Vasopressin and Its Analogues: From Natural Hormones to Multitasking Peptides.

Human neurohormone vasopressin (AVP) is synthesized in overlapping regions in the hypothalamus. It is mainly known for its vasoconstricting abilities, and it is responsible for the regulation of plasma osmolality by maintaining fluid homeostasis. Over years, many attempts have been made to modify this hormone and find AVP analogues with different pharmacological profiles that could overcome its limitations. Non-peptide AVP analogues with low molecular weight presented good affinity to AVP receptors. Natural peptide counterparts, found in animals, are successfully applied as therapeutics; for instance, lypressin used in treatment of diabetes insipidus. Synthetic peptide analogues compensate for the shortcomings of AVP. Desmopressin is more resistant to proteolysis and presents mainly antidiuretic effects, while terlipressin is a long-acting AVP analogue and a drug recommended in the treatment of varicose bleeding in patients with liver cirrhosis. Recently published results on diverse applications of AVP analogues in medicinal practice, including potential lypressin, terlipressin and ornipressin in the treatment of SARS-CoV-2, are discussed.

An analysis of fluid loss during transcervical resection of submucous myomas.

OBJECTIVE: To determine the contribution of several variables to fluid loss during transcervical resection of submucous myomas. DESIGN: An observational study using multiple linear regression analyses. SETTING: A university-affiliated training hospital and a university department of clinical epidemiology and biostatistics. PATIENT(S): Patients with submucous myomas. INTERVENTION(S): Transcervical resection of submucous myomas and monitoring of fluid loss. MAIN OUTCOME MEASURE(S): Patient age, uterine enlargement, treatment with GnRH analogues or 8-ornithine-vasopressin, type of anesthesia, number of myomas, intramural extension of the myoma (type of myoma), and operating time were tested as variables. RESULT(S): Only intramural extension of the myoma and operating time were obviously related to fluid loss. For the other variables, such a relation was weak at best. The relation between fluid loss and operating time was not modified by any of the other variables. CONCLUSION(S): Because fluid loss is an important limiting factor in the transcervical resection of submucous myomas, special attention should be paid to reduction of the operating time and preoperative assessment of the intramural extension of the myoma to guide appropriate patient selection.

Preliminary study of microsurgical repairs of the inferior alveolar nerve in rats using primary suturing and laser weld techniques.

A comparison of primary suturing and a new laser weld technique is described for the microsurgical repair of the inferior alveolar nerve in Wistar rats. A reliable method of exposure of the inferior alveolar nerve has been developed in order to allow intraosseous repairs of the nerve involving suturing with 10:0 nylon and a laser weld technique using an albumin-based solder, containing indocynine cardiogreen, plus an infrared (810 nm wavelength) diode laser. Seven cases of microsuture and laser weld repairs were performed with a 29.4% reduction in total operating time in the laser weld group. Histochemical analysis showed comparable mean neuron counts and mean tracer uptake by neurons for the microsuture and laser weld groups. Giant cell reactions were identified in two of the primary suture cases and axon deflection in three cases demonstrating possible advantages of the laser weld technique which showed no adverse reactions by axons or epineurium to the coagulative repair with the solder. The technique of laser weld repair, on initial analysis, therefore appears comparable with traditional suture repairs and indeed may possess several advantages. Further studies are recommended.

Management of patients with persistent beta-hCG values following laparoscopic surgical and local drug treatment for ectopic pregnancy.

OBJECTIVES: To show that the beta-human chorionic gonadotropin (hCG) decline following tubal-preserving techniques for ectopic pregnancy (EP) can take a longer course than currently believed, indicating expectant management; and to define the indications for a second-look laparoscopy if beta-hCG persists. METHODS: Three hundred thirty-seven patients treated for EP were retrospectively reviewed. In order to define the 'normal' beta-hCG decline following tubal-preserving techniques we acquired a Kaplan-Meier curve for 98 patients treated by laparoscopic linear salpingotomy, the main method performed for EP (253 patients). The Mann-Whitney U-test served as a statistical test. The patient population requiring a second-look laparoscopy for proliferating trophoblastic remnants is described. RESULTS: Twenty-eight patients (8.3%) required a second-look laparoscopy (acute abdominal pain and sonographically suspect findings combined with increasing beta-hCG values). The majority (15 patients) underwent a preceding laparoscopic linear salpingotomy (6.5% unresolved cases). The relative beta-hCG values differed significantly from the unresolved group compared to the group with resolved EP starting at postoperative day 2 (P < 0.01). A maximal beta-hCG decline period of 77 days postoperatively was observed. CONCLUSIONS: Patients with slowly declining beta-hCG levels following tubal-preserving techniques for EP can be managed expectantly. Increasing beta-hCG values combined with abdominal pain and sonographically suspect observations indicate a second-look laparoscopy.

Use of POR-8 in the management of burned children.

In the paediatric burn unit of Brugmann University Hospital, children are treated conservatively for three weeks before excision and grafting. In order to avoid excessive bleeding during tangential excision of the granulating tissue, sub-eschar infiltration with Para-Ornithin-8-Vasopressin (POR 8), a synthetic neurohypophyseal-like hormone, has been performed since 1979 on 145 children. Bleeding is reduced dramatically by this technique. Therefore, since 1984, infiltration of the donor site with POR 8 was also performed in 25 children. Excision and grafting of areas up to 20% of total body surface are possible in one operation with a graft take rate of 95 to 100%. We didn't record any variation in heart rate. A 5 to 10% increase of arterial blood pressure occurred in all children. No general or local complications have been observed. We believe this technique to be of great help in the operative treatment of burns in children.

[Use of etilefrin as local vasoconstrictor in lower gynecologic surgery ]. / Utilisation de l'étiléfrine comme vasoconstricteur local dans la chirurgie gynécologique par voie basse.

In this randomized prospective study the authors have compared the effectiveness and side-effects of two local vasoconstrictor agents, etilefrine (Effortil) and ornithine 8 vasopressin (Por 8) in vaginal gynaecological surgery. Thirty-three patients entered the trial and were divided into two groups: G1 (15 patients) received Effortil, and G2 (18 patients) received Por 8. The products, administered at random, were diluted in saline 40 ml and injected into the cervix through 6 points. A 3-minute interval was allowed between injection and incision. The results were assessed on the basis of trans- and postoperative haemorrhage and haemodynamic variations. Palor of the cervix was achieved after 3 minutes in both groups; moderate bleeding was observed in only one of the G1 patients. Postoperative renewal of packing was necessary in 2 patients in G1 and 4 patients in G2. No electrocardiographic anomaly was recorded in any of the two groups. Diastolic BP was significantly higher in G2 than in G1 (P less than 0.002, Fisher test). Systolic BP was also elevated in that group (P less than 0.03, chi 2 test). Moderate reduction in heart rate was observed in both groups (P less than 0.3, Fischer test), but severe (48 beats/min) bradycardia was noted in one G2 patient.

[Value of POR 8 in the treatment of burns]. / Intérêt du POR 8 pour le traitement des brûlés.

Excision and skin grafting is the best treatment for burn wounds. In order to avoid excessive bleeding during the operation, sub-eschar infiltration with POR 8 (para ornithine 8 - vasopressin) has been performed in 115 patients between 1979 and 1984. The results being encouraging, infiltration was later also performed under the donor site. Bleeding was reduced enough by this technique to allow one stage excision and grafting of surfaces up to 20% of the body surface. No general or local complication of POR 8 infiltrations has been observed except a slight increase of blood pressure without clinical consequence.

Enhancement of renal function with ornipressin in a patient with decompensated cirrhosis.

An infusion with Ornipressin (8-ornithin vasopressin) in a patient with decompensated alcoholic liver cirrhosis increased urinary volume from 30 ml/h to 500 ml/h, creatinine clearance from 24 to 65 ml/min, and fractional sodium excretion from 0.86% to 11.1%. Free water clearance decreased from -10.2 ml/h to -26.2 ml/h and noradrenaline plasma concentrations dropped from 2.04 to 1.37 ng/ml. After stopping Ornipressin infusion all values returned to initial concentrations. Possible effects are an increase of renal blood flow secondary to an increase in arterial blood pressure, possibly potentiated by the vasodilatory effect of the fall in noradrenaline and/or angiotensin concentration.

Effect of L-ornithine 8-vasopressin on blood loss during liposuction.

In this comparative study, we carried out liposuction on 20 patients randomly divided in two groups to find an alternative medication to epinephrine that would not result in secondary effects at the cardiovascular level but would offer a similar vasoconstricting capacity. Also, a variation of the wet technique is described that decreases blood loss secondary to liposuction. The area to undergo liposuction is infiltrated with a cannula of our own design. Epinephrine is not used as a vasoconstrictor but rather L-ornithine 8-vasopressin at a concentration of 0.01 IU/ml chilled saline. With this new technique, the amount of blood removed is minimal, even in the case of extraction of large volumes of fat.

[Celioscopic treatment of extra-uterine pregnancy]. / Traitement coelioscopique de la grossesse extra-utérine.

The treatment of extrauterine pregnancy by coelioscopy is the most extreme refinement of coelioscopic surgery. It is recorded in the modern context of endoscopic surgery. This technique was received with reserve some years ago, when we presented the first case. After more than 250 cases the validity of the treatment has been established, and it has been adopted by other groups, foreigners in particular. It is applicable to non-ruptured tubal pregnancies, and necessitates an early diagnosis. Compared with techniques carried out by laparotomy, it offers the advantage of considerable gain of operative time, and of a considerable reduction in hospitalization, with excellent results on later fertility.

Beneficial effect of 8-ornithin vasopressin on renal dysfunction in decompensated cirrhosis.

In nine patients with decompensated alcoholic cirrhosis of the liver and impaired renal function the effect of 8-ornithin vasopressin (ornipressin) on renal function and haemodynamic parameters was studied. Ornipressin was infused at a dose of 6 IU/h over a period of four hours. During ornipressin infusion an improvement of renal function was achieved as indicated by an increase of creatinine clearance (76 (15)%; p less than 0.01), urine volume (108 (29)%; p less than 0.05) and sodium excretion (168 (30)%; p less than 0.05). The hyperdynamic circulation of hepatic failure, as characterised by increased cardiac index and heart rate as well as decreased systemic vascular resistance was reversed to a nearly normal circulatory state during ornipressin infusion. The raised noradrenaline plasma concentration (1.74 (0.31) ng/ml) and plasma renin activity (13.5 (3.9) ng/ml/h) were lowered during ornipressin infusion to 0.87 (0.21) ng/ml and 5.9 (2.1) ng/ml/h, respectively (p less than 0.01). The efficacy of a vasoconstrictor agent in reverting a hyperdynamic state and improving renal function provides evidence for the substantial role of accumulation of vasodilator substances and subsequent activation of sympathetic nervous system and renin-angiotensin-axis in the pathogenesis of renal dysfunction in hepatic failure. Values are expressed as mean (SE).

Local infiltration of ornithine 8-vasopressin (POR 8) as a vasoconstrictive agent in surgical pelviscopy (applied to myoma enucleation, salpingotomy in cases of tubal pregnancy and peripheral salpingostomy).

For better hemostasis in cases of operative pelviscopy in 60 patients Ornithine-8 Pitressin (POR 8) was applied locally as a vasoconstrictive agent in quantities of up to 50 ml at a concentration of 0.05 IU/ml. From the broad spectrum of indications for operative pelviscopy, the following procedures employing local application of a 5% POR 8 solution to produce intraoperative ischemia are described: Myoma enucleation, longitudinal salpingotomy with conception product extraction in the conservative treatment of a tubal pregnancy, ovarian cystectomy and salpingostomy. The tolerance was optimal no side effects were observed.

Myometrial biopsy in the diagnosis of adenomyosis uteri.

OBJECTIVE: Automatic cutting needle sampling was used for diagnosis of adenomyosis uteri. The purpose of this study was the establishment of myometrial biopsy as a clinically applicable method. STUDY DESIGN: Sensitivity and specificity of myometrial biopsy in diagnosis of uterine adenomyosis was estimated by examining 680 biopsy specimens from 68 surgically removed uteri. In 34 patients with clinical symptoms of adenomyosis uteri 70 myometrial biopsies were performed during laparoscopy, and vaginal ultrasonographically guided myometrial biopsy was performed in six patients (14 specimens) without complications. Prevention of myometrial bleeding was achieved by prophylactic injection of ornipressin into the biopsy cannula. RESULTS: The sensitivity of a single myometrial sample for diagnosing adenomyosis uteri ranged from 8% to 18.7%; specificity was 100%. CONCLUSION: Our results may encourage further investigation on the clinical use of myometrial biopsy.

Reversibility of hepatorenal syndrome by prolonged administration of ornipressin and plasma volume expansion.

Hepatorenal syndrome is caused by a marked vasoconstriction of the renal circulation. It is suggested that the renal vasoconstriction is related to an overactivity of vasoconstrictor systems secondary to a vasodilation of the arterial circulation that causes a reduction in effective arterial blood volume. To test this hypothesis, 16 cirrhotic patients with hepatorenal syndrome were treated with a combination of ornipressin, a potent vasoconstrictor agent, and plasma volume expansion with albumin to improve effective arterial blood volume. The combined treatment was administered either for 3 or 15 days (8 patients each), and the effects on renal function, vasoactive systems, and systemic hemodynamics were assessed. The 3-day treatment with ornipressin and albumin was associated with a normalization of the overactivity of renin-angiotensin and sympathetic nervous systems, a marked increase in atrial-natriuretic peptide levels, and only a slight improvement in renal function. However, when ornipressin and albumin were administered for 15 days, a remarkable improvement in renal function was observed, with normalization of serum-creatinine concentration, a marked increase in renal plasma flow and glomerular filtration rate, and a persistent suppression in the activity of vasoconstrictor systems. However, 3 of 8 patients on 15-day therapy treatment had to be discontinued because of ischemic complications. In conclusion, the decrease in effective arterial blood volume and the activation of vasoconstrictor systems play a crucial role in the pathogenesis of hepatorenal syndrome. Although the prolonged administration of ornipressin combined with plasma volume expansion reverses hepatorenal syndrome, this treatment should be used with great caution in clinical practice because of the risk of ischemic complications.

[Clinico-pharmacological case (2). Bradycardia and ventricular tachycardia of the torsades de pointes type as a side effect of vasopressin: 3 case reports]. / Der klinisch-pharmakologische Fall (2).Bradykardie und ventrikuläre Tachykardia vom Typ Torsade de pointes als Nebenwirkung von Vasopressin: drei Fallberichte.

We present three patients with ornipressin-induced bradycardia, one of which developed also ventricular tachycardia of the torsade de pointes type. All three patients were treated with this vasopressin derivative because of bleeding esophageal varices due to portal hypertension in liver cirrhosis. Bradycardia ceased after discontinuing ornipressin therapy. One patient was treated successfully with atropine, one with isoprenalin and magnesium (he had to be defibrillated); the third patient recovered after cessation of ornipressin administration. Bradycardia is a known but rarely reported side effect of vasopressin and its derivatives. Animal studies suggest that this effect is due to its cardiodepressive action and also to a vagus-mediated reflex following vasopressin-induced increase in blood pressure. When injected directly into the ventricles of the brain, vesopressin leads to a decrease of the heart rate without affecting blood pressure; however, it remains unclear whether this mechanism is responsible for bradycardia after intravenous administration. Careful monitoring is essential during the treatment with vasopressin and its derivatives.