Cardiovascular dysfunction (CD) in multiple sclerosis (MS) is related to involvement of reflex pathways in the brainstem. The battery of CD tests was applied to a group of 40 healthy subjects and 40 patients with MS, divided in 2 subgroups according to the expanded disability status scale (EDSS). The tests included: 1) postural blood pressure changes, 2) postural heart rate changes, 3) heart rate changes on inspiration/forced expiration and 4) ECG R-R interval measurement on the Valsalva maneuver. Both groups were subjected to the functional independence scale (FIM). Imaging studies were reviewed and autonomic dysfunction at other levels was explored. The results showed a statistically significant difference (P < 0.05) in all tests when comparing patients to controls. Tests 1 and 4 had the highest significance, with findings of more severe involvement in patients with a higher EDSS and lower FIM. A correlation was also found between CD and brainstem lesions on MRI (P < 0.01). A significant number of MS patients had evidence of CD. Test 1 may be considered a simple marker, in daily clinical practice, to detect subclinical CD. Subclinical CD is a cause of disability in this group of patients.
Clinical trials of new antidepressants usually compare a new drug to a reference antidepressant and to a placebo. The placebo is intended to validate the trial in the case of a no-difference outcome, i.e., it helps in assessing equivalence. The aim of the present paper is to test whether placebo has indeed helped establish equivalence of effect in comparative trials of new antidepressants. We carried out an example of sample size determination first in a trial to show a difference between the new and control drug, and second in a trial to assess equivalence between two competing drugs. Finally, we retrospectively calculated the maximum difference accepted as equivalence of effect in published trials of new antidepressants. Assuming a response rate to antidepressants of 70%, 294 subjects for each treatment group are needed to show a 10% difference between two antidepressant drugs and more than 1,300 to assess equivalence at a 5% level of delta, the maximum difference acceptable as equivalence of effect. The level of delta in published trials of new antidepressants ranges between 12 and 43%, suggesting they cannot claim to demonstrate equivalence of effect. Therefore, the presence of a placebo arm for comparison didn't help establish whether both drugs really worked the same way. Comparative trials of new antidepressants should adopt a two-arm design, a suitable number of patients and a high standard in the experimental design in order to minimise possible control-event rate variation.
Neo-synephrin 2 differs chemically from epinephrine only in the absence of the hydroxy group in the para position on the benzene ring. The first pharmacological studies with this substance emphasized the conclusion that the pharmacological action of neo-synephrin resembles that of epinephrine in all respects, but the potency is less and the duration of effects is longer (12,13,21). Inspection of the data in these papers shows, however, that the pressor effect is relatively much more prominent than the cardio-accelerator action.The pressor action of neo-synephrin has been utilized with some success in the treatment of surgical shock (10,11,17), in the prevention of the hypotension of spinal anesthesia (1, 2) and in the treatment of orthostatic hypotension (6,8). Neo-synephrin is widely used as a local vaso-constrictor and may prevent cardiac standstill in patients with a hyperactive carotid sinus reflex (18). A prominent effect of this drug in normal man is the production of marked bradycardia (14). MATERIALS AND METHODSThe subjects ranged from 16 to 60 years of age but the majority were from 18 to 30. Thirty-nine of them were men, 9 were women. With the exception of 10 cardiac patients they were all trained as experimental subjects, so that psychic effects were at a minimum.The studies were carried out in the morning in the basal fasting state with an absolute minimum of exciting influences. In all but a few cases the room temperature was between 750 and 80°F. and humidity was between 40 and 70 per cent. Most of the experiments were made with the subject horizontal; in the others, the subject rested in a chair designed for x-ray studies. Minute output was measured by the acetylene method of Grollman (7). In those experiments in which this method was applied the sequence was: rest 15 minutes; measurement of oxygen consumption, acetylene rebreathing; rest 10 minutes; drug administration; wait 5 to 10 minutes; measurement of oxygen consumption (8 minutes), acetylene rebreathing, final measurement of oxygen consumption.Venous pressure was measured in the horizontal position by the direct method with citrated saline in the manometer. Circulation time (arm-to-tongue) was measured by injection of 5 ml. of a 20 per cent solution of sodium dehydrocholate ("decholin"). For this purpose the syringe needle was inserted into the vein and a minute or two allowed to elapse before the injection was started.The injection was then made as rapidly as possible and the time was measured from the start of the injection until the first sensation of the bitter taste.Threshold for subcutaneous injection The threshold dose of neo-synephrin to produce cardiovascular effects was determined for subcutaneous injection in 36 experiments on normal adults. In each case injection was made under the skin on the outside of the upper arm; the site
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