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Two cases of persistent hematuria associated with the presence of sickle cell hemoglobin were treated intravenously with triglycyl vasopressin, a drug not previously used for this condition. One patient, a 16-year-old boy, had hemoglobin AS. Both patients had a history of severe hematuria persisting over several months, resistant to the usual forms of therapy, and requiring numerous transfusions. In each patient, the condition responded to intravenous triglycyl vasopression therapy, with cessation of hematuria. Experimental studies in dogs indicate that triglycyl vasopressin reduces renal blood flow substantially. Further trial of triglycyl vasopressin in severe hematuria associated with the presence of sickle cell hemoglobin appears to be indicated.

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Renal concentration tests were carried out on 45 healthy volunteers and 106 patients with chronic renal disease of moderate degree involving impaired concentrating ability. Each subject served as his own control. The control experiment involved a total of 36 hr of "dehydration" (no fluids per os or food with a high fluid content such as fruit) in which 4 hr clearance periods were started from the 12th and continued to thd 36th hr. The first 12 hr involved an overnight period from 20.00 hr. One week later the same subjects were given 10 micrograms demopressin (dDAVP) at the 13th hr and a subsequent 4 hr clearance period provided blood and urine samples to compare desmopressin-induced urine concentration with various stages of concentration during oral fluid withdrawal alone. The drug was given intranasally. We measured urine osmolality and concentrations of urea. Na, K and calculated the U/P creatinine concentration ratios and creatinine clearances (CCr). Using Uosm as the criterion, the dDAVP experiment at 12 hr gave the same results as 24 hr of fluid withdrawal alone. With the U/PCr ratio as the criterion, dDAVP + 12 hr gave the same results as 36 hr of fluid withdrawal alone. Between 32 and 36 hr dehydration, CCr decreased - otherwise it remained unchanged in both healthy and ill subjects, with and without dDAVP. The only side-effect was the discomfort of more than 12 hr dehydration. This would appear to simplify a potentially useful diagnostic and prognostic test.

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The long-acting oxytocin (OT) analog 1-desamino-1-monocarba-E12-Tyr(OMe)]-OT(dCOMOT) was given IV to 13 pregnant cows near to term, but not in actual labor. The animals were para 1 to 5. Of these cows, four were treated with 20 mg of dexamethoasone 48 hours before the peptide was injected; the remaining nine animals were given no other medication. The animals usually were given a single injection of 5 mg of dCOMOT into the jugular veiw (5 to 7 micrograms/kg of body weight). In those instances where delivery was not complete within six hours, a second injection of peptide was given. In all instances, the first injection initiated labor as judged by the behavior of both uterus and cow. In most instances, there was also intermittent spurting of colostrum from the udder over a six-hour period after injection. In the four cows treated first with dexamethasone, the mean duration of induced labor was 4.35 hours after dCOMOT injection. In the nine non-treated cows, the mean duration of induced labor was 14.25 hours. The difference between the two values was significant. For both groups separately, and all data together, there was a linear inverse relation between the size of the external ostium uteri at injection and the duration of labor after peptide injection. All calves were healthy with no signs of hypoxia and the dose rates used did not result in any instance of uterine tetany or tachyphylaxis.

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Structural requirements of the systemic factor VIII response to intravenous vasopressin in man has been investigated using vasopressin analogues. With the analogues available the receptor specificity of this phenomenon could not be distinguished from those associated with the previously described plasminogen activator release or antidiuretic effects of this hormone. Further studies using 1-desamino-[8-D-arginine]vasopressin showed a dose-related release of both procoagulant and antigenic components of the factor VIII complex. The newly released factor VIII could not be distinguished from circulating factor VIII on the basis of molecular size, electrophoretic mobility or in vitro stability despite apparent differences in the duration of response of the procoagulant and antigenic components in vivo.

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Brattleboro rats with diabetes insipidus (DI) will, if no other fluid is offered, drink their own previous day's urine. Such oral urine-recycling, where normal elimination is effective only in 15%, does not result in clinical or laboratory signs of uraemia even after 20 days. Serum electrolytes and creatinine remained normal, serum osmolarity and urea were slightly raised, but none of the parameters measured could be classified as uraemic. Extrarenal excretion of electrolytes increased. It is suggested that when the excreted load is represented to the organism from the gut lumen (as opposed to re-presentation into the peritoneal cavity or cessation of renal function) the gut wall serves a protective function by not reabsorbing significant portions of both the inorganic and organic loads in the urine. More detailed analysis will be required to establish this suggestion.

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Desmopressin (1-desamino-[8-D-Arg]-vasopressin) (DDAVP) was given by nose drops to 22 children with persistent nocturnal enuresis (mean age, 6.6 +/- 2.9 years; range, 4 to 12 years) the evening before sleep. With saline alone as placebo and with comparison to enuretic frequency before the onset of the trial, fortnightly periods were compared under double-blind conditions with the children at home. Pretreatment and placebo fortnights showed wetting frequencies (nights per fortnight) of 10.6 +/- 4.9 and 11.0 +/- 4.4, respectively. The value of the fortnight during desmopressin therapy was 4.2 +/- 4.5, which was significantly different from either of the previous means (P less than .01). Of the 22 subjects, four failed to react to therapy at all. There was decreased enuretic frequency in the remaining 18, of whom 12 decreased markedly or ceased wetting. One month after the trial, seven of the respondents were dry with desmopressin therapy. There was clear evidence of a large nocturnal volume of dilute urine before treatment in six of the respondents in whom such measurements could be reliably made. These children responded to dehydration with urine concentration, however, so that the suggestion can be made that a failure to develop a normal diurnal pattern of urine volume and concentration may underly some cases of enuresis.

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Natural vasopressins have been used, with varying success, in attempts to stop bleeding from esophageal varices for over two decades. Reasons for lack of success include (a) failure to induce a sufficiently prolonged and constant vasoconstrictor effect at the bleeding site, (b) dangerous side-effects, and (c) release of plasminogen activator induced by the peptides which can lyse any clot as it forms.IN THE LAST DECADE ANALOGS OF VASOPRESSIN HAVE BEEN DEVELOPED WITH A PROLONGED ACTION, USING TWO SEPARATE PRINCIPLES OF CHEMICAL MODIFICATION: (1) hormonogens, and (2) blockage of sites of inactivating enzymatic cleavage (in particular "carba" analogs without a disulfide bridge). These two categories of analog are compared here: the carba analogs have the advantages of high potency (higher than the parent hormone) with prolongation, but are also very active on the plasminogen activator release system. The hormonogens combine prolongation with low potency, but have lost not only a releasing action on plasminogen activator, but also, by virtue of altered release kinetics, have effectively lost cardiovascular toxicity.Mechanisms of analog action and receptor interaction are presented, along with initial clinical experiences.

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In a pilot study 12 women with severe uterine bleeding received an intravenous injection of 0.2 mg of a vasopressin hormonogen, glypressin. In 11 of the patients a rapid reduction or cessation of blood loss were observed. Two patients had facial pallor following the injection but no other side effects occurred. Five of the older women with long histories of menorrhagia were placed on a regime of one injection of glypressin on the first day of menstruation for six months; in all of them the duration of bleeding was reduced to three days and the monthly blood loss became very slight. On the basis of these results more extensive clinical trials in menorrhagia and metrorrhagia are recommended.

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Seven patients with compensated liver cirrhosis and esophageal varices, all with a base line wedge hepatic vein pressure greater than 20 cm H2O, received 1-mg doses of vasopressin hormonogen (tGLVP) intravenously. There was a significant mean decrease in wedge pressure of 32%, which lasted for at least 20 min (the duration of measurement), with no change in cardiac output measured. The only cardiac response was a 10 to 20% bradycardia at the height of the moderate pressor response-otherwise the ECG was without change. In 5 patients who received the same tGLVP dose during surgery, direct measurements of portal venous pressure showed the same degree of decrease within 10 min of intravenous injection. Fifteen patients with liver cirrhosis and severe bleeding from esophageal varices were treated conservatively with blood transfusion and tGLVP as the only major drug aside from antibiotics. A nonrandomized control group of 13 patients with the same age distribution, stage of disease, number of previous bleeds, etc., was treated conservatively in the same manner, except that they received either no hemodynamically active drugs or short acting neurohypophysial peptide preparations such as Pitressin. In the control group there was a 61.5% total mortality, a 53.8% mortality directly related to uncontrollable bleeding, and a mean duration of the bleeding episode of 11 days. In the tGLVP-treated group total mortality was 20%, mortality directly related to uncontrollable bleeding was 13.3%, and mean duration of the bleeding episode was 2.9 days. These results appear to justify a large scale clinical trial of the vasopressin hormonogen in this disease.

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The antidiuretic action of a number of vasopressin analogues has been measured in the rat and man in water diuresis. These analogues had the following categories of structural alteration: a) substitution of -CH2CH2-(dicarba) and -SCH2-(6-monocarba) for the natural -SS- bridge between residues 1 and 6, b) changes in the nature of the C-terminal tripeptide produced by substitution of D-arginine and L-Nalpha-methylarginine for L-arginine in sequence position 8 and L-leucine for proline in position 7, and c) combinations of a and b. In addition, a highly active analogue which results when valine is substituted for glutamine in position 4 was tested. Trained, unanesthetized rats and normal human volunteers were complemented by a volunteer patient with posttraumatic diabetes insipidus (DI) in the total group of experimental subjects. The only change in the C-terminal tripeptide which was associated with a high antidiuretic action was D-Arg substitution. The meArg and Leu analogues showed low to very little activity and no signs of antidiuretic antagonist action. All of the carba analogues showed both high potency and prolongation of antidiuretic action in the following order (for both potency and duration): monocarba + 8-D-Arg greater than 4-Val + 8-D-Arg greater than 8-D-Arg alone, all in deamino form. None of the 8-D-Arg analogues had any side effects on the cardiovascular system, gut, uterus, bladder, etc. The prolongation was such that even with a DI patient refractory to the action of lysine-vasopressin and relatively resistant to deamino-[8-D-Arg]-vasopressin, water turnover could be reduced from untreated levels of 20 to 30 liters/day to less than 2 liters/day with only a single administration of deamino-6-carba-[8-D-Arg]-vasopressin as nose drops. The significance of these structural alterations in the vasopressin molecule for interaction with both antidiuretic and smooth muscle receptors was discussed.

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Nalpha-glycyl-glycyl-glycyl-(8-lysine)-vasopressin, a hormone analogue with prolonged pharmacological action due to slow release of active nonapeptide by enzyme action in vivo, has been administered to 5 control subjects and to 14 patients actively bleeding from upper gastrointestinal sites. The control subjects showed a prolonged pressor response to 100mug/kg body weight associated with a rise in cardiac output, with no ECG signs of myocardial toxicity. 13 of the 14 bleeding patients showed not only pressor responses and haemodynamic and clinical improvement when administering doses of 20-100 mug/kg, but clear signs of standstill of upper gastrointestinal bleeding.

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Cardiac output and regional blood flows to myocardium, gut, uterus and kidney were determined in anaesthetised female rats by a single injection of 86RbCl. The haemodynamic responses were measured at various time intervals up to 2 h after single I.V. injections of lysine-vasopressin and the following of its analogues: a) with extended peptide chains at the N-terminal (including "hormonogens") Nalpha-glycyl-glycyl-lysine-vasopressin, Nalpha-glycyl-glycyl-glycyl-arginine-vasopressin and Nalpha-D-valyl-lysine-vasopressin, b) "carba" modifications desamino-carba6-arginine-vasopressin, desamino-carba6-D-arginine8-vasopressin, desamino-carba6-ornithine8-vasopressin, desamino-dicarba-arginine-vasopressin and c) other steric alterations - desamino-D-arginine8-vasopressin and desamino-N-methylarginine8-vasopressin. Sub-pressor doses of lysine-vasopressin were followed by marked reductions in gut and uterus blood flows which reached a peak at 10 min. and had completely receded by 60 min. The presence of steric alterations in the C-terminal tripeptide of the molecule- D-arginine or N-methylarginine in sequence position 8 - practically completely eliminated vascular activity. The same was true for Nalpha-D-valyl-lysine-vasopressin. None of the latter three analogues showed any inhibitor properties to the action of lysine-vasopressin. The two hormonogens (triglycyl N-terminal extensions) had to be given in doses 10 times greater to obtain a vasoconstrictor effect in gut and uterus equivalent in amplitude to that of a lysine-vasopressin, but this effect was still present to the same degree 2 h later with the hormonogen of lysine-vasopressin, and was only starting to return to baseline values at the same time with the arginine-vasopressin hormonogen. The vascular potency of both mono-carba L-analogues was higher than that of lysine-vasopressin, and the effect was as prolonged as with the hormonogens. The dicarba analogue also showed a prolonged action, but with much reduced potency. No significant changes in renal or myocardial blood flows were observed at all. Molecular features of vasopressin smooth muscle activity were discussed, and a receptor model was proposed. It was suggested that the -S-S-, -CH2CH2-bridges in the above analogues are not directly bound in the peptide-receptor complex and constitute the limiting factor determining complex duration, or persistence of the active peptide in the "receptor compartment". These results provide an experimental basis for possible clinical application of triglycyl-vasopressin and carba-vasopressin in bleeding from both gut and uterus and for induction of menstruation.

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