chromatographic procedure with a detection limit of approximately 0.25 ng/ml. Pharmacokinetic parameters of prazosin were virtually the same in both groups, whereas mean terazosin plasma concentrations were higher in the older group and pharmacokinetic analysis revealed higher peak plasma concentrations and a longer terminal elimination half-life. There was no evidence of increased sensitivity to the hypotensive action of the drug, as peak upright blood pressure falls were similar in the two groups. Symptoms of dizziness in the upright position were also less common. In view of their lack of sedative effects and minimal metabolic disturbances, further studies should be conducted to assess the suitability of these drugs as monotherapy for hypertension in elderly patients.

Adrenergic alpha-Antagonists↗
PubMed1987

Neurotransmitters and neuropeptides in blood pressure regulation in the spontaneously hypertensive rat.

Studies of the roles played by neurotransmitters in the development of hypertension in the spontaneously hypertensive (SHR) rat are complicated by the presence of genetic differences between SHR and normotensive control rats, which are not related to differences in blood pressure. One approach that may be used in an attempt to overcome this difficulty is to study the manner in which neurotransmitter and metabolite levels change with age, and to relate these changes to alterations in blood pressure with ageing. Noradrenaline (NA) levels in the brainstem and spinal cord of SHR and Wistar Kyoto rats fell with age, while 3,4-dihydroxyphenylethyleneglycol (DHPG) levels (a neuronal metabolite of noradrenaline) remained constant. Similar changes were seen when NA and DHPG levels were measured in the discrete brainstem A1, A2, and C2 region, and when adrenaline, NA, and DHPG levels were examined in the C1 region. Differences in age-related changes of neuropeptide Y (NPY) levels were also found in the ventromedial nucleus of the hypothalamus and the locus coeruleus, and of beta-endorphin in the anterior hypothalamic nucleus, the paragigantocellular nucleus of the brainstem, and the locus coeruleus. These changes may indicate either a progressive increase in the activity of neurons in the sympathoexcitatory C1 region or a progressive reduction in the activity of vasodepressor A1, A2, and C2 regions with ageing, or both. However, changes in catecholamines and metabolites with age were similar in both strains and therefore cannot readily explain the more rapid rise in blood pressure with ageing in SHR rats.

Aging↗
PubMed1987

Angiotensin II receptors and angiotensin converting enzyme in the medulla oblongata.

Quantitative in vitro autoradiography was used to map angiotensin II (ANG II) receptors and angiotensin converting enzyme (ACE) in sections from rat, rabbit, sheep, and human medulla oblongata and to follow changes in receptor and ACE density after disruption of vagal projections by nodose ganglionectomy in the rat. ANG II receptors and ACE are both concentrated in the nucleus of the solitary tract and dorsal motor nucleus of vagus of the rat, rabbit, sheep, and human. An ANG II receptor-containing band connecting the nucleus of the solitary tract with the dorsolateral medulla was seen in rabbit and human tissue, providing evidence for association of ANG II receptors with vagal afferent fibers. ANG II receptors were found to be concentrated in the rostral and caudal ventrolateral medulla, which corresponded to the region of C1 and A1 catecholamine-containing cell groups in the rabbit. This localization was also evident in rat and human tissue. In all four species, a prominent, ANG II receptor-rich band in the intermediate reticular nucleus was found to connect the ventrolateral medulla and the dorsal vagal complex. In humans and sheep, this band contains puncta that overlie cell bodies. One week after nodose ganglionectomy in the rat, the density of ANG II receptors in the ipsilateral dorsal vagal complex fell markedly. This fall was most prominent in the rostral dorsal motor nucleus of vagus (to 46% of control density) and in the nucleus of the solitary tract (to 56% of control). ACE levels and calcitonin gene-related peptide receptor density were unchanged in both nuclei after ganglionectomy.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1987

Dynorphin(1-8) immunoreactivity in brainstem and hypothalamic nuclei of normotensive and age-matched hypertensive rat strains.

The concentration of dynorphin (1-8) immunoreactivity [ir-dyn(1-8)] was measured in 10 hypothalamic and 11 brainstem nuclei of Sprague-Dawley (SD) and 6- and 14-week old Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) rats. The highest concentrations of ir-dyn(1-8) were found in the lateral preoptic and lateral hypothalamic areas of the hypothalamus and the solitary tract nucleus of the brainstem. Levels of the peptide were low in other brainstem nuclei compared to hypothalamic areas. There was a significant reduction in ir-dyn(1-8) concentrations at 14 weeks of age compared to 6 weeks of age in all 9 nuclei examined in SH and WKY rats. However, there were no differences between the strains at either age. These changes may be related to the increase in blood pressure that occurs in both SH and WKY rats over this age range although other factors must also be involved to produce the higher blood pressure levels of the SH rat.

Age Factors↗
PubMed1987

A pharmacokinetic study of carvedilol (BM 14.190) in elderly subjects: preliminary report.

This study in eight elderly male volunteers examined the pharmacokinetics of carvedilol following intravenous and oral administration of the drug. Blood pressure and pulse rate responses were also determined and compared with those to labetalol. Carvedilol was absorbed rapidly after oral administration with a bioavailability of approximately 45% and obeyed linear pharmacokinetics over the dose range 25-50 mg. The terminal elimination half-life varied between 5 and 14 h. Administration of the drug with food did not alter the bioavailability or kinetic handling of carvedilol. The hemodynamic responses to carvedilol followed the same pattern as those to labetalol. There was a rapid dose-related fall in blood pressure maximal after 4-5 h and disappearing by 12 hours. Tachycardia that was evident on placebo was inhibited by both drugs. Postural hypotension and dizziness were also apparent with both drugs.

Administration, Oral↗
PubMed1987

Comparison of pharmacokinetics and pharmacodynamics of adrenoceptor agonists and antagonists as antihypertensive agents.

Central and peripheral alpha-adrenoceptors play an important role in cardiovascular regulation, and selective alpha 1-adrenoceptor antagonists and alpha 2-adrenoceptor agonists have an established place in the therapy of hypertension. Prazosin is a selective alpha 1-antagonist that is both effective in lowering blood pressure and well tolerated. However, the more recently developed alpha 1-antagonists doxazosin and terazosin offer the advantage of having longer half-lives, allowing once daily administration. Clonidine is a centrally acting alpha 2-agonist whose clinical use has often been limited by the dose dependent side effects of dry mouth and sedation, and the belief that it should be given three times per day. However, recent studies have shown that it has substantial antihypertensive efficacy with minimal side effects at low doses, and that half-life is long enough to allow twice daily administration. An improved understanding of the pharmacodynamics and pharmacokinetics of drugs acting on alpha-adrenoceptors allows a more rational approach to their clinical application.

Adrenergic alpha-Agonists↗
PubMed1987

Regional brain concentrations of several putative peptide neurotransmitters in normotensive and spontaneously hypertensive rats: effects of continuous (10-day) clonidine infusion.

In the present study, the mean arterial pressures (MAP) and heart rates (HR) were measured in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) that had received a 10-day continuous subcutaneous infusion of either saline or the centrally acting alpha-adrenoceptor agonist clonidine (10 micrograms/kg/h). In separate groups of similarly treated rats, the concentrations of neurotensin (NT), vasoactive intestinal polypeptide (VIP), cholecystokinin octapeptide (CCK-8), calcitonin gene-related peptide (CGRP), and neuropeptide Y (NPY) were measured in the cortex (COR), hypothalamus (HYP), medulla oblongata/pons (MO/P), and cervical (CSC) and thoracic (TSC) spinal cord. In comparison to the WKY rats, the SHR had significantly lower neuropeptide concentrations within the COR (NPY, CCK-8), HYP (NT), MO/P (NPY, NT, and CCK-8), CSC (all neuropeptides), and TSC (NPY, NT, CCK-8, and VIP). The infusion of clonidine lowered the MAP of the WKY and SHR rats (-10 and -35 mm Hg, as compared with respective saline controls) and HR in the WKY rats (-45 beats/min). In general, the infusion of clonidine produced decreases in neuropeptide levels within the CNS of the WKY rather than the SHR strain. When there was a strain difference (i.e., SHR less than WKY), it was evident, particularly within the spinal cord, that clonidine reduced the levels of the neuropeptides in the WKY rats to those levels in the SHR. These findings suggest that the reduced neuropeptide concentrations of the SHR (particularly those within the CSC) and TSC may be a result of, rather than a causal factor in, hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Measurement of penicillamine and N-acetylcysteine in human blood by high-performance liquid chromatography and electrochemical detection.

A rapid and precise high-performance liquid chromatographic assay for both N-acetylcysteine and penicillamine in blood samples is described using selective reductive electrochemical detection and a high-efficiency C18 reversed-phase column. The use of an internal standard compensated for changes in detector responses during a run and for variable sample recovery. The detection limits for N-acetylcysteine and penicillamine were 25 and 10 ng/ml, respectively, using 500-microliters blood samples. Reproducibility of measurement for both thiols was excellent. This method allows routine monitoring of blood levels and pharmacokinetic studies with N-acetylcysteine and penicillamine.

Acetylcysteine↗
PubMed1986

6-Hydroxydopamine and excitotoxin lesions of medial prefrontal cortex fail to affect schedule-induced drinking in the rat.

Schedule-induced drinking was examined in rats following 6-hydroxydopamine and N-methyl-D-aspartate lesions of the medial prefrontal cortex. 6-Hydroxydopamine reduced the concentrations of dopamine and noradrenaline in the medial prefrontal cortex to 17 and 37% of control values respectively, while changes were not observed in the nucleus accumbens. Lesions with N-methyl-D-aspartate were confined to the medial prefrontal cortex. Schedule-induced water consumption, determined over 11 consecutive 1 h/day testing sessions, was not significantly altered by either lesion. These results suggest that the mesocortical dopaminergic projection to the medial prefrontal cortex, and reciprocal projections from medial prefrontal cortex to the nucleus accumbens and the ventral tegmental area, are not essential for the acquisition of schedule-induced drinking.

Animals↗
PubMed1986

Perhexiline maleate treatment for severe angina pectoris--correlations with pharmacokinetics.

Perhexiline maleate, which causes inhibition of myocardial fatty acid catabolism with a concomitant increase in glucose utilization, is particularly useful in the management of patients with severe angina pectoris. While perhexiline exerts no significant negative inotropic or dromotropic effects, its short- and long-term use has hitherto been restricted because of complex pharmacokinetics and the eventual development, in many patients, of hepatitis and peripheral neuropathy. Correlations between perhexiline dose, plasma drug concentrations, efficacy and development of toxicity were examined prospectively in 3 groups of patients. The first group (n = 29) were patients in whom perhexiline was added to previously prescribed anti-anginal medication for short-term (pre-surgical or post-myocardial infarction) control of angina pectoris. Over a mean treatment period of 18 +/- 2 (SEM) days, 13 patients experienced a marked reduction in frequency and severity of attacks. No adverse effects occurred. A second group of patients (n = 19) were treated chronically with 50-400 mg/day of perhexiline, dosage being adjusted to minimize symptoms. Over a mean treatment period of 8.8 +/- 1.7 months, 5 patients became asymptomatic, while 9 developed evidence of hepatitis or neurotoxicity, with concomitant plasma perhexiline concentrations of 720-2680 ng/ml. Subsequently, a further group of similar patients (n = 22) were treated for 12.4 +/- 2.6 months, perhexiline dosage being adjusted to maintain plasma perhexiline concentrations below 600 ng/ml. Nine patients became asymptomatic, while none developed adverse effects. It is concluded that perhexiline is useful both as a short-term adjunct to anti-anginal therapy and in the long-term management of patients unsuitable for coronary artery bypass grafting. The risk of long-term toxicity can be reduced markedly by maintenance of plasma drug concentrations below 600 ng/ml without significantly compromising anti-anginal efficacy.

Adult↗
PubMed1986

Cardiac alpha-adrenoceptors: postjunctional and prejunctional.

Postjunctional alpha-adrenoceptors subserve positive inotropic and chronotropic responses. When beta-adrenoceptors are blocked, agonists that act on alpha 1-adrenoceptors evoke positive chronotropic responses in the pithed rat and rat isolated atria. The rank order of potency for this effect is adrenaline greater than noradrenaline greater than phenylephrine greater than methoxamine. The order of potency for antagonists to block the responses is prazosin greater than phentolamine greater than yohimbine. Thus, the postjunctional alpha-adrenoceptors are of the alpha 1-subtype. The positive chronotropic responses elicited by activating alpha 1-adrenoceptors have a slower time course than those elicited by activation of beta-adrenoceptors. When beta-adrenoceptors are blocked by propranolol, the positive chronotropic response to phenylephrine is enhanced by increasing the calcium concentration or by the calcium channel activator Bay K 8644 (0.1 microM), whereas the response is decreased by lowering the calcium concentration or by calcium antagonists (verapamil, nifedipine, nicardipine and diltiazem). Therefore, the positive chronotropic response to alpha 1-adrenoceptor activation involves an increased influx of calcium through calcium channels. Prejunctional alpha 1-adrenoceptors are involved in autoinhibitory feedback regulation of transmitter release from noradrenergic neurones. In rat atria, the release of noradrenaline induced by sympathetic nerve stimulation is inhibited by both clonidine and methoxamine, and is enhanced (by disruption of noradrenaline-mediated autoinhibition) by both idazoxan and prazosin. Thus, the prejunctional alpha-adrenoceptors are of both alpha 1- and alpha 2-subtypes. Drugs which produce blockade of postjunctional alpha 1-adrenoceptors could also produce an increase in neurogenic release of noradrenaline due to blockade of prejunctional alpha 1-adrenoceptors, and this might result in more complex effects than would be anticipated.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1986

The effectiveness of ranitidine in reducing gastric acid-secretion decreases with continued therapy.

To examine whether changes in inhibition of gastric acid secretion occur during chronic ranitidine therapy, duodenal ulcer patients in remission were studied before and after 9 months of maintenance ranitidine therapy (150 mg nocte). At each time, the effect of a bolus i.v. dose of ranitidine (50 mg) on pentagastrin-stimulated maximal acid output was measured. Oral and intravenous pharmacokinetic studies were also performed to examine whether changes in absorption or disposition occur during long-term dosage. After 9 months' therapy, ranitidine inhibited pentagastrin-stimulated secretion by a median of 62%, substantially less than the median inhibition of 95% pre-treatment. Median acid output in the period 60-120 min post-ranitidine was six times the pretreatment value. Since pharmacokinetic parameters were unaltered, this reduced ability to inhibit acid output appears to indicate reduced sensitivity of acid secreting mechanisms to ranitidine after prolonged dosage.

Administration, Oral↗
PubMed1986

Acute and chronic pharmacokinetic studies of slow release ketoprofen (Oruvail) in rheumatoid arthritis.

Slow release preparations of non-steroidal anti-inflammatory drugs are used to simplify dose regimes in the treatment of rheumatoid arthritis with the aim of improving patients compliance. This study examines the acute and chronic pharmacokinetics of slow release ketoprofen in 13 rheumatoid patients with a mean age of 59.8 years. Pharmacokinetic parameters following the first dose including Tmax which was 6.92 h (s.e.m. = 0.80), Cmax 3.87 micrograms/ml (s.e.m. = 0.54), apparent half-life 8.8 h (s.e.m. = 1.0) and AUC 41.92 micrograms.h/ml (s.e.m. = 4.02) were not significantly different from those following the last dose after 3 months of chronic treatment, when these were Tmax 6.38 h (s.e.m. = 0.84) Cmax 3.57 micrograms/ml (s.e.m. = 0.33) apparent half-life 8.8 h (s.e.m. = 1.1) and AUC 43.18 micrograms.h/ml (s.e.m. = 5.34) respectively. These results show that no accumulation of ketoprofen occurred with chronic treatment. Clinical assessments were performed in an open design and showed significant improvement in pain, articular index, grip strength and duration of morning stiffness when these parameters were compared to treatment with paracetamol during an initial washout. The drug was well tolerated although there was a trend for the haemoglobin to fall and this parameter should be monitored during therapy with ketoprofen.

Administration, Oral↗