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Biomedical subjects

A M Shepherd

Publications and source records attributed to A M Shepherd.

At least 55 records · Page 3Linked to original sources
PubMed1988

Alpha adrenergic blocking activity of urapidil in man.

Urapidil is a new antihypertensive vasodilator agent whose pharmacologic action in man has not yet been fully defined. We have assessed the alpha adrenergic blocking activity of urapidil 15 and 30 mg given intravenously in a single blind study in 8 healthy volunteers. Urapidil produced dose-dependent parallel shift of the phenylephrine log dose/blood pressure response curve, consistent with significant competitive peripheral alpha 1 antagonism. Mean dose ratios were 2.99 and 5.48 for the 15 mg and 30 mg doses respectively. The pA2 for alpha 1 blockade is 7.3. Given these data, the major mechanism of antihypertensive effect of urapidil may be alpha 1 antagonism in the peripheral vasculature.

Adrenergic alpha-Antagonists↗
PubMed1987

The analysis of dose-response curves--a practical approach.

The rationale for the objective assessment of dose-response curves (DRCs) is presented. Using data derived from isoprenaline/heart rate responses studies, two new statistical methods of objectively defining the terminal linear segment of an incomplete DRC are presented. Using data derived from phenylephrine/diastolic blood pressure response studies, the parallel shift quadratic model of Sumner et al. (1982) has been extended to include a measure of the suitability of the quadratic model for each individual data set using the Akaike information criterion. A parallel shift Emax model is proposed for complete DRCs.

Blood Pressure↗
PubMed1986

The assessment of the beta-blocking activity of urapidil: a new method.

Urapidil is an antihypertensive vasodilator agent whose pharmacological action in man has not yet been fully defined. We have assessed the beta blocking activity of urapidil 15 mg and 30 mg i.v. in a single blind study of 10 healthy male volunteers. Urapidil at plasma concentrations in the same range as those shown to have antihypertensive affect did not significantly attenuate the chronotropic effect of isoproterenol. Propranolol 5 mg iv, the positive control, significantly shifted the isoproterenol dose-response curve to the right. We describe a new method of analyzing incomplete dose response curves whereby a linear terminal segment can be reproducibly defined.

Adrenergic beta-Antagonists↗
PubMed1986

Medical dilatation of the non-pregnant cervix: the effect of ethinyl oestradiol on the visibility of the transformation zone.

The cervical transformation zone (TZ) was not fully visible in 25 women referred to the colposcopy clinic with cytological suspicion of cervical intraepithelial neoplasia (CIN). Each was given a 5-day course of oral ethinyl oestradiol during the follicular phase of the menstrual cycle, and colposcopy was then repeated. The transformation zone was visible at this second examination in 16 of the 25 patients. Of these patients, 11 were treated with a local destructive technique, nine by laser, two by cryocautery; one patient had a cone biopsy, and four patients did not require treatment. Although cone biopsy was necessary in 8 of the remaining 9 patients it is encouraging that the use of a simple medical regimen allowed us to avoid conisation and its morbidity in almost two thirds of these patients.

Adult↗
PubMed1985

Effects of advancing age on hypothalamic neurotransmitter content and on basal and norepinephrine-stimulated LHRH release.

In order to elucidate possible mechanism(s) responsible for the age-related decline in LH secretion, basal and norepinephrine (NE)-stimulated LHRH release was measured from median eminence (ME) fragments of 4-, 11-, 18- and 27-month-old male F344 rats. Serum LH levels declined significantly between 11 and 18 months and were still lower at 27 months of age, while testosterone levels declined continuously between 4 and 27 months. Hypothalamic NE and dopamine (DA) content also declined significantly with age, while serotonin and 5-hydroxy-indoleacetic acid content increased with age. Despite the decline in serum LH levels with age, in vitro basal LHRH release increased gradually with age as did NE-stimulated LHRH release. These data suggest that the age-related reduction in LH secretion by the male rat is due to a reduction in hypothalamic NE metabolism and not to an inability of the LHRH neuron to respond to NE stimulation.

Aging↗
PubMed1984

Effect of food on blood hydralazine levels and response in hypertension.

A study with a nonspecific hydralazine assay reported that food increased hydralazine concentrations in plasma. We used a specific HPLC hydralazine assay to determine the effect of food on hydralazine blood levels and hemodynamic responses after oral hydralazine. Six subjects with uncomplicated essential hypertension were given 1 mg/kg hydralazine solution orally on two occasions at least 3 days apart. On 1 study day subjects fasted and on the other they were given a standard meal 45 min before hydralazine. Mean arterial pressure and heart rate were monitored for 2 hr before and for 4 hr after hydralazine and frequent venous blood samples were drawn for hydralazine assay. Hepatic blood flow was estimated by determination of indocyanine green clearance before food, after food, and 30 min after hydralazine. Peak blood hydralazine concentrations fell in all (46.2% +/- 11.5%; means +/- SE) and areas under the blood hydralazine concentration/time curves fell (45.7% +/- 9.5%) after food. This could not be explained by changes in liver blood flow. Food-related reductions in blood levels of hydralazine were associated with reduced vasodepressor effects (41.5% +/- 5.6%). It is possible that food increases intravascular conversion of hydralazine to hydralazine pyruvic acid hydrazone. The reduction in vasodepressor response suggests that patients with hypertension should take hydralazine at a fixed time in relation to meals.

Administration, Oral↗
PubMed1984

Effect of oral dose size on hydralazine kinetics and vasodepressor response.

Levels of hydralazine in blood are log-linearly related to its vasodepressor effect. We examined the effect of oral dose size on the proportion of hydralazine that reaches systemic circulation. Nine subjects with hypertension were given hydralazine in oral doses in the therapeutic range. Blood hydralazine levels, effective liver blood flow, blood pressure, and heart rate were measured. As the hydralazine dose increased, the ratios of the AUC of hydralazine to hydralazine dose and of peak blood hydralazine concentration to hydralazine dose increased, indicating an increase in the proportion of the dose in blood. Liver blood flow tended to increase (maximum 40%) as dose increased above 0.5 mg/kg. Vasodepressor response and degree of tachycardia increased disproportionately with increasing hydralazine dose. There were strong log-linear relationships between peak hydralazine levels and both vasodepressor response and tachycardia that did not change with increasing hydralazine dose. Thus blood hydralazine and vasodepressor response increase disproportionately with increasing hydralazine doses in hypertension.

Acetylation↗
PubMed1984

Maximum perineal stimulation. A controlled study.

Previous workers have debated the value of maximal perineal stimulation (MPS) in the treatment of urinary incontinence in women. In order to assess the efficacy of this simple technique a prospective study was undertaken on 107 consecutive incontinent women. They included those with stress, urge and mixed patterns of leakage. Patients were placed at random into treatment and control groups. All underwent clinical assessment, urodynamic study and a single session of pelvic floor re-education with measurement of pelvic contraction and cystoscopy. Those in the treatment group were given MPS using monophasic square wave pulses while under anaesthesia. Independent follow-up assessment was performed 6 and 12 weeks after treatment. Of the 107 patients 94 completed the trial. Forty-five were treated and 49 acted as controls. Analysis of age, parity, duration and severity of incontinence showed that randomisation had produced comparable results between the treated and the control groups. Sixty per cent of the treatment group and 66% of the control group had significant symptomatic improvement. Pelvic floor function was re-assessed, using a perineometer, and found to be more efficient, having increased equally in both groups. Both groups of women improved irrespective of the pattern of incontinence. This suggests that MPS does not contribute to the management and that a single physiotherapy session with skillful counselling can produce beneficial results in women with all types of urinary incontinence.

Clinical Trials as Topic↗
PubMed1983

Effect of intravenous dose on hydralazine kinetics after administration.

Six male hypertensive patients, three rapid and three slow acetylators, each received four different intravenous hydralazine doses by constant infusion over 100 sec. Two to four days elapsed between doses. Plasma or whole-blood hydralazine concentrations were measured by HPLC after each dose. There was no influence of acetylator phenotype on hydralazine kinetics after intravenous dosing. There also was no consistent effect of dose size on hydralazine clearance or volume of distribution at doses up to 0.45 mg (2.3 mumol/kg). One subject, who received doses up to 0.6 mg/kg (3.05 mumol), had an apparent decrease in clearance at the higher doses. These findings are consistent with the fact that hydralazine is converted intravascularly to hydralazine pyruvic acid hydrazone and the fact that potentially saturable hepatic metabolic pathways play only a modest role in systemic clearance.

Dose-Response Relationship, Drug↗
PubMed1983

The response of plasma catecholamines to intravenous labetalol: a comparison with sodium nitroprusside.

Changes in mean arterial pressure (MAP), heart rate (HR), and plasma concentrations of norepinephrine (NE) and epinephrine were measured in eight hypertensive patients in a supine position after stepwise infusion of incremental sodium nitroprusside doses and intravenous injection of cumulative labetalol doses. Both drugs induced rises in plasma NE concentration that were linearly related to reductions in MAP. For any reduction in blood pressure (BP), however, the rise in plasma NE concentration induced by labetalol was approximately four times that induced by sodium nitroprusside. The difference can be explained by two effects of labetalol: impairment of neuronal NE uptake and beta-adrenergic-receptor blockade, which are known to reduce NE clearance from plasma. After both drugs there was a correlation between changes in HR and changes in BP and a correlation between changes in HR and changes in plasma NE concentration. Slopes of the regression lines for both relationships were less after labetalol than after sodium nitroprusside, presumably because of the beta-adrenergic-blocking properties of labetalol. Multiple-regression analysis indicated that the plasma NE rise was an important determinant of the vasodepressor response to each drug. The greater plasma NE elevation after labetalol may limit its antihypertensive effect.

Adult↗
PubMed1983

Effects of hydralazine and sodium nitroprusside on plasma catecholamines and heart rate.

Hydralazine and sodium nitroprusside induce different effects on systemic hemodynamics, but their effects on sympathetic neuronal activity have not been compared. Five hypertensive subjects receiving only hydrochlorothiazide were studied during two sessions. During one session, four doses of hydralazine, 0.1 to 0.6 mg/kg, were given intravenously at least 3 days apart, and during the other session, sodium nitroprusside was infused in stepwise doses, 0.05 to 4.8 micrograms/kg/min for 10 min per dose. Mean arterial pressure (MAP), heart rate (HR), and plasma norepinephrine (NE) and epinephrine concentrations were determined before and after dosing. The following correlated linearly for hydralazine and sodium nitroprusside: delta HR/delta MAP, delta NE/delta MAP, and delta HR/delta NE. Comparison of these relationships, however, indicated significant differences between the sympathetic neuronal and hemodynamic responses to hydralazine and sodium nitroprusside. Increase in HR relative to decrease in MAP was greater for hydralazine than for sodium nitroprusside. There were greater increases in plasma NE concentration relative to falls in MAP with sodium nitroprusside than with hydralazine, but increases in HR relative to increases in plasma NE concentration were smaller for sodium nitroprusside than for hydralazine. Such responses may reflect differential effects of hydralazine and sodium nitroprusside on the systemic clearance of NE or of the activity of cardiopulmonary baroreceptors.

Adult↗
PubMed1983

Latamoxef (moxalactam) kinetics in volunteers studied by a specific HPLC assay technique.

Pharmacokinetic parameters were calculated from plasma and urine latamoxef ('Moxalactam') levels determined by HPLC assay after single and multiple intramuscular (im) and single intravenous (iv) doses of 500 mg given to eight healthy volunteers. After im administration, systemic bio-availability was 92% after both the first and sixth doses. Peak plasma concentration was 18 mg/l (first dose) and 22 mg/l (sixth dose), reached at 1.2 h and 1.3 h respectively. The terminal phase half-lives were 2.5 h and 2.7 h respectively. After iv administration, the initial phase plasma half-life was 0.23 h and the terminal phase half-life, 2.4 h. Plasma clearance was 87.0 ml/min. The steady state distribution volume was 210 ml/kg. After iv administration, 72% of the dose was found in the urine in the first 24 h. Urinary clearance was 66 ml/min (iv dose) and 63 ml/min (sixth im dose). Most systemic infections will permit eight hourly dosing with 500 mg im or iv. Many urinary infections will be best treated with im administration, rather than iv administration.

Adult↗
PubMed1983

Antithyroid effect of chlorpropamide?

1 The relationship between plasma chlorpropamide concentration and thyroid function was examined in 87 maturity onset diabetic patients receiving chronic therapy. 2 Although plasma chlorpropamide concentration was weakly negatively correlated with serum thyroxine (r = 0.33, P less than 0.01) the mean serum thyroxine and thyrotrophin (TSH) were not different from that of a matched control group of diabetics treated with diet alone. 3 Serum thyroxine was negatively correlated with the duration of diabetes in both groups. 4 These results suggest that chlorpropamide does not have a clinically significant antithyroid effect.

Adult↗