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OBJECTIVE: The goal of this study was to compare carbetocin, a long-acting oxytocin analog, with oxytocin in the prevention of uterine atony after cesarean section. STUDY DESIGN: We enrolled 694 patients undergoing elective cesarean section in a Canadian multicenter, double-blind, randomized clinical trial. We compared the effect of a single 100 microg dose of carbetocin with that of a standard 8-hour infusion of oxytocin. The primary outcome was the proportion of patients requiring additional oxytocic intervention for uterine atony. A variable sample size, sequential design was used. RESULTS: The overall oxytocic intervention rate was 7.4%. The odds of treatment failure requiring oxytocic intervention was 2.03 (95% confidence interval 1.1 to 2.8) times higher in the oxytocin group compared with the carbetocin group, respectively, 32 of 318 (10.1%) versus 15 of 317 (4.7%), P <.05. CONCLUSIONS: Carbetocin, a new drug for the prevention of uterine atony, appears to be more effective than a continuous infusion of oxytocin and has a similar safety profile.

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OBJECTIVES: A double-blind randomized study involving pregnant women undergoing cesarean section was conducted to compare the effectiveness of a single 100 micrograms intravenous injection of the long-acting oxytocin analog, carbetocin, with that of a standard infusion of oxytocin with respect to intraoperative blood loss. The two treatments also were compared for safety and ability to maintain adequate uterine tone. STUDY DESIGN: The study drug was administered to 57 women during elective cesarean section after placental delivery; blood was collected until abdominal closure. Intraoperative blood loss was calculated with a sensitive colorimetric method. Position, tone of the fundus, and vital signs were assessed up to 24 hours after the operation. The need for additional uterotonic agents was recorded. RESULTS: A single 100 micrograms intravenous injection of carbetocin was as effective as a continuous 16 hour infusion of oxytocin in controlling intraoperative blood loss after placental delivery. Mean blood loss after carbetocin administration was 29 ml less than after oxytocin administration (p = 0.3). Subset analysis deleting two patients who received oxytocic intervention in the operating room and one extreme outlier revealed a mean blood loss of 41 ml less in the carbetocin group (p = 0.14) with lower variances (p = 0.02). The percentage of patients with blood loss of 200 ml or less was greater with carbetocin (79% vs 53%; p = 0.041). Carbetocin enhanced early postpartum uterine involution. The fundus was below the umbilicus in more patients who received carbetocin at 0, 2, 3, and 24 hours on the ward (p < 0.05). There were no significant differences in uterine tone or type or amount of lochia. Additional oxytocin was used to treat three patients for postpartum hemorrhage or persistent uterine atony. All interventions were in the oxytocin group. Vital signs and hematologic values were comparable in each group, confirming similar safety profiles. CONCLUSIONS: A single 100 micrograms intravenous injection of carbetocin is as effective and more reliable than a standard continuous infusion of oxytocin in maintaining adequate uterine tone and preventing excessive intraoperative blood loss during cesarean section after delivery of the placenta. Patients receiving carbetocin required less intervention. Carbetocin was well tolerated.

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OBJECTIVE: To study the transfer of carbetocin into human breast milk. METHODS: Five healthy nursing women, 7-14 weeks postpartum, emptied their breasts using a breast pump and then received 70 micrograms carbetocin by intramuscular injection. Using a radioimmunoassay, the concentrations of carbetocin were measured in plasma and breast milk samples obtained before carbetocin administration and at 15, 30, 60, 90, 120, and 240 minutes after drug administration. RESULTS: For plasma, the mean (+/- standard deviation) area under the curve (AUC) of carbetocin versus time was 1119.3 +/- 315.9 pg/mL, a value about 50 times higher than the mean AUC for carbetocin in breast milk (18.6 +/- 13.7 and 29.0 +/- 23.8 pg/mL for the right and left breast, respectively). The ratio of milk to plasma AUC was low: 1.7 +/- 0.9 and 3.1 +/- 2.8% for the left and right breast, respectively. No serious adverse reactions occurred and no clinically significant changes in vital signs were found. CONCLUSION: Very little carbetocin is transferred into human breast milk, presenting little risk to breast-fed infants.

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Carbetocin, a long-acting oxytocin analog, was administered by intravenous and intramuscular injection to 40 women 24 to 48 hours postpartum. Intravenous injection of 8 to 30 micrograms produced a tetanic uterine contraction within 2 minutes, lasting about 6 minutes, followed by rhythmic contractions for a further 60 +/- 18 minutes. Intramuscular injection of 10 to 70 micrograms also produced tetanic contraction in less than 2 minutes, lasting about 11 minutes, and followed by rhythmic contractions for an additional 119 +/- 69 minutes. The prolonged duration of activity after intramuscular compared with the intravenous carbetocin was significant (p = 0.020). Carbetocin produced mild lower abdominal cramping in most patients and severe pain in three patients who received 50 or 100 micrograms intravenously or 70 micrograms intramuscularly. Approximately half of the patients also experienced flushing and warmth. Although carbetocin has not yet been studied immediately postpartum, its prolonged uterine activity suggests that carbetocin may offer advantages over oxytocin in management of the third stage of labor.

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A 23 year old woman with diabetes insipidus who had previously been treated with pitressin, pituitary snuff and chlorpropamide, was treated with DDAVP during pregnancy. DDAVP concentrations immunoassayed as vasopressin were determined in maternal serum and breast milk. Oxytocin antibodies were also determined in maternal serum.

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Sixty-nine female patients were assessed for anxiety before receiving premedication. Thirty-three were given lorazepam and 36 were given papaveretum. Re-evaluation 90 min after premedication indicated that lorazepam reduced significantly the level of anxiety, but that papaveretum did not. Anxiety was assessed by means of a five-point nurse-rating scale and the Multiple-Affect Adjective Check List self-rating form. This self-rating anxiety scale was sensitive and proved suitable for recumbent patients in hospital. The test scores compared favourably with previously published values.

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The retention and distribution of tritiated methotrexate (MTX-3H) after direct intracerebral or intraneoplastic injection were studied in mice bearing subcutaneous or intracerebral ependymoblastomas. After intracerebral injection of MTX-3H in nontumor-bearing animals, a large amount of the drug was retained in the head, much more than could have been retained after systemic administration, and there was rpaid spreading of the drug through the ipsilateral hemisphere. Intraneoplastic injection of subcutaneous and intracerebral tumors produced rapid spreading of the drug through the tumors. Intially, the drug was mainly in the intersititial fluid of the tumors followed by earlier cellular uptake than was seen after intravenous injection. Even though the distribution of the drug in the intracerebral tumors was not uniform, and some intracranial tumor deposits contained less radioactivity than areas closer to the site of injection, intraneoplastic injection may have advantages for brain-tumor chemotherapy. However, further experimental study is necessary before clinical application can be recommended, especially evaluation of neurotoxicity after intracerebral, intraneopasltic injection of MTX or other chemotherapeutic agents.

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An intracranial mouse glioma model was used to study the effectiveness of chemotherapy with methotrexate )MTX) or radiotherapy. Maximum tolerable doses of MTX were established by toxicity studies in nontumor-bearing mice for the intraperitoneal and intracerebral routes of drug administration with and without leucovorin as an antidote. These maximum tolerable doses were then given either by the intraperitoneal route or directly into the tumor to mice bearing intracerebral tumors. The glioma model proved to be extremely useful for assessing the modalities studied, including repeated intraneoplastic injection of MTX. Dosage schedules were successfully developed for administering large amount of MTX and for preventing systemic toxicity by the administration of the antidote. Radiotherapy in single doses and 800 rads delayed the median day of death and produced several long-term survivors. Higher doses were toxic. Intraperitoneal or intraneoplastic MTX was completely ineffective as a chemotherapeutic agent for this tumor, even though very large amounts could be delivered due to the protection from systemic toxicity afforded by leucovorin. It is concluded that MTX is a poor chemotherapeutic agent for this experimental brain tumor, but that the technique of intraneoplastic administration of chemotherapeutic agents is feasible with this model system and should be studied further.

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Currently available diagnostic tracers for brain tumors are not specific. Tumor-specific tracers would improve the detection of brain tumors by gamma encephalography. Glucose is an important substrate for tumor metabolism and is known to be taken up in large amounts. The authors have studied five labeled carbohydrates in an attempt to find a tumor-specific tracer: three were tritiated (L-galactose-1-3H, L-fucose-3H, and 4,6-dideoxy-xylo-hexose-3H) and two were radioiodinated (methyl-6-125I-6-deoxy-D-glucoside and 6-125I-6-deoxy-D-glucose). The uptake of these tracers by a transplantable mouse ependymoblastoma after intravenous injection was determined by liquid and well scintillation counting. The highest tumor-to-brain ratio was 7.1 to 1 for the tritiated tracers and 6.2 to 1 for the radioiodinated tracers. Although these ratios are not high enough for gamma encephalography, one of the iodinated tracers may be useful for enhancement of contrast in computerized axial tomography.

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No tumor-specific tracer has yet been found for the detection of brain tumors by external scintiscanning. Glucose is a substrate in high demand by almost all tumors, and therefore an investigation was undertaken into the potential value of glucose and its analogs as tracers for brain tumors. The compounds studied were D-)1-3H)glucose, D-(1-14C)glucose, (3H)3-O-methyl-D-glucose and L-(1-14C)glucose. The tracers were injected i.v. into C57BL/6J mice carrying a transplantable s.c. ependymoblastoma. At specific time intervlas after injection, mice were sacrificed and the radioactivity of 6 tissues including tumor and brain were assayed by means of an automated combustion technique and liquid scintillation counting. Tumor uptake, expressed as percentage mean body concentration, was 60% for 2 of the tracers, and 92 and 143%, respectively, for 2 others. Brain uptake was over 130% mean body concentration, with 3 of the 4 tracers studies. With L-glucose, brain uptake was only 15.4% mean body concentration, and a maximum tumor-to-brain ratio of 9.5 was achieved. The very high tumor uptake achieved with two of these carbohydrated demonstrates that a carbohydrate analog may be found that shows high tumor specificity and uptake, and that may be useful for external scintiscanning.

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