Effect of certain drugs in perfused human placenta XII: autacoid antagonism by phenothiazines

The effects of chlorpromazine, prochlorperazine, and trifluoperazine on the pressor actions of serotonin, angiotensin, and bradykinin in the perfused vessels of full-term human placentas were investigated. A significant inhibition of the effect of serotonin was observed with trifluoperazine and chlorpromazine but not with prochlorperazine. The inhibition is attributed to the ability of phenothiazines to cause adrenergic blockade. Because both bradykinin and angiotensin could not be consistently antagonized, it is concluded that they must act primarily via musculotropic mechanisms and only secondarily by stimulation of adrenergic receptors.     

Tremorogenic effects of intracaudate d-amphetamine and their suppression by dopamine

Pronounced tremors were produced in unanesthetized cats following intracaudate (I.C.) injections of either d-amphetamine (15 mug), dl-methamphetamine (20 mug), l-amphetamine (48 mug) or 3-methoxytyramine (68-120 mug). Yet, a series of other chemically and pharmacologically related phenylethylamines, including dopamine (90 mug), were not tremorogenic even at substantially higher doses. The d-amphetamine tremors developed rapidly, failed to exhibit tachyphylaxis to repeated challenging doses (15 mug) and were not influenced by pretreatment with alpha-methyl-p-tyrosine. They also developed independently of local acetylcholine activity as evidenced by the inability of cholinergic antagonists (scopolamine and hemicholinium) to interfere with the tremors. Significant qualitative differences were found between the I.C. effects of d-amphetamine (15 mug) and dopamine (15-90 mug): d-amphetamine further increased the intensity of ongoing tremors induced by physostigmine (111 mug I.C.), whereas, dopamine readily inhibited the latter. When superimposed, I.C. dopamine was equally effective in suppressing d-amphetamine tremor activity. The results emphasize the selective tremorogenic actions of d-amphetamine and call attention to the contrasting stabilizing role of dopamine. This would suggest that two types of adrenergic receptor sites are operative in the caudate in neuroregulation of involuntary movements.     

Cardiovascular effects of ajmaline

Ajmaline, a rauwolfia derivative, has been found to possess potent antiarrhythmic effects. The present study has been designed to define the cardiovascular effects of this drug. Hemodynamic studies performed in anesthetized and conscious dogs demonstrated no significant changes in measured hemodynamic parameters at doses equal to or less than 2 mg. per kilogram. Studies in isolated papillary muscle demonstrated no negative inotropic effects until concentrations of 1 X 10(-4). Disparate results were obtained with regard to heart rate reflecting the state of autonomic tone. Electrophysiologic studies in both anesthetized and conscious dogs demonstrated a significant depression of intraventricular conduction with no significant effect on AV nodal conduction; ventricular automaticity was not affected. Ajmaline did not alter digitalis-induced AV nodal conduction prolongation. However, ajmaline dramatically altered or abolished ventricular arrhythmias secondary to acute ischemia. In conclusion, these studies demonstrate that ajmaline specifically depresses intraventricular conduction, suggesting that this drug would be particularly effective in the treatment of re-entrant ventricular arrhythmias.     

Frontal EMG-biofeedback training of athetoid cerebral palsy patients: a report of six cases

108 tendons of the m. extensor hallucis longus were examined with a tensile testing machine within 36 h after death. The specimen were kept at a resting length of 20 mm. After the "steady state" was reached by cyclic loading, the tendons were stretched up to a maximum load of 18 kp, then deloaded to a certain level and after that the elongation was kept constant. At high loading level the tension of the tendon decreases with time (relaxation). At medium and low loading level the tension increases slightly (mechanical recovery). Between that two regions there is a certain load, where the tension will not change with time (isorheological point). The position of the isorheological point depends on the velocity of the elongation. At low velocity (2 mm/min) the isorheological point is situated at 70%, at high velocity (12 mm/min) at 60% of the maximum load. One will find the maximum relaxation, when no deloading occurs. The mechanical recovery, however, has its maximum at 5--25% of the maximum load. But when the tendon is totally deloaded, there seems to occur no recovery. The maximum relaxation is 5 to 6 times larger than the maximum recovery. Supposingly the relaxation- and recovery-processses will happen at the same time but with different intensity depending on the loading level. At least the relaxation-process consists of different relaxation components with different relaxation times. This will explain the phenomenon of a "secondary relaxation": After a long time of registration the recovery will turn into a slight relaxation.     

Diagnosis and pathophysiology of paradoxical embolism

A review of the experience with 134 consecutive patients with germinal cell testicular neoplasia indicates that definitively accurate staging of the malignancy at presentation is the single most important prognostic factor. Nearly two-thirds of the patients with all types of germinal malignancies survived or died of other causes and the highest survival rates were seen among patients with earlier stages of seminoma. In recent years patients with all types of germinal malignancies of the testis have been treated by radical retroperitoneal lymphadenectomy with enhancement of survivals. Patients with seminoma and non-seminomatous tumors exhibited increased survival rates with node dissection. In 66 consecutive lymphadenectomies the complication rate was less than 14 per cent, with only 1 death related to the operation. Retroperitoneal lymphadenectomy not only affords therapeutic advantage but also provides an opportunity for accurate surgical staging of disease and allows for rational decision relative to additional treatment, radiation therapy or chemotherapy.     

Inhibition and alternate-substrate studies on the mechanism of malic enzyme

A number of dead-end inhibitors and alternate substrates were examined to gain an understanding of the substrate specificity and mechanism of malic enzyme. Comparison of Ki values for competitive inhibitors suggested that binding of the l-carboxyl of L-malate is by ion pairing with lysine or arginine, while binding of the 4-carboxyl is weaker, and probably of the induced-dipolar type. The 2-hydroxyl hydrogen bonds to a catalytic group, which, when it is protonated, adsorbs the keto form of oxalacetate. Since the only molecule other than L-malate that is oxidized is L-malate-beta-amide, carbon 4 must be trigonal for substrate activity, although a tetrahedral carbon bearing one or two hydroxyl groups gives good binding. Hydroxy groups at carbon 3 contribute to binding, but prevent substrate activity. Hydroxy and ketomalonates are bound more strongly than any of the four carbon acids, suggesting that the latter are bound with some strain. In inhibition studies, pyruvate analogues were competitive vs. pyruvate but noncompetitive vs. malate, while malate analogues were competitive vs. malate and noncompetitive vs. pyruvate. These compounds thus bind to both enzyme-triphosphopyridine nucleotide (E-TPN) and enzyme-reduced triphosphopyridine nucleotide (E-TPNH), but only malate analogues prevent release of TPN, while pyruvate analogues prevent release of TPNH. Ketomalonate and oxalacetate, both of which are slowly reduced by the enzyme in the presence of TPNH and thus must combine in the keto form with E-TPNH,, appear to combine with E-TPN mainly in the gem-diol (or for oxalacetate, also the enol) form. The substrate for the decarboxylation of oxalacetate at pH 4.5 is the keto form.