Intranasal Oxytocin for Obesity
Franziska PlessowLiya KeremMarie‐Louis WronskiElisa AsanzaMichelle L. O’DonoghueFatima Cody StanfordKamryn T. EddyTara M. HolmesMadhusmita MisraJennifer J. ThomasFrancesca GalbiatiMaged MuhammedAluma Chovel SellaKristine HauserSarah E. SmithKatherine HolmanJulia GydusAnna AulinasMark VangelBrian C. HealyArvin KheterpalMartin TorrianiLaura M. HolsenMiriam A. BredellaElizabeth A. Lawson
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Accumulating preclinical and preliminary translational evidence shows that the hypothalamic peptide oxytocin reduces food intake, increases energy expenditure, and promotes weight loss. It is currently unknown whether oxytocin administration is effective in treating human obesity.1-l-Penicillamine-oxytocin and 1- deaminopenicillamine-oxytocin are analogues of oxytocin that have been found to be potent inhibitors of the oxytocic activity of oxytocin in the rat. The 2 analogues were tested on the rabbit uterus in vivo with regard to the uterine response both to endogenously released oxytocin and to intravenously administered synthetic oxytocin. They were found to be devoid of inhibitory activity when administered in molar ratios of inhibitor to oxytocin between 170:1 and 10000:1. Both analogues had an oxytocic effect on the rabbit uterus in vivo but were approximately 500 to 1000 times less potent than oxytocin in the same preparation. Neither analogue inhibited the milk-ejection effect of oxytocin as judged by the milk yield obtained by the pups from unanesthetized mothers. Both analogues had milkejecting activity estimated on the basis of the milk yield in anesthetized rabbits. This activity was about 50 to 100 times less than that of synthetic oxytocin. A sensitive chronic preparation for testing oxytocic substances in rabbits in vivo is described. (Endocrinology86: 71, 1970)
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Oxytocin plays an important role in social behavior. Thus, there has been significant research interest for the role of the oxytocin system in several psychiatric disorders, and the potential of intranasal oxytocin administration to treat social dysfunction. Measurement of oxytocin concentrations in saliva are sometimes used to approximate peripheral levels of oxytocin; however, the validity of this approach is unclear. In this study, saliva and plasma oxytocin was assessed after two doses of Exhalation Delivery System delivered intranasal oxytocin (8IU and 24IU), intravenous oxytocin (1IU) and placebo in a double-dummy, within-subjects design with men. We found that intranasal oxytocin (8IU and 24IU) administration increased saliva oxytocin concentrations in comparison to saliva oxytocin concentration levels after intravenous and placebo administration. Additionally, we found that saliva oxytocin concentrations were not significantly associated with plasma oxytocin concentrations after either intranasal or intravenous oxytocin administration. Altogether, we suggest that saliva oxytocin concentrations do not accurately index peripheral oxytocin after intranasal or intravenous oxytocin administration, at least in men. The data indicates that elevated oxytocin saliva levels after nasal delivery primarily reflect exogenous administered oxytocin that is cleared from the nasal cavity to the oropharynx, and is therefore a weak surrogate for peripheral blood measurements.
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l982년 6윌부터 9월까지 약 4개월간 연세대학교 의과대학부속 원주기독병원 산부인과에 분만하기 위하여 입원한 건강한 산모중에서 분만된 건강한 신생아 100예를 대상으로 하여 oxytocin 주입군 50예(유도분만 25예와 촉진분만 25예) 와 대조군 50예(자연분만 25예와 선택적제왕절개슬 25예)로 나누어 oxytocin 주입분만이 신생아혈청담적소치에 미치는 영향 및 과담적소혈증 발생정도를 연구하기 위해 생후즉시 제대혈액 및 생후 36~60시간에 신생아혈액을 채취하여 혈청 담적소치를 비교하였고 나아가서 그기전을 설명하기 위하여 혈청 나트륨, 혈색소, 헤마토크리트. 적혈구수를 측정하였고 oxytocin의 주입용량, 주입시간과의 관계를 조사분석하여 다음과 같은 결론을 얻었다. 연구결과를 요약하면 다음과 같다. 1. 혈청담적소치가 oxytocin 주입군의 제대혈액 및 신생아혈액에서 의의있게 증가하였다. 2. 과담적소혈증은 oxytocin 주입군 50예중의 4예 (8%) 예서만 발생하였다 3. oxytocin 주입용량이 증가함에 따라 제대혈액 및 신생아혈액에서 헐청담적소시가 증가하였으며 전체 oxytocin 주입용량이 5 unit 이상인 경우 의미있는 혈청 담적소치의 증가를 보였다. 4. oxytocin 주입시 간이 증가함에 따라 제대혈액 및 신생아혈액에서 혈청 담적소치가 증가하였다. 5. oxytocin 주입군의 제대혈액에서 혈색소, 혜마토크리트, 적혈구수가 증가이는 양상을 보였으며 혈청나트륨치는 변화가 없었다. 이상의 결과로 보아 oxytocin 주입분만시신생아 혈청 담적소치가 증가하였고 증가된 혈청담적소치는 oxytocin 주입용량과 시간에 비례하는 것으로 사료되었다.
Oxytocin receptor
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Oxytocinの代謝に関する基礎的研究のために, まず3H-Oxytocinおよび131I-Oxytocinを調製し, これらの標識ホルモンを用いてラットにおける体内分布を検討した.Oxytocinは代謝臓器と考えられる腎臓に最も多く分布し, 次いで肝臓, 下垂体および卵巣などに多く認められたが, 子宮には特に著明な取り込みは見られなかつた.また体内分布の経時的変化の検討により卵巣など, 二, 三の生殖系臓器に貯留が認められた.
Posterior pituitary
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The disappearance of phe 3 ‐oxytocin, val 3 ‐oxytocin and oxytocin from the circulation of male rats was shown to be due to qualitatively similar mechanisms, that is, it depends on uptake in the kidneys and organs of the splanchnic vascular area. However, compared to phe 3 ‐oxytocin and oxytocin (whose half‐lives were essentially similar) val 3 ‐oxytocin took twice as long to reach half its initial blood concentration. In lactating rats the mammary glands probably participated in the uptake of phe 3 ‐oxytocin, but the rate of disappearance of val 3 ‐oxytocin was not different from that in non‐lactating animals. In male nephrectomized rats without splanchnic circulation, phe 3 ‐oxytocin, unlike val 3 ‐oxytocin, was quickly distributed in a volume equal to two‐thirds of the total body water. Using oxytocin as the standard, val 3 ‐oxytocin and phe 3 ‐oxytocin were more potent when assayed on a superfused uterus or on a rat uterus in vivo than when assayed by the pharmacopoeial method (1958) on the isolated uterus in an organ bath. The difficulties of assaying oxytocin analogues against oxytocin (or the international standard preparation) are discussed.
Oxytocin receptor
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The ability of [1-L-pcnicillamine]oxytocin and [1-β-mercapto-β,β-diethyl-propionic acid]oxytocin to suppress the contractions induced by oxytocin in the uteri of 12- to 16-day-pregnant rats has been demonstrated, using a new technique for recording uterine activity in vivo.
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Oxytocin receptor
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Abstract Background Single measurements of salivary and plasmatic oxytocin are used as indicators of the physiology of the oxytocin system. However, questions remain about whether they are sufficiently stable to provide valid biomarkers of the physiology of the oxytocin system, and whether salivary oxytocin can accurately index its plasmatic concentrations. Methods Using radioimmunoassay, we measured baseline plasmatic and/or salivary oxytocin from two independent datasets. Dataset A comprised 17 healthy men sampled on four occasions approximately at weekly intervals. We administered exogenous oxytocin intravenously and intranasally in a triple dummy, within-subject, placebo-controlled design and compared baseline levels and the effects of routes of administration. Dataset B comprised baseline plasmatic oxytocin measurements from 20 healthy men sampled on two separate occasions. Additionally, in dataset A, we tested whether salivary oxytocin can predict plasmatic oxytocin at baseline and after intranasal and intravenous oxytocin administration. Results Single measurements of plasmatic and salivary oxytocin showed poor reliability across visits in both datasets. Intranasal administration of exogenous oxytocin increases salivary oxytocin, but intravenous administration of a considerable dose does not produce any changes. Saliva and plasma oxytocin did not correlate at baseline or after administration of exogenous oxytocin. Conclusions Our findings question the use of single measurements of baseline oxytocin concentrations in saliva and plasma as valid biomarkers of the physiology of the oxytocin system in humans. Salivary oxytocin is a weak surrogate for plasmatic oxytocin. The increases in salivary oxytocin observed after intranasal oxytocin most likely reflect unabsorbed peptide and should not be used to predict treatment effects.
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