Interaction of thyroxine sodium with antimalarial drugs.
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Biomedical subjects
Publications and source records attributed to Y Munera.
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Therapeutic drugs are the main cause of postural hypotension, notably in elderly people. This syndrome is harmful as it reduces patients' compliance with treatment and is responsible for severe accidents. Drugs which lower cardiac output by acting on heart rate and cardiac muscle contractility, and drugs which decrease blood volume may produce postural hypotension; diuretics are often responsible for hypovolemia and hypokalaemia. The principal mechanisms involved are interferences of drugs with vegetative blood pressure regulation. They include vasomotor centre depressors (morphine-like compounds, antihypertensive agents, neurosedatives, neuroleptics, antiparkinsonians); ganglioplegics; inhibitors of noradrenaline production (methyldopa, disulfiram) or re-uptake (antidepressants); catecholamine depressors (guanethidine); drugs acting on chromaffin granules (monoamine oxidase inhibitors) and those which inhibit post-synaptic receptors (alpha- and beta-blockers). Drugs which act on vascular smooth muscle tone (nitrites, calcium channel antagonists, angiotensin-converting enzyme inhibitors) occasionally cause postural hypotension. To the actions of these drugs must be added endogenous and exogenous factors and notably physiological ageing of the baroceptor reflex; these factors must be taken into account whenever therapeutic drugs are prescribed.
Because of the benefit-risk ratio in their favor, calcium channel antagonists are considered to be a safe form of treatment of hypertension in the elderly. However, the outcome of dizziness in some patients over 65 yr old during the first few days of treatment with these drugs has to be considered. Five cases of "malaise" have been mentioned, which occurred during the first few days of treatment. The imputability of the drug in question has been evaluated. Additional factors have been found, ie orthostatic hypotension whatever its mechanism, and association with diuretics, with or without hyponatremia. The above-mentioned cases led to a study in 10 supine elderly women (mean age 85 +/- 3 yr) with normal blood pressure. In this study, systolic and diastolic blood pressure were monitored after a 20-mg oral dose of nicardipine for 3 h. Even in the supine position, a significant fall in blood pressure was observed as early as the 15th min after administration, which could be significant, occasionally reaching 45% of the initial value. Before administering a calcium channel antagonist to an elderly person, orthostatic hypotension has to be investigated. Association with a diuretic results in high risk due to hypovolemia that can enhance the vasodilatory effect of calcium antagonists.
Changes in heart rate induced by inclining an orthostatic table to 30 degrees and 60 degrees and by standing was studied in 200/healthy volunteers of either sex. Study subjects were divided in eight ten-year age groups, from 16 to 97 years. The 56-65 year age group was the youngest group to develop systolic orthostatic hypotension. This response occurred in 4% of subjects aged 56-65 years and became increasingly prevalent from one age group to the next (25%, 36% and 44%). In some patient, the fall in systolic BP reached 70 mmHg. Systolic hypotension occurred in some patients at 30 degrees but in most cases developed only at 60 degrees. No significant difference was found between the falls in SBP seen at 60 degrees and during active standing (90 degrees), indicating that muscular activity does not play a major role in BP regulation. Diastolic hypotension was less common and was mainly seen in patients above 75 (20%) who also had systolic hypotension. Orthostatism was responsible for tachycardia but this response became increasingly less common beyond 55 years of age (60, 60, 52 and 36% in the four age groups above 55). This reflects increasing loss of sensitivity of the baroreflex with advancing age. These date are useful for comparing the age-specific effects of disease states (e.g. diabetes mellius, alcohol abuse) or treatments (psychoactive drugs, antihypertensive agents).
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The beta 1- and beta 2-adrenoreceptor blockade by means of the systemic diffusion of three beta-blocker eyedrops--timolol, carteolol, and betaxolol--was evaluated in a randomized, single-blind, three-way crossover study in 18 volunteers. The blockade was evaluated by analyzing the variations of the beta 1- and beta 2-blockade effects of isoproterenol before and after instillation of one drop in each eye. The beta 1-blockade effect was judged on the variation of heart rate, and the beta 2-blockade effect was judged on the change in peripheral blood flow measured by veno-occlusive plethysmography. Comparison of the blockade by these drops showed that carteolol and timolol totally inhibited the beta 1 and beta 2 effects of a dose of isoproterenol able to increase heart rate by 50% (placebo eyedrops were used as a control). Betaxolol differ significantly because it allowed the same effects with the same dose of isoproterenol. Intensity of the blockade was measured by comparison of the effective doses of isoproterenol. Carteolol and timolol were shown to be four times more inhibitory.
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B antagonists eye drops are most effective for the treatment of chronic open angle glaucoma. By this way of administration they have a very good systemic bioavailability. Bronchial, and cardiovascular effects of three of these topicals: timolol, carteolol and metipranolol have been evaluated in three parallel groups of asthmatic patients. The three topics induce bronchoconstriction without significant difference between them, and lower heart rate (sometimes very intensely) whatever the B antagonist studied. From these data, it is recommended to practitioners to follow carefully the rules of administration of B blockers, even in eye drops.
Effects of three beta antagonist eye drops are studied in three parallel groups of asthmatic patients. Each ocular topic lowers FEV1 with a maximal effect of -13.4 +/- 2.1% for timolol (n = 15), -17.9 +/- 3.3% for metipranolol (n = 10), and -8.6 +/- 3.0% for carteolol (n = 10). Vital capacity, systolic and diastolic pressure scarcely change, but all three eye drops give a dose dependent sinus bradycardia. Intravenous infusion of isoproterenol (exclusive beta agonist) shows an important inhibition of cardiac receptors by timolol. Doses necessary to increase heart rate of 50% are of 0.242 +/- 0.019 microgram/kg before eye drops are instilled and of 0.647 +/- 0.054 microgram/kg after timolol treatment. This study stresses out the necessity of following recommended doses and respecting carefully classical contra indications of beta blocking agents and specially asthma.
Systemic effects of two topical B adrenergic blocking agents, carteolol and metipranolol, recently introduced in the treatment of open angle chronic glaucoma, were investigated in two groups of 10 asthmatic patients, according to a controlled trial device. Saline eye drops as placebo, then, 30 mn later beta blocker eye-drops, were instillated at usual dose. Heart rate, systolic and diastolic blood pressure, vital capacity (VC) and expiratory outflow (FEV1), were checked every 15 mn during 90 mn. They did not vary under placebo. After carteolol and metipranolol, heart rate decreased more than 10% in 7 out of 10 patients in each group (extreme individual changes: -16.7 and -25.0%). Bradycardia was always sino atrial. FEV1 was lowered in 3 patients with carteolol and in 6 with metipranolol (extreme individual values: -32.3 and -31.8%). If time is not taken in consideration, the lowest values were -8.6 +/-4.6% with carteolol and -17.9 +/- 3.3% with metipranolol. CV was reduced only in 1 patient under carteolol and 2 patients under metipranolol. Systemic blood pressure remained unchanged. 7 patients complained of ocular pain when metipranolol was instillated. Comparison of both ocular topics shows that metipranolol lowers heart rate and FEV1 more than carteolol, which has a sympathomimetic intrinsic activity. These two drugs have the same clinical efficiency. Our results point out the risks outcoming from their systemic diffusion, and the absolute necessity to comply with the general rules of good use of beta blockers, even with eye drops, mainly the contra-indications and the strict adjustment of individual doses.
The bronchomotor properties of calcium antagonists were investigated in 10 patients with paroxysmal asthma, using a double-blind, cross-over method. Each patient received, in random order, either a placebo (5% glucose solution) or bepridil (2 mg/kg) administered by intravenous infusion over 30 min. There were no changes in mean values of vital capacity, FEV1 and systolic blood pressure. Bradycardia was regularly present. Diastolic blood pressure was lowered in 4 patients. An analysis of individual responses showed that FEV1 was unimpaired in 9 patients and was increased by more than 25% in one case. Thus, contrary to beta-blockers, bepridil and other calcium antagonists have no adverse effects on the bronchi of asthmatics; on the other hand, their bronchorelaxant effect is too inconstant for these drugs to be used in the symptomatic treatment of paroxysmal asthma.
The systemic effects of timolol eye drops were investigated in 35 patients divided into three groups: 1. (15 asthmatics); 2. (10 non-asthmatic patients suffering from glaucoma); 3. (10 elderly control subjects). A placebo eye drops was given at time 0, the timolol maleate drops were given at time 30 mn. The control parameters were checked every 15 minutes. They did not show variations under placebo. After administration of timolol, systolic and diastolic blood pressures as well as vital capacity remained unchanged. Heart rate decreased in 91% of subjects by a mean: 18.5% and, extreme 38%: Bradycardia was always sino-atrial and there was a dose effect relationship. Also F.E.V., decreased in 13 of the 15 asthmatics and in 2 patients with chronic bronchitis: in 4 patients the decrease in flow exceeded 20%. The importance of timolol in the treatment of open-angle chronic glaucoma is well-established, but the results reported here and else where emphazing frequent risks should induce prescribers to comply with the rules of good use: analysis of previous history, and compliance with general contra-indications to beta blockers. Routine E.C.G. and strict adjustment of dosage is recommended.
Two stimulation trials with isoprenaline were performed in two groups of 50 and 55 patients considered as spasmophilic. The first trial was to check the sensitivity of the beta 1 type cardiac receptors : the average isoprenaline hydrochloride dose raising by 50 p. 100 the rest cardiac rate was equal to 0.147 +/- 0.09 micrograms/kg for 0.23 +/- 0.09 micrograms/kg in the control group. A second trial allowed to stabilize the cardiac rate between + 40 and + 50 p. 100 of its initial value : the symptoms, reappearing during stimulation, under the influence of isoprenaline, were studied. In 43 out of the 50 investigated patients the usual symptoms reappeared, particularly the acrocontractural attacks which were observed then in 46 p. 100 of cases, and sometimes an acute tetanic attack with opisthotonus. All these signs which are characteristic of "the spasmophilic state" seem to relate to vegetative regulation in which the beta-adrenergic component would show the most important : hypersensitivity of the beta receptors might be the common physiological base.
A computer was used for a statistical analysis of the results of treatment in 162 patients (130 women and 32 men with an average age of 29 years), with chronic idiopathic tetany. Symptoms leading to diagnosis were mainly feelings of ill-health (27.2 %), motor disorders (19.7 %), and sensory problems (19.1 %). The onset of acute attacks is related, more especially, to psychogenic factors. The frequency of the various clinical manifestations, and their symptomatic grouping were analyzed. The clinical profile is similar in both sexes apart from 7 of the 89 items: lipothymia, abnormal feelings of warmth, pseudo-contraction of the larynx, abnormalities of the exoskeleton, and digestive disorders are more frequent in women, while precordalgia is more often present in men. Factorial analysis of correspondence between 38 variables reveals a very large dispersion of the variables, as the first three factors, which are the most significant, supply only 30% of the total information. Furthermore, very few variables share significant relationships in each factor. In spite of the amount of information collected, this dispersion of the symptomatology does not permit the definition of one or more profile-types of spasmophilia.
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The authors report the results of a study of propranolol perfused intravenously at a dose of 1 mcg/kg/mn during 30 mn to 50 asthmatic patients. The VC decreased by 8.3 and by 10.9% in the middle and at the end of the perfusion. The FEV1 decreased by 18.3 and 23% concomitantly. Classifying patients in 4 groups according to the clinical severeness of the asthma showed that the response to propranolol increased with that severenesse. Exploration of obstructive bronchopneumopathies by propranolol provided valuable data or the differential diagnosis of asthma and chronic bronchitis.
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