RESUMEN
It has been suggested that marine predators be assessed for biologically relevant contamination levels because of their trophic position. Accordingly, in studying radioactive contamination in the marine environment around the UK, tissues from seals and porpoises have been chosen. Liver and muscle tissue from dead seals and porpoises found stranded around the UK coast have been analysed for the following radionuclides: 134Cs, 137Cs, 238Pu, 239Pu + 240Pu. Multifactor analysis of variance indicated that, for radiocaesium, there was no significant difference for harbour seals, grey seals or porpoises in terms of species or gender; however, the tissue activity concentration increased with body weight and decreased with distance from Sellafield, the major nuclear reprocessing plant in the UK. The levels of radiocaesium in muscle were higher than those in liver, while there appeared to be a concentration factor of approximately 3-4 for muscle radiocaesium when compared to radiocaesium levels reported for fish, the main food source of the marine mammals under study. Approximate radiation dose calculations indicated that the average dose from radiocaesium was less than 10% of the dose from the naturally occurring radioisotope of potassium, 40K. The highest tissue activity concentration for plutonium of 0.037 Bq/kg (239Pu + 240Pu) was detected in a grey seal stranded at Rathlin Island in Northern Ireland. Calculation of approximate radiation doses from plutonium contamination showed that, as with radiocaesium, the average dose was small compared with that from 40K. In summary, the radiocaesium contamination in seals and porpoises decreased with distance from Sellafield indicating that the BNF plc processing plant was the major source of the contamination. The marine mammals concentrated radiocaesium from their environment by a factor of 300 relative to the concentration in seawater indicating the value of using marine mammal tissue to measure radiocaesium contamination in the marine environment. The maximum radiation dose to the marine mammals from radiocaesium was higher than doses previously assessed for critical groups of humans living near Sellafield, while the maximum dose from plutonium was comparable to the doses for humans.
Asunto(s)
Marsopas/metabolismo , Phocidae/metabolismo , Contaminantes Radiactivos del Agua/farmacocinética , Animales , Radioisótopos de Cesio , Ecosistema , Monitoreo del Ambiente , Cadena Alimentaria , Hígado/metabolismo , Músculos/metabolismo , Plutonio , Radioisótopos de Potasio , Centrales Eléctricas , Dosis de Radiación , Agua de Mar/análisis , Reino Unido , Contaminantes Radiactivos del Agua/análisis , Contaminantes Radiactivos del Agua/toxicidadRESUMEN
In 1986, a statistically significant excess of leukaemia was reported in young people living near the Dounreay Nuclear Establishment in northern Scotland. The committee on Medical Aspects of Radiation in the Environment (COMARF) confirmed this finding and concluded that, based on conventional dose and risk estimates, the radioactive discharges from the plant could not be held responsible. However, COMARF, recognizing the uncertainties involved in the dose and risk calculations, recommended that levels of radioactivity should be measured in the general population living near the plant. Alpha-emitting contamination has been measured by urinary 239Pu analysis and 241Am in-vivo skull measurements in 66 subjects associated with the Dounreay area and in 42 subjects living remote from reprocessing plants. Whole-body counting was employed to check for gamma ray-emitting contamination. Urinary 90Sr and chromosome abnormality analyses were also carried out on subsets of the study group. No significant inter-group differences for measurements of contamination were demonstrated for groups of leukaemia cases, siblings, parents, matched local controls and controls living remote from reprocessing plants. The findings suggest that it is unlikely that the observed increased incidence in leukaemia is due to the single factor of personal radioactive contamination from the Dounreay Nuclear Establishment.
Asunto(s)
Leucemia Inducida por Radiación/etiología , Monitoreo de Radiación , Adolescente , Adulto , Americio/análisis , Niño , Aberraciones Cromosómicas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Plutonio/orina , Dosis de Radiación , Escocia , Estroncio/orinaAsunto(s)
Exposición a Riesgos Ambientales , Padre , Leucemia/congénito , Reactores Nucleares , Adulto , Inglaterra , Humanos , Recién Nacido , MasculinoRESUMEN
Thirty-seven essential hypertensives received placebo for 3 weeks followed by nifedipine retard (n = 14) or enalapril (n = 13) or doxazosin (n = 10) as monotherapy for 6 weeks and attended study days to evaluate the effects of placebo, first dose, and chronic (1-6 weeks) treatment. On each study day, pressor responses to i.v. infusions of phenylephrine (PE) and angiotensin II (AII) were measured 1.5-3 h after drug administration and the derived PD20 values (dose required to increase mean blood pressure by 20 mm Hg) compared. Each treatment produced comparable reductions in BP. Nifedipine significantly attenuated the pressor responses to AII and PE: for AII, the mean PD20 (ng/kg/min) increased from 8.2 (placebo) to 9.9 (first dose), 13.9 (1 week), and 17.4 (6 weeks). Pressor responsiveness to both AII and PE was unchanged following enalapril: for PE, the mean PD20 (micrograms/kg/min) was 2.1 (placebo), 1.5 (first dose), and 1.5 (6 weeks). Doxazosin produced rightward shifts of the PE pressor dose-response curves but had no effect on responses to AII. The relationship between the simultaneous BP and HR changes during the infusion of PE was used as an index of cardiac baroreflex activity. In contrast to enalapril and doxazosin, which had no effect, nifedipine reduced the slope of the HR/BP relationship from -0.62 (placebo) to -0.38 (first dose) and -0.31 beats/min/mm Hg (6 weeks). For comparable reductions in BP, doxazosin only affects adrenergic mechanisms whereas nifedipine affects both adrenergic and non-adrenergically mediated vasoconstriction. The ACE inhibitor enalapril had no effect on pressor responses to AII and PE.
Asunto(s)
Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Adulto , Anciano , Aldosterona/sangre , Angiotensina II/sangre , Angiotensina II/uso terapéutico , Catecolaminas/sangre , Doxazosina , Enalapril/sangre , Enalapril/uso terapéutico , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Nifedipino/sangre , Nifedipino/uso terapéutico , Peptidil-Dipeptidasa A/sangre , Fenilefrina/sangre , Fenilefrina/uso terapéutico , Prazosina/análogos & derivados , Prazosina/sangre , Prazosina/uso terapéutico , Reflejo/efectos de los fármacos , Flujo Sanguíneo Regional/efectos de los fármacos , Renina/sangreRESUMEN
It has long been accepted that enhanced vascular reactivity is an integral part of the hypertensive state. This study investigates pressor responsiveness to the selective alpha 1-adrenoceptor agonist, phenylephrine, in 62 normotensive and hypertensive subjects aged 20-70 years. Since blood pressure increases with age, it is possible that effects attributed specifically to blood pressure will be confounded by age. The present study showed no correlation between responsiveness and starting blood pressure. However, responsiveness was positively correlated with age. These results suggest that it may be an oversimplification to attribute increased vascular responsiveness to the hypertensive state.
Asunto(s)
Envejecimiento/fisiología , Presión Sanguínea/fisiología , Hipertensión/fisiopatología , Adulto , Anciano , Envejecimiento/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Humanos , Persona de Mediana Edad , Fenilefrina/farmacología , Receptores Adrenérgicos alfa/efectos de los fármacos , Receptores Adrenérgicos alfa/fisiologíaRESUMEN
1. The relationship between fall in systolic blood pressure and initial systolic blood pressure has been investigated in 255 mixed normotensive and hypertensive subjects given placebo or one of five types of antihypertensive drug (ACE inhibitors, calcium antagonists, direct vasodilators, alpha-adrenoceptor blocker, beta-adrenoceptor blocker). 2. In all cases there was a significant correlation between the change in blood pressure and initial blood pressure. When Oldham's transformation was used (replacing the initial blood pressure by the mean of the initial and minimum pressures) the correlation coefficients were all reduced, although five out of six were still statistically significant. 3. In a subset of 43 hypertensive subjects given four antihypertensive agents, concentration-effect analysis was carried out. For three of the agents a linear model was used to relate effect to concentration; for the remaining agent a Langmuir type model was used. 4. For all four sets of data for which concentration-effect analysis was carried out, there was a significant correlation between the sensitivity of response and the initial blood pressure. 5. The observed relationships between initial blood pressure, change in blood pressure and sensitivity of response can be qualitatively explained by postulating a general form of dose-response relationship for all antihypertensive agents.
Asunto(s)
Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , HumanosRESUMEN
1. Ebastine, through its carboxylic acid metabolite has antihistamine (H1-receptor) activity in man. 2. We have examined in a single blind placebo controlled study the effects of 10 mg and 50 mg of ebastine on cardiovascular, autonomic and psychomotor function in healthy subjects. 3. Ebastine had no effect on blood pressure or heart rate and there was no evidence of any anticholinergic activity on circulatory reflexes or salivation. 4. Ebastine did not impair psychomotor performance as assessed by critical flicker fusion at either dose. 5. Ebastine 10 mg had no effect on sedation measured by visual analogue scale or direct questioning, however ebastine 50 mg did cause a modest increase in indices of sedation. 6. Ebastine did not have detectable sedative properties at the 10 mg dose where long-lasting antihistamine effects can be demonstrated.
Asunto(s)
Sistema Nervioso Autónomo/efectos de los fármacos , Butirofenonas/farmacología , Antagonistas de los Receptores Histamínicos H1/farmacología , Piperidinas/farmacología , Desempeño Psicomotor/efectos de los fármacos , Adulto , Presión Sanguínea/efectos de los fármacos , Fusión de Flicker/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Hipnóticos y Sedantes , Masculino , Tiempo de Reacción/efectos de los fármacos , Salivación , Encuestas y Cuestionarios , Factores de TiempoRESUMEN
In clinical pharmacological studies, where it is not possible to describe the full dose-response curve, the construction of dose-response relationships ideally depends upon achieving a reproducible and readily measurable response for each dose administered. This study investigates in normotensive males the technique of dose-response analysis for the blood pressure and heart rate increases with constant infusions of incremental doses of vasoactive drugs, particularly catecholamines. Steady state responses could be adequately obtained using 5 min infusion periods (at each dose level) for noradrenaline and alpha-methyl noradrenaline. At least 7 min was required for phenylephrine and 8 min for isoprenaline. There was an approximate correlation between the time to achieve the steady state response and the half-life of the offset of the agonist effect. For interindividual comparisons it is desirable to compare steady state responses and so the time at each dose level will vary according to which agonist is being used. For intraindividual comparisons it may not be essential that steady state responses are achieved. For example, assessment of the effect of prazosin on the responses to phenylephrine, by calculation of dose ratios, indicated that 5 min dose intervals were adequate.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Vasos Sanguíneos/efectos de los fármacos , Receptores Adrenérgicos/efectos de los fármacos , Adulto , Angiotensina II/farmacología , Relación Dosis-Respuesta a Droga , Epinefrina/farmacología , Humanos , Isoproterenol/farmacología , Masculino , Nordefrin/farmacología , Norepinefrina/farmacología , Fenilefrina/farmacologíaRESUMEN
The effects of the calcium antagonists verapamil and nifedipine on mean arterial blood pressure, heart rate and pressor responses to a range of alpha-adrenoceptor agonists were examined in male normotensive New Zealand white rabbits and in rabbits with perinephritis hypertension. Verapamil and nifedipine caused a greater fall in mean arterial pressure in hypertensive compared to normotensive rabbits both when the fall was expressed as an absolute and as a percentage change. Effects on heart rate were similar in normotensive and hypertensive animals. Pressor responses to phenylephrine were attenuated by nifedipine and verapamil in normotensive and hypertensive rabbits. Pressor responses to alphamethyl noradrenaline were also attenuated by nifedipine, but pressor responses to BHT 920 were not significantly altered by either calcium antagonist in normotensive or hypertensive rabbits at the dose used. Thus the calcium antagonists had a greater effect on alpha 1 - than alpha 2-adrenoceptor mediated responses in both normotensive and hypertensive rabbits. Hypertensive animals showed an increased responsiveness to phenylephrine and alphamethyl noradrenaline but not BHT 920 compared to normotensives. This difference remained after treatment with both the calcium antagonists.
Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Presión Sanguínea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Hemodinámica/efectos de los fármacos , Hipertensión Renal/tratamiento farmacológico , Animales , Azepinas/farmacología , Interacciones Farmacológicas , Masculino , Nifedipino/farmacología , Nordefrin/farmacología , Fenilefrina/farmacología , Conejos , Verapamilo/farmacologíaRESUMEN
We have examined the effects of 7 days treatment with beta adrenoceptor antagonists in 8 healthy volunteers in a placebo controlled, crossover study. We investigated three beta-adrenoceptor antagonists (atenolol, oxprenolol, and propranolol), which have differing profiles of selectivity and partial agonist properties (intrinsic sympathomimetic activity, ISA). We studied adrenaline-induced hypokalaemia, the vasodilator response to an infusion of adrenaline (0.06 micrograms X kg-1 X min-1 for 90 min), and lymphocyte beta 2-adrenoceptor number, determined by (-) [125I]-iodocyanopindolol binding, and measured these variables both before and after 7 days of treatment. The beta 2-mediated depressor response to adrenaline infusion was abolished by propranolol and oxprenolol but persisted after atenolol. In contrast, the hypokalaemia induced by adrenaline was abolished by all three beta-blockers. Lymphocyte beta 2-adrenoceptor number increased significantly following propranolol treatment, but not after oxprenolol for atenolol. We conclude that up-regulation of lymphocyte beta 2-adrenoceptors is dependent on beta 2-receptor blockade and is modified by ISA. The reversal of the hypokalaemic response by atenolol suggests that beta 1 receptors may contribute to the former effect. Alternatively, since different populations of beta 2-adrenoceptors differ in their susceptibility to antagonists there may also be differences in agonist coupling to beta 2-responses between tissues.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Hemodinámica/efectos de los fármacos , Linfocitos/metabolismo , Potasio/sangre , Receptores Adrenérgicos beta/metabolismo , Antagonistas Adrenérgicos beta/sangre , Adulto , Atenolol/farmacología , Humanos , Oxprenolol/farmacología , Propranolol/farmacología , Distribución AleatoriaRESUMEN
Vitamin D deficiency is common in the house-bound and institutionalised elderly population of Britain. A study of patients over 65 years discharged with a diagnosis of osteomalacia from Greater Glasgow Health Board hospitals between 1970 and 1981 inclusive showed a low incidence in the 65 to 74 years age group but a steeply rising incidence in older age groups. The majority (83%) of patients were female. The fortification of margarine, butter and milk with concentrations of vitamin D acceptable to the general population does not produce significant elevations in serum 25-hydroxyvitamin D (25-OHD) levels in vitamin D-deficient elderly patients. Low intensity background ultraviolet radiation (UVR) and intermittent high intensity UVR produce significant elevations in serum 25-OHD levels in elderly patients but both methods have disadvantages which limit their widespread use. Vitamin D supplements equivalent to 10 micrograms daily produce significant elevations in serum 25-OHD levels in vitamin D-deficient elderly patients. A vitamin D supplement policy for the housebound and institutionalised elderly population of Britain is required.
Asunto(s)
Alimentos Fortificados , Terapia Ultravioleta , Deficiencia de Vitamina D/prevención & control , Vitamina D/uso terapéutico , Anciano , Anciano de 80 o más Años , Calcifediol/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Osteomalacia/etiología , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/complicaciones , Deficiencia de Vitamina D/terapiaRESUMEN
This study investigated the effects in normotensive males of the calcium channel blockers, verapamil and nisoldipine, on the pressor responses mediated via alpha-adrenergic and non-adrenergic mechanisms. After the first doses of each drug and after 4 days continued treatment both verapamil and nisoldipine significantly attenuated the responses to angiotensin II with three- to fivefold rightward shifts of the pressor dose-response curves. Rightward shifts of comparable magnitude were obtained for phenylephrine (selective alpha 1-agonist), but with alpha-methylnoradrenaline (preferential alpha 2-agonist) only nisoldipine caused a significant twofold rightward shift and only during continued treatment. This study demonstrated that peripheral vascular adrenergic responses mediated via both alpha 1- and alpha 2-adrenoceptors in man are affected by calcium channel blocking drugs. There was no evidence that this effect was specifically linked to the alpha 2-adrenoceptor. The functional antagonism of peripheral vasopressor mechanisms was not significantly different for verapamil and nisoldipine.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Hemodinámica/efectos de los fármacos , Receptores Adrenérgicos alfa/fisiología , Adulto , Presión Sanguínea/efectos de los fármacos , Humanos , Masculino , Nisoldipino/farmacología , Flujo Sanguíneo Regional/efectos de los fármacos , Verapamilo/farmacologíaRESUMEN
There is evidence that responses mediated via alpha adrenoceptors are dependent on calcium fluxes and it has been suggested that the alpha 2 adrenoceptor is particularly associated with the increased entry of extracellular calcium ions, which is preferentially antagonised by calcium channel blocking drugs. This study investigates in normotensive men the effects of calcium antagonism with verapamil and the dihydropyridine nisoldipine on the pressor responses to adrenergic and nonadrenergic vasoconstriction. Phenylephrine and alphamethylnoradrenaline were intravenously infused to assess respectively alpha 1 and alpha 2 adrenoceptor-mediated peripheral vascular responsiveness and angiotensin II was used to assess nonadrenergic responsiveness. After 4 days oral treatment, both verapamil and nisoldipine significantly attenuated the responses to angiotensin II with three- to fivefold rightward shifts of the mean pressor dose-response curves. Rightward shifts of comparable magnitude were obtained for phenylephrine but with alphamethylnoradrenaline, although the overall trend was similar, only nisoldipine caused a significant twofold rightward shift. These data demontrate, in humans, that peripheral vascular adrenergic responses mediated via both alpha 1 and alpha 2 adrenoceptors are affected by calcium channel blocking drugs. There was no evidence that this effect was specifically linked to the alpha 2 adrenoceptor.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Hemodinámica/efectos de los fármacos , Receptores Adrenérgicos alfa/fisiología , Adulto , Angiotensina II/farmacología , Presión Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Nifedipino/análogos & derivados , Nifedipino/farmacología , Nisoldipino , Norepinefrina/fisiología , Normetanefrina/farmacología , Fenilefrina/farmacología , Distribución Aleatoria , Receptores Adrenérgicos alfa/efectos de los fármacos , Verapamilo/farmacologíaRESUMEN
In this study of 10 patients with essential hypertension inadequately controlled by standard beta-blocker-diuretic combination therapy, the addition of 5 mg of MDL-899, a peripheral arteriolar vasodilator, resulted in significant reductions in blood pressure, both supine and standing, which was maximal 4-8 h after dosing, with no additional orthostatic component. There were associated small rises in heart rate but no evidence of significant activation of the sympathetic or renin-angiotensin systems. Six patients continued for 4 weeks receiving MDL-899 twice daily with significant improvement in their blood pressure control--from a mean of 182/95 to 146/77 mm Hg (supine) and from 161/93 to 138/79 mm Hg (erect). These six patients experienced no significant side effects, but four patients were unable to proceed with the study as a result of adverse effects, particularly headache, following the first few doses. It seems likely that these side effects are dose related. In a combined drug regimen, MDL-899 is an effective vasodilator drug that significantly improved the blood pressure control of patients with essential hypertension.
Asunto(s)
Hipertensión/tratamiento farmacológico , Piridazinas/uso terapéutico , Vasodilatadores/uso terapéutico , Anciano , Aldosterona/sangre , Presión Sanguínea/efectos de los fármacos , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Piridazinas/efectos adversos , Renina/sangre , Factores de Tiempo , Vasodilatadores/efectos adversosRESUMEN
The effect of acute and continued administration of verapamil on pharmacokinetics and regional blood flow has been studied in eight normotensive subjects. Continued administration resulted in a significant decrease in verapamil clearance, compared to that following acute dosing, as assessed by increases in both terminal elimination half-life (from a mean +/- s.d. of 5.2 +/- 2.3 h to 6.7 +/- 2.0 h) and AUC (from a mean +/- s.d. of 800 +/- 353 ng ml-1 h to 1455 +/- 244 ng ml-1 h). The relative clearance of norverapamil was not changed. Acute administration of verapamil resulted in a significant increase (P less than 0.005) in apparent liver blood flow which with continued administration fell significantly (P less than 0.01) towards placebo values. Effective renal plasma flow similarly increased with acute verapamil administration (P less than 0.05) and with chronic administration reduced again to be not significantly different from placebo. Acute and chronic verapamil administration did not significantly alter glomerular filtration rates. These results suggest that there may be a relationship between the acute increase in liver blood flow and the relatively increased clearance of verapamil following acute dosing.
Asunto(s)
Circulación Hepática/efectos de los fármacos , Circulación Renal/efectos de los fármacos , Verapamilo/farmacología , Adulto , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Cinética , Masculino , Matemática , Modelos Biológicos , Verapamilo/metabolismoRESUMEN
The densities of [3H]-prazosin and [3H]-clonidine binding sites were determined in spleen and brain membrane preparations from rabbits treated 1 to 48 h previously with benextramine (5 mg/kg). In other rabbits pressor responses to phenylephrine and BHT 920 were examined 1 to 72 h after benextramine administration. After benextramine there was a reduction in the density of both [3H] prazosin and [3H] clonidine binding sites in spleen and a non-parallel shift in pressor dose response curves to selective alpha 1- and alpha 2-adrenoreceptor agonists. Recovery of in vivo responses and binding site densities were relatively slow. No reduction in the maximum density of either [3H] prazosin or [3H] clonidine binding sites in brain was found after intravenous administration of benextramine. It is concluded that after intravenous administration benextramine binds irreversibly to peripheral alpha 1- and alpha 2-adrenoreceptors in the rabbit but fails to cross the blood brain barrier in appreciable quantities and bind to central alpha-adrenoreceptors. Recovery of in vivo responses was more rapid than that previously observed after alpha-adrenoreceptor blockade with phenoxybenzamine. The longer time course of recovery after phenoxybenzamine may be a result of redistribution of this lipophilic drug from fat.
Asunto(s)
Antagonistas Adrenérgicos alfa/farmacología , Cistamina/análogos & derivados , Receptores Adrenérgicos alfa/efectos de los fármacos , Agonistas alfa-Adrenérgicos/farmacología , Animales , Azepinas/farmacología , Presión Sanguínea/efectos de los fármacos , Encéfalo/metabolismo , Clonidina/metabolismo , Cistamina/farmacología , Inyecciones Intravenosas , Masculino , Membranas/metabolismo , Fenoxibenzamina/farmacología , Fenilefrina/farmacología , Prazosina/metabolismo , Conejos , Receptores Adrenérgicos alfa/metabolismo , Bazo/metabolismo , Factores de TiempoRESUMEN
Aldosterone and renin responses to head-up tilt (60 degrees for 1 h) and angiotensin II infusions (2,5 and 10 ng/kg/min) 1 h later were compared in six normal subjects during infusions of somatostatin (3 micrograms/kg/min) or saline. The infusions were performed on separate days two weeks apart. The increase in aldosterone due to exogenous angiotensin II and orthostasis were significantly attenuated by somatostatin. Neither the increase in plasma renin activity (PRA) nor the angiotensin II mediated suppression of PRA were affected by somatostatin. These findings are consistent with the recent observation that somatostatin suppresses aldosterone release in response to angiotensin II in rat adrenal cells in culture and they indicate a possible role for somatostatin in the regulation of aldosterone secretion.