RESUMO
BACKGROUND: Intravenous oxytocin is commonly used for labor induction. However, a consensus on the initial dosing regimen is lac with conflicting research findings and varying guidelines. This study aimed to develop a population kinetic-pharmacodynamic (K-PD) model for oxytocin-induced uterine contractions considering real-world data and relevant influencing factors to establish an optimal starting dosing regimen for intravenous oxytocin. METHODS: This retrospective study included pregnant women who underwent labor induction with intravenous oxytocin at Peking University Third Hospital in 2020. A population K-PD model was developed to depict the time course of uterine contraction frequency (UCF), and covariate screening identified significant factors affecting the pharmacokinetics and pharmacodynamics of oxytocin. Model-based simulations were used to optimize the current starting regimen based on specific guidelines. RESULTS: Data from 77 pregnant women with 1095 UCF observations were described well by the K-PD model. Parity, cervical dilation, and membrane integrity are significant factors influencing the effectiveness of oxytocin. Based on the model-based simulations, the current regimens showed prolonged onset times and high infusion rates. This study proposed a revised approach, beginning with a rapid infusion followed by a reduced infusion rate, enabling most women to achieve the target UCF within approximately 30 min with the lowest possible infusion rate. CONCLUSION: The K-PD model of oxytocin effectively described the changes in UCF during labor induction. Furthermore, it revealed that parity, cervical dilation, and membrane integrity are key factors that influence the effectiveness of oxytocin. The optimal starting dosing regimens obtained through model simulations provide valuable clinical references for oxytocin treatment.
Assuntos
Trabalho de Parto Induzido , Ocitócicos , Ocitocina , Contração Uterina , Humanos , Ocitocina/administração & dosagem , Ocitocina/farmacocinética , Ocitocina/farmacologia , Feminino , Contração Uterina/efeitos dos fármacos , Gravidez , Trabalho de Parto Induzido/métodos , Estudos Retrospectivos , Ocitócicos/administração & dosagem , Ocitócicos/farmacocinética , Ocitócicos/farmacologia , Adulto , Infusões Intravenosas , Administração Intravenosa , Relação Dose-Resposta a Droga , Modelos BiológicosRESUMO
Objectives Prolonged oxytocin exposure may result in increased blood loss during delivery. Our objective was to determine whether an oxytocin rest period before cesarean delivery had an impact on blood loss. Methods We performed a retrospective cohort study of women who underwent primary cesarean delivery after oxytocin augmentation. The primary outcome was change between pre- and postoperative hematocrit (Hct) in women with less than 60-min oxytocin rest period (<60 min) and greater than 60-min rest period (>60 min). Results There was no difference in demographic characteristics (age, BMI, or gestational age at delivery) between the two groups. Women in the >60 min group had a higher cumulative dose and longer duration of oxytocin administration. There was no significant difference in change in Hct between the two groups when controlling for these factors. Conclusions We did not find a significant correlation between the duration of the oxytocin rest period and blood loss. Oxytocin washout periods of greater than 60 min may not result in decreased blood loss at cesarean delivery, and thus, women may not benefit from such oxytocin washout periods.
Assuntos
Perda Sanguínea Cirúrgica , Cesárea , Relação Dose-Resposta a Droga , Duração da Terapia , Trabalho de Parto Induzido , Ocitocina , Hemorragia Pós-Parto , Adulto , Perda Sanguínea Cirúrgica/prevenção & controle , Perda Sanguínea Cirúrgica/estatística & dados numéricos , Cesárea/efeitos adversos , Cesárea/métodos , Feminino , Humanos , Trabalho de Parto Induzido/efeitos adversos , Trabalho de Parto Induzido/métodos , Avaliação de Processos e Resultados em Cuidados de Saúde , Ocitócicos/administração & dosagem , Ocitócicos/efeitos adversos , Ocitócicos/farmacocinética , Ocitocina/administração & dosagem , Ocitocina/efeitos adversos , Ocitocina/farmacocinética , Hemorragia Pós-Parto/diagnóstico , Hemorragia Pós-Parto/etiologia , Hemorragia Pós-Parto/prevenção & controle , Gravidez , Cuidados Pré-Operatórios/efeitos adversos , Cuidados Pré-Operatórios/métodos , Contração Uterina/efeitos dos fármacosRESUMO
The pharmacokinetics of carbetocin, which is used to control postpartum hemorrhage after giving birth, was studied in cows and gilts after a single intravenous (IV) or intramuscular (IM) injection. Blood samples from animals were assessed by oxytocin radioimmunoassay, and then the pharmacokinetic parameters were calculated using a noncompartmental model. For gilts, there was no significant difference between half-life (T1/2λZ ), mean residue time (MRT), and maximum concentration (Cmax ) between IM and IV administration. Conversely, the time to reach the Cmax (Tmax ) and MRT were higher following administration of 350 µg/animal in cows via the IM administration compared with IV. The longest T1/2λZ was 0.85 hr, indicating carbetocin was absorbed and eliminated rapidly in both animal species after administration. The Tmax was similar between cows and gilts following IM administration. Moreover, the Cmax after IM injection was about half that of IV administration in both animals. The bioavailability was more than 80% in cows, suggesting administration via the IM route is efficient. This is in agreement with the longer T1/2λZ in cows after IM administration. However, the IV route is recommended for gilts due to a lower bioavailability (35%) and shorter T1/2λZ after IM administration compared with IV.
Assuntos
Bovinos/sangue , Ocitócicos/farmacocinética , Ocitocina/análogos & derivados , Suínos/sangue , Animais , Área Sob a Curva , Disponibilidade Biológica , Meia-Vida , Injeções Intramusculares , Injeções Intravenosas , Ocitócicos/administração & dosagem , Ocitocina/administração & dosagem , Ocitocina/farmacocinética , Especificidade da EspécieRESUMO
AIM: Prostaglandins have a dual action of cervical ripening and induction of uterine contraction. This study was designed to compare the effectiveness of vaginal washing just before insertion of intravaginal dinoprostone. METHODS: A randomized controlled trial was conducted at the Zeynep Kamil Women and Children's Health Training and Research Hospital. One hundred and ninety-one women with singleton, term pregnancy who underwent labor induction were randomly assigned to two groups: Group 1 consisted of 95 pregnant women with vaginal washing before intravaginal dinoprostone (Propess system for slow release system of 10 mg of dinoprostone) insertion (study group), and 96 pregnant women constituted the control group who did not undergo vaginal washing before intravaginal dinoprostone insertion. A parallel randomized controlled trial was conducted with an allocation ratio of 1:1 to compare the effectiveness of vaginal washing before intravaginal dinoprostone insertion. RESULTS: The groups had similar mean age, body mass index, gestational age, gravidity, parity and Bishop score before agent insertion (P > 0.05). Duration of dinoprostone kept intravaginally, duration from the beginning of dinoprostone insert vaginally to the active phase of labor and duration from the time of intravaginal dinoprostone insertion to delivery were significantly longer in the control group (P < 0.05). Uterine hyperstimulation rate was significantly higher in study group compared to control group (P < 0.05). Meconium passage, fetal infection and neonatal intensive care unit admission were significantly higher in the control group (P < 0.05). CONCLUSION: Vaginal washing before intravaginal dinoprostone insertion may increase Prostaglandin E2 bioavailability as we found shorter duration and better outcome of labor induction in the present study.
Assuntos
Administração Intravaginal , Dinoprostona/administração & dosagem , Trabalho de Parto Induzido/métodos , Avaliação de Resultados em Cuidados de Saúde , Ocitócicos/administração & dosagem , Solução Salina/administração & dosagem , Ducha Vaginal/métodos , Adulto , Dinoprostona/farmacocinética , Feminino , Humanos , Ocitócicos/farmacocinética , Gravidez , Fatores de Tempo , Adulto JovemRESUMO
Postpartum hemorrhage is a major cause of mortality and morbidity related to childbirth in developing countries. The recommended treatment includes administration of oxytocin; however, oxytocin is a heat-labile protein, and it must be given as an intramuscular injection by skilled health care providers. To address these challenges, we developed a freeze-dried oxytocin fast-dissolving tablet (FDT) for sublingual (SL) needle-free administration. Using methods developed previously, we produced a robust FDT that maintained oxytocin stability at 40 °C, 75% relative humidity for 12 months. This formulation contains 9% sucrose, 1.5% (hydroxypropyl)methyl cellulose, 9% mannitol, 4% dextran, 1% carbomer, 1% sodium taurocholate, and 100 IU oxytocin. An in vitro study showed a > 30% reduction in tissue transepithelial electrical resistance after treatment with the oxytocin FDT, implying an increase in the permeability of the mucosal tissue to oxytocin. Anesthetized Yucatan miniature swine were administered a SL FDT, and blood was periodically collected for a pharmacokinetic study. Higher plasma concentrations were seen when larger SL doses were given. The maximum concentrations for SL and intramuscular doses in anesthetized pigs were 207 and 612 pg/mL, respectively. Whether the levels attained will be sufficient to elicit beneficial results in humans is yet to be determined. This study demonstrates the feasibility of our approach for developing a heat-stable oxytocin tablet that can be administered successfully via the SL route.
Assuntos
Ocitócicos/administração & dosagem , Ocitocina/administração & dosagem , Hemorragia Pós-Parto/prevenção & controle , Administração Sublingual , Animais , Estabilidade de Medicamentos , Feminino , Acessibilidade aos Serviços de Saúde , Temperatura Alta , Ocitócicos/sangue , Ocitócicos/farmacocinética , Ocitocina/sangue , Ocitocina/farmacocinética , Suínos , ComprimidosRESUMO
Oxytocin is one of the most commonly used medications in obstetrics and has been associated with claims of negligence in cases of adverse outcomes. Errors involving intravenous oxytocin administration for induction or augmentation of labor are most commonly dose related and include failure to avoid or treat tachysystole or failure to asses or treat a fetal heart rate pattern indicative of disruption in oxygenation. Clinicians should be knowledgeable regarding pharmacokinetics of oxytocin and the effect of uterine contractions on fetal oxygenation as well as safe titration of oxytocin to achieve the desired effect while minimizing harm.
Assuntos
Trabalho de Parto Induzido , Enfermagem Neonatal , Ocitocina , Contração Uterina , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Feminino , Monitorização Fetal/métodos , Humanos , Trabalho de Parto Induzido/métodos , Trabalho de Parto Induzido/enfermagem , Trabalho de Parto Induzido/normas , Enfermagem Neonatal/métodos , Enfermagem Neonatal/normas , Ocitócicos/administração & dosagem , Ocitócicos/farmacocinética , Ocitocina/administração & dosagem , Ocitocina/farmacocinética , Gravidez , Padrão de Cuidado , Contração Uterina/efeitos dos fármacos , Contração Uterina/fisiologia , Monitorização Uterina/métodosRESUMO
Oxytocin is a neuropeptide hormone used clinically for more than 50 years due to its ability to induce uterine contractions and milk ejection. Vagitocin is a vaginal oxytocin gel developed as a potential treatment of vaginal atrophy in postmenopausal women. The aim of this study was to characterize the oxytocin pharmacokinetics following vaginal and intravenous administration in postmenopausal women. Data from 33 participants enrolled in 2 clinical studies were used in the analysis, with a total of 651 observed oxytocin plasma concentrations, of which 78 were baseline observations, 178 observations following intravenous administration (10 IU), and 395 observations following vaginal administration (100 or 400 IU). The population pharmacokinetics of oxytocin was described using a 2-compartment disposition model with a flexible parallel absorption model accounting for double-peak profiles following vaginal administration. The clearance, volume of distribution at steady state, distribution half-life, and terminal half-life were estimated to be 27 L/h, 15 L, 5.5 minutes, and 1.2 hours, respectively. The bioavailability following vaginal administration was estimated to be 2.5% for the typical patient, but with considerable variability both between individuals (interindividual variability of 374%) and between occasions (interoccasion variability of 79%). The data and the developed model add new and important information as to the clinical pharmacokinetics of oxytocin.
Assuntos
Ocitócicos/administração & dosagem , Ocitócicos/farmacocinética , Ocitocina/administração & dosagem , Ocitocina/farmacocinética , Administração Intravaginal , Administração Intravenosa , Idoso , Feminino , Géis , Humanos , Pessoa de Meia-Idade , Pós-MenopausaRESUMO
The neuropeptide oxytocin has shown promise as a treatment for symptoms of autism spectrum disorders (ASD). However, clinical research progress has been hampered by a poor understanding of oxytocin's dose-response and sub-optimal intranasal delivery methods. We examined two doses of oxytocin delivered using a novel Breath Powered intranasal delivery device designed to improve direct nose-to-brain activity in a double-blind, crossover, randomized, placebo-controlled trial. In a randomized sequence of single-dose sessions, 17 male adults with ASD received 8 international units (IU) oxytocin, 24IU oxytocin or placebo followed by four social-cognitive tasks. We observed an omnibus main effect of treatment on the primary outcome measure of overt emotion salience as measured by emotional ratings of faces (η2=0.18). Compared to placebo, 8IU treatment increased overt emotion salience (P=0.02, d=0.63). There was no statistically significant increase after 24IU treatment (P=0.12, d=0.4). The effects after 8IU oxytocin were observed despite no significant increase in peripheral blood plasma oxytocin concentrations. We found no significant effects for reading the mind in the eyes task performance or secondary outcome social-cognitive tasks (emotional dot probe and face-morphing). To our knowledge, this is the first trial to assess the dose-dependent effects of a single oxytocin administration in autism, with results indicating that a low dose of oxytocin can significantly modulate overt emotion salience despite minimal systemic exposure.
Assuntos
Administração Intranasal/instrumentação , Transtorno do Espectro Autista/tratamento farmacológico , Cognição/efeitos dos fármacos , Ocitócicos/farmacocinética , Ocitocina/farmacocinética , Administração Intranasal/métodos , Adolescente , Adulto , Transtorno do Espectro Autista/psicologia , Cognição/fisiologia , Estudos Cross-Over , Emoções/efeitos dos fármacos , Emoções/fisiologia , Expressão Facial , Humanos , Masculino , Avaliação de Resultados em Cuidados de Saúde , Ocitócicos/administração & dosagem , Ocitócicos/farmacologia , Ocitocina/administração & dosagem , Ocitocina/sangue , Ocitocina/farmacologia , Comportamento Social , Adulto JovemRESUMO
AIM: The consequences that intrapartum administration of hormones can have on breastfeeding are unclear. The aim of the study is to determine if synthetic intrapartum oxytocin, used routinely for induction/stimulation, has a relationship to initiation/duration of breastfeeding. PATIENTS AND METHODS: We conducted a cohort study that was carried out in a tertiary university hospital distinguished by WHO-UNICEF as a BFHI (Baby-Friendly Hospital Initiative). A group of 53 mother and newborn dyads who had been exposed to intrapartum synthetic oxytocin were compared with 45 nonexposed dyads. A breastfeeding questionnaire was administered by a midwife blind to patient group through phone calls 3 and 6 months after delivery. RESULTS: No statistically significant differences were observed between the two groups in the rates of mothers exclusively breastfeeding (EBF) or nonexclusively breastfeeding. The percentage of those who were EBF when discharged was 97.3% in the oxytocin-nonexposed group and 87.1% in the oxytocin-exposed group (p = 0.14). At 3 months, the group rates of exclusive breastfeeding were 72.5% in the nonoxytocin-exposed group versus 65.9% in the oxytocin-exposed group (p = 0.71). At 6 months, rates of breastfeeding were 31.4% versus 27.9% (p = 0.53) in the oxytocin-nonexposed and oxytocin-exposed groups, respectively. CONCLUSIONS: In this study, no statistically significant effect of intrapartum synthetic oxytocin administration was observed pertaining to the initiation or duration of breastfeeding.
Assuntos
Aleitamento Materno , Comportamento do Lactente/efeitos dos fármacos , Ocitócicos/farmacologia , Ocitocina/farmacologia , Comportamento de Sucção/efeitos dos fármacos , Aleitamento Materno/estatística & dados numéricos , Relação Dose-Resposta a Droga , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Mães , Ocitócicos/efeitos adversos , Ocitócicos/farmacocinética , Ocitocina/efeitos adversos , Ocitocina/farmacocinética , Gravidez , Cuidado Pré-Natal , Estudos Prospectivos , Espanha , Comportamento de Sucção/fisiologia , Fatores de TempoRESUMO
BACKGROUND: Research examining the effects of oxytocin (OT) interventions on psychiatric, social-behavioral, and social-cognitive outcomes regularly collect peripheral levels of OT as markers of central bioavailability. Such inferences rest on the assumption that central and peripheral levels of OT are directly associated. However, conflicting evidence from coordinated sampling of central and peripheral OT question the validity of this assumption. The purpose of this meta-analysis is to evaluate the correlation between central and peripheral OT, as well as to account for potential heterogeneity in the literature. METHODS/DESIGN: Studies that report coordinated sampling of central and peripheral OT in humans and animals will be identified. Research investigating concentrations in both basal states and after exogenous administration will be considered. PubMed and Embase databases will be searched, along with citation lists of retrieved articles. Peer-reviewed studies written in English published from 1971 onwards will be included in the meta-analysis. Data will be extracted from eligible studies for a random-effects meta-analysis. For each study, a summary effect size, heterogeneity, risk of bias, publication bias, and the effect of categorical and continuous moderator variables will be determined. DISCUSSION: This systematic review and meta-analysis will identify and synthesize evidence to determine if there is an association between central and peripheral OT concentrations. If significant associations are observed, evidence would provide a rationale for future research to use peripheral measures as a proxy for central OT concentrations. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015027864.
Assuntos
Ocitocina/sangue , Ocitocina/líquido cefalorraquidiano , Animais , Ensaio de Imunoadsorção Enzimática , Humanos , Ocitócicos/farmacocinética , Ocitocina/farmacocinética , Radioimunoensaio , Reprodutibilidade dos Testes , Saliva/química , Revisões Sistemáticas como AssuntoRESUMO
The risk of Pitocin as a cause of autism attributable to oxytocin receptor desensitization in the brain of the fetus is evaluated in terms of a mathematical model. A composite unit, D, for oxytocin receptor desensitization levels is established with the form ((IU-h)/ml)E-3, where IU is the international unit for oxytocin. The desensitization values for oxytocin receptor desensitization at a concentration of 10 nmol of oxytocin per liter for 3, 4.2 and 6h corresponding to 0%, 50% and 100% desensitization are calculated to be 15 D, 21 D, and 30 D, respectively. The permeability of the blood-brain barrier in the fetus to oxytocin is discussed, and the upper limit of the concentration of Pitocin in the placenta, and its possible diffusion into the blood and brain of the fetus, is calculated for a routine dose of 6 milli U per minute of Pitocin over a 12h labor. This dose of Pitocin is shown to result in a desensitization value in units of D that is more than a factor of 10 below the 0% desensitization value of 15 D. This indicates that routine doses of Pitocin are not a significant cause of autism attributable to oxytocin receptor desensitization. This is consistent with the findings of a major epidemiological study of the association of Pitocin with autism in Denmark entitled, "Oxytocin-augmented labor and risk for males", Behavioral Brain Research, May 1, 2015; 284:207-212, which found no association between the use of Pitocin during labor and the incidence of autism for females, and a modest association for males.
Assuntos
Transtorno Autístico/metabolismo , Ocitócicos/administração & dosagem , Ocitocina/administração & dosagem , Efeitos Tardios da Exposição Pré-Natal , Receptores de Ocitocina/metabolismo , Transtorno Autístico/epidemiologia , Barreira Hematoencefálica/metabolismo , Feminino , Humanos , Masculino , Ocitócicos/efeitos adversos , Ocitócicos/farmacocinética , Ocitocina/efeitos adversos , Ocitocina/metabolismo , Ocitocina/farmacocinética , Placenta/metabolismo , Gravidez , RiscoRESUMO
Fifteen parturient camels given chlortetracycline (CTC) as intrauterine pessaries (3 g/head) were divided into the control group (n = 5), which remained untreated, oxytocin-treated group (50 IU, intramuscular; n = 5), and cloprostenol-treated group (Estrumate, 500 µg, intramuscular; n = 5). Serum samples were collected at 0, 1, 2, 4, 8, 24, 48, and 72 hours after treatment and CTC was determined. The CTC appeared in blood within 1 hour. The maximum concentration of CTC was detected in blood after 72 (543.58 ± 117.85 µg/L), 8 (520.48 ± 13.65 µg/L), and 1 hour (831.98 ± 111.01 µg/L) of administration in control, oxytocin-, and PGF2α-treated camels, respectively. There was a high significant effect of time (P < 0.001) and treatment-by-time interaction (P < 0.001) on serum CTC concentration. In the control group, there was a significant (P < 0.05) increase in CTC concentrations at 72 hours compared to the other times. In the oxytocin group, there was a significant (P < 0.05) decrease in CTC concentrations at 24, 48, and 72 hours compared to its level after 1 or 8 hours. In PGF2α, there was a significant (P < 0.001) decrease in CTC concentrations at 2, 4, 8, 24, 48, and 72 hours compared to its level after 1 hour. Treatment contrast at different time points showed a significant (P < 0.001) increase in CTC concentration after 1 hour in the PGF2α-treated group compared to oxytocin and control groups. By 72 hours, CTC concentrations were significantly (P < 0.05) lower in PGF2α and oxytocin groups than in the control group. In conclusion, serum CTC concentration in dromedary camels increases within 1 hour after intrauterine administration and remains elevated for at least 72 hours in control, oxytocin-, and PGF2α-treated animals.
Assuntos
Camelus , Clortetraciclina/farmacocinética , Dinoprosta/farmacocinética , Ocitocina/farmacocinética , Animais , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Clortetraciclina/administração & dosagem , Clortetraciclina/sangue , Dinoprosta/administração & dosagem , Feminino , Ocitócicos/administração & dosagem , Ocitócicos/farmacocinética , Ocitocina/administração & dosagem , Período Pós-Parto , GravidezRESUMO
A total of 200 women planned for labour induction were randomised to receive high-dose oxytocin (6 mU/min with similar increments every 45 min) or intermediate-dose oxytocin (3 mU/min with similar increments every 45 min). Oxytocin solution was prepared with 30 units in 500 ml saline with which the infusion rate in ml/h is numerically equal to oxytocin in mU/min. We observed that the caesarean rate (18% vs 6%, p = 0.009), contraction abnormalities (35% vs 14%, p = 0.0005) and neonatal bilirubin levels (7.99 ± 2.70 vs 6.80 ± 2.65, p = 0.002) were higher with high-dose than with intermediate-dose. The induction-delivery interval (IDI) was similar (10 h 13 min with high-dose and 11 h 5 min with intermediate-dose; p = 0.237, NS). Nulliparous women benefited more with intermediate-dose as the caesarean rate was higher with high-dose (24.6% vs 7.9%, p = 0.011). Although the caesarean rate was higher in multiparous women with high-dose oxytocin, it was statistically not significant (5.7% vs 2.7%; p = 0.609). Oxytocin regimens for labour induction are usually high-dose (4-6 mU/min) or low-dose (1-1.5 mU/min). The former is associated with more contraction abnormalities and the latter with prolonged IDI; both result in an increased caesarean rate. In order to offset these disadvantages, an intermediate- dose regimen was selected. The increment interval of 45 min was selected in accordance with the pharmacokinetics of oxytocin. We observed a lower caesarean rate when compared with the high-dose regimen, without any increase in the IDI. Hence, we propose that the intermediate-dose oxytocin regimen should be preferred to the high-dose regimen for labour induction.
Assuntos
Trabalho de Parto Induzido , Ocitocina , Contração Uterina/efeitos dos fármacos , Adulto , Cesárea/métodos , Cesárea/estatística & dados numéricos , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Trabalho de Parto Induzido/efeitos adversos , Trabalho de Parto Induzido/métodos , Ocitócicos/administração & dosagem , Ocitócicos/farmacocinética , Ocitocina/administração & dosagem , Ocitocina/farmacocinética , Gravidez , Resultado da Gravidez , Resultado do TratamentoRESUMO
Oxytocin (OT) in the central nervous system (CNS) influences social cognition and behavior, making it a candidate for treating clinical disorders such as schizophrenia and autism. Intranasal administration has been proposed as a possible route of delivery to the CNS for molecules like OT. While intranasal administration of OT influences social cognition and behavior, it is not well established whether this is an effective means for delivering OT to CNS targets. We administered OT or its vehicle (saline) to 15 primates (Macaca mulatta), using either intranasal spray or a nebulizer, and measured OT concentration changes in the cerebral spinal fluid (CSF) and in blood. All subjects received both delivery methods and both drug conditions. Baseline samples of blood and CSF were taken immediately before drug administration. Blood was collected every 10 minutes after administration for 40 minutes and CSF was collected once post-delivery, at the 40 minutes time point. We found that intranasal administration of exogenous OT increased concentrations in both CSF and plasma compared to saline. Both delivery methods resulted in similar elevations of OT concentration in CSF, while the changes in plasma OT concentration were greater after nasal spray compared to nebulizer. In conclusion our study provides evidence that both nebulizer and nasal spray OT administration can elevate CSF OT levels.
Assuntos
Barreira Hematoencefálica/metabolismo , Ocitócicos/farmacocinética , Ocitocina/farmacocinética , Administração Intranasal , Animais , Macaca mulatta , Masculino , Ocitócicos/administração & dosagem , Ocitócicos/sangue , Ocitócicos/líquido cefalorraquidiano , Ocitocina/administração & dosagem , Ocitocina/sangue , Ocitocina/líquido cefalorraquidiano , Distribuição TecidualRESUMO
To determine the intercyclic effect of oxytocin and carbetocin on equine myometrial tissue, the effect of the drugs was evaluated through pharmacokinetic and pharmacodynamic studies. The complete pharmacokinetic profile for oxytocin was unknown and had to be established. To do so, 25 IU of oxytocin were administered intravenously to six cycling mares and blood samples were collected before and 2, 4, 8, and 15 min after administration. The half-life of oxytocin was determined to be 5.89 min, the clearance rate 11.67 L/min, mean residence time (MRT) 7.78 min. The effective plasma concentration was estimated to be 0.25 ng/mL. This was similar to the concentration achieved for the organ bath study where the concentration that produced 50% of the maximum effect (EC(50)) was calculated at 0.45 ng/mL. To determine the intercyclic effect of oxytocin and carbetocin uterine myometrial samples were collected from slaughtered mares in estrus, diestrus, and anestrus. The samples were mounted in organ baths and exposed to four ascending, cumulative doses of oxytocin and carbetocin. Area under the curve and amplitude, maximum response (E(max)), and concentration that produced 50% of the maximum effect were studied for each agonist and statistically evaluated. The effect of oxytocin on equine myometrial tissue was higher during diestrus, and surprisingly anestrus, than during estrus, whereas the effect of carbetocin was the same independent of the stage of estrous cycle. A significant difference was found for estrous and anestrous samples when oxytocin was used but not when carbetocin was used.
Assuntos
Cavalos/fisiologia , Miométrio/efeitos dos fármacos , Ocitócicos/farmacologia , Ocitocina/análogos & derivados , Ocitocina/farmacologia , Anestro/fisiologia , Animais , Diestro/fisiologia , Estro/fisiologia , Feminino , Meia-Vida , Injeções Intravenosas/veterinária , Taxa de Depuração Metabólica , Ocitócicos/farmacocinética , Ocitocina/administração & dosagem , Ocitocina/farmacocinéticaRESUMO
PURPOSE: To quantify and compare the time-course and potency of the analgesic and antipyretic effects of naproxen in conjunction with the inhibition of PGE(2) and TXB(2). METHODS: Analgesia was investigated in a rat model with carrageenan-induced arthritis using a gait analysis method. Antipyretics were studied in a yeast-induced fever model using telemetrically recorded body temperature. Inhibition of TXB(2) and PGE(2) synthesis was determined ex vivo. Pharmacokinetic profiles were obtained in satellite animals. Population PKPD modeling was used to analyze the data. RESULTS: The IC(50) values (95% CI) of naproxen for analgesia (27 (0-130) µM), antipyretics (40 (30-65) µM) and inhibition of PGE(2) (13 (6-45) µM) were in similar range, whereas inhibition of TXB(2) (5 (4-8) µM) was observed at lower concentrations. Variability in the behavioral measurement of analgesia was larger than for the other endpoints. The inhibition of fever by naproxen was followed by an increased rebound body temperature. CONCLUSION: Due to better sensitivity and similar drug-induced inhibition, the biomarker PGE(2) and the antipyretic effect would be suitable alternative endpoints to the analgesic effects for characterization and comparisons of potency and time-courses of drug candidates affecting the COX-2 pathway and to support human dose projections.
Assuntos
Dinoprostona/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Modelos Químicos , Naproxeno/farmacologia , Naproxeno/farmacocinética , Proteínas com Domínio T/metabolismo , Animais , Antipiréticos/farmacocinética , Antipiréticos/farmacologia , Artrite/tratamento farmacológico , Artrite/metabolismo , Modelos Animais de Doenças , Febre/tratamento farmacológico , Febre/metabolismo , Concentração Inibidora 50 , Masculino , Ocitócicos/antagonistas & inibidores , Ocitócicos/farmacocinética , Ocitócicos/farmacologia , Dor/tratamento farmacológico , Dor/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
Misoprostol, a prostaglandin E1 derivative, has been widely used in nonpregnant women because of its cervical ripening and uterotonic effects. A large number of studies have demonstrated its effectiveness in enhancing ease of cervical dilation. This review article describes its pharmacokinetic profile and the relationship between prostaglandins and cervical ripening and uterine contraction and provides a review of the clinical use of misoprostol in nonpregnant women including cervical priming before hysteroscopy, before insertion of an intrauterine device, in endometrium biopsy, preoperatively in myomectomy, and before intrauterine insemination to improve pregnancy rates. Adverse effects are also described.
Assuntos
Colo do Útero/efeitos dos fármacos , Misoprostol/uso terapêutico , Ocitócicos/uso terapêutico , Cuidados Pré-Operatórios , Biópsia , Perda Sanguínea Cirúrgica/prevenção & controle , Dilatação Patológica , Endométrio/patologia , Feminino , Hormônio Liberador de Gonadotropina/agonistas , Humanos , Histeroscopia , Inseminação Artificial , Dispositivos Intrauterinos , Misoprostol/farmacocinética , Miométrio/cirurgia , Ocitócicos/farmacocinética , Pós-Menopausa , Pré-MenopausaRESUMO
Chronic use of high oxytocin (OT) dosages can cause a reduced response to endogenous OT. In this study the OT dosages used in the milking practice of 82 dairy cow farms were recorded. The OT dosages per cow used were high, especially when injected i.m. (23+/-2 IU) compared with i.v. (7+/-1 IU). In addition, the minimum OT dosages needed to obtain normal milk removal in cows with disturbed milk ejection were investigated. Seventeen cows routinely treated with OT during milking (group T) and 17 cows without previous OT treatment were used (group C). After cessation of spontaneous milk flow, both T and C groups were injected i.v. with a low dosage of OT (0.2 or 0.5 IU/cow). The time from injection until cessation of the OT-induced milk flow was recorded (response phase). The response phase and the amounts of removed milk by effect of the OT injection increased with increasing OT dosage. Values for 0.2 and 0.5 IU/cow of OT injected i.v. were (response phase and amount of milk removed) 198+/-27 and 302+/-18s and 3.4+/-0.7 kg and 6.5+/-1.3 kg, respectively, for the C group, and 157+/-15 and 221+/-16s and 3.2+/-0.5 and 5.5+/-1.0 kg, respectively, for the T group. Within 20 min of the OT injection, plasma concentrations returned to basal levels. The threshold OT concentration at cessation of milk flow after injection of 0.2 or 0.5 IU/cow of OT was calculated based on the OT plasma half-life. The threshold increased with increasing dosages of OT and was higher in group T (8+/-1 and 14+/-1 pg/mL for 0.2 and 0.5 IU/cow, respectively) than in group C (7+/-1 and 11+/-1 pg/mL for 0.2 and 0.5 IU/cow, respectively). In conclusion, desensitization of the udder toward OT occurs when the udder is exposed to elevated OT plasma concentrations, both short-term during the actual milking and long-term due to chronic high-dosage OT treatment. However, low-dosage OT treatments to induce normal milk removal can minimize the observed side effects.
Assuntos
Bovinos/fisiologia , Ejeção Láctea/efeitos dos fármacos , Ocitócicos/administração & dosagem , Ocitocina/administração & dosagem , Animais , Bovinos/metabolismo , Indústria de Laticínios , Meia-Vida , Ocitócicos/farmacocinética , Ocitocina/sangue , Ocitocina/farmacocinética , Distribuição AleatóriaRESUMO
This is a clinical case presentation of a full term newborn infant who suffered severe hyponatremia and early seizures, associated with maternal fluid overload with electrolyte free solutions and high doses of oxytocin for labor augmentation. Although this condition has been recognized since the 1960's with isolated reports, this particular case has features that needs further investigation, not only for the unsually severe hyponatremia, but most importantly we think, for the prominent signs of fluid retention, the infant had, that suggest excessive antidiuretic activity probably due to oxytocin. These findings are consistent with syndrome of inappropriate secretion of antidiuretic hormone. Although until now there is no proof that oxytocin by itself produces this syndrome. We think the association is possible in certain clinical circumstances, such as those found in this case. We also, briefly discussed the pathophysiology of perinatal hyponatremia, the neonatal treatment of this condition and the current guidelines for the women in labor. Hyponatremia should not be considered a benign condition, since in the neonate, it may affect brain function.