DrugBank:APRD00691 - FACTA Search

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Query: DrugBank:APRD00691 (EE2)
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Two weeks after surgery, ovariectomized (OVX) rats were treated for 3 days with either 17 beta-estradiol (10 or 100 micrograms/kg, SC, per day) or the oil vehicle. They were then tested for morphine-induced hyperactivity (4 mg/kg, IP), analgesia and catalepsy (15 and 20 mg/kg, IP) 24 or 72 hr after the last steroid or oil injection. Estradiol treatment did not affect the locomotion or the sensitivity to nociceptive stimuli of OVX rats and did not induce a cataleptic state in animals. Estradiol- (100 micrograms/kg) treated OVX rats exhibited attenuated morphine-induced hyperlocomotion regardless of the time that had elapsed after estradiol treatment cessation, attenuated morphine-induced catalepsy at 24 hr after estradiol treatment and unaltered morphine-induced analgesia. OVX rats treated with a lower estradiol dose (10 micrograms/kg) exhibited significantly increased morphine-induced analgesia and slightly increased catalepsy. The results show that the sensitivity of brain opiate systems controlling some of the behavioral effects of morphine is modified following estradiol treatment to OVX rats.
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PMID:Estrogen treatment to ovariectomized rats modifies morphine-induced behavior. 365 86

The Authors after personal experimental studies and bibliographic researches, propose, through the formulation of the dermatoneuromeric theory, an explanatory model for the understanding of the reflexotherapeutic results in the visceral pathology treatment. The fact that different authors propose many different points for the functional balance of the internal organs and consequent diseases, that these points are located in many cases on the same dermatomes and that these are connected with the starting neuromes of autonomic fibres (Ortho and Parasympathetic) to the organ to be cured, indicates that Acupuncture is a spinal metameric reflexotherapy with scanty modulation of the supraxial centres, in opposition to Acupuncture analgesia. The Alarm (Mo) and Concurring (Yu) points of each channel are the most distant and nearest to the spinal cord and their stimulation establishes the upper and lower limit of the part of cord that we want to stimulate. Anesthetic blocks outside the "firing tract" do not influence the output, while the selective blocks can limit or abolish the Acupuncture effect. Ancient and modern therapeutic methods utilize these reflexes, giving an unique interpretation to alla reflexotherapies.
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PMID:[The importance of the metamere in the interpretation of the therapeutic results obtained with acupuncture. Elaboration of the dermatoneuromeric theory and critical comment]. 723 54

Gonadal hormones may modulate analgesia responses induced by acute stress in humans and rats. To evaluate the effects of gonadal hormones in modifying neuropathic pain, we measured autotomy changes following sciatic nerve resection in ovariectomized rats and in the presence of estrogen replacement. Two groups of female rats were subjected to ovariectomy and sham surgery. Each group was then divided into two subgroups receiving subcutaneously sesame oil with or without estradiol benzoate (5 microg/day/rat). All rats then underwent sciatic nerve resection in one hindlimb. Degree of self-mutilation was measured daily for 8 weeks. Estradiol treatment resulted in significantly lower autotomy scores in ovariectomized rats (3.6 +/- 0.6 vs. 5.5 +/- 0.3, p < 0.01) and in sham-operated rats (3.4 +/- 0.7 vs. 5.1 +/- 0.4, p < 0.05). The results of this study indicate that estrogen can modify the autotomy behavior, an indicator of neuropathic pain, in rats after nerve injury.
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PMID:Effects of estrogen on autotomy in normal and ovariectomized rats. 1045 69

Gonadal hormones have been shown to exert modulatory effects on nociception and analgesia. To investigate the role of gonadal hormones in the response by female rats to both phasic and persistent nociceptive stimulation, we evaluated the effects of long-term ovariectomy (OVX, 6 months) on the thermal pain threshold and on formalin-induced responses. The thermal pain threshold was evaluated with the plantar test apparatus, while persistent pain was induced by a subcutaneous injection of dilute formalin (50 microliter, 10%) in the dorsal hind paw. The formalin test was carried out in an open field apparatus where the animal's spontaneous behavior and formalin-induced responses (licking duration, flinching frequency and flexing duration of the injected paw) were recorded for 60 min. Estradiol and corticosterone plasma levels were determined in blood collected from the anesthetized animals at the end of the test. In OVX females, the duration of formalin-induced licking was longer than in Intact females during both the first and the second phase; flinching and flexing did not differ from Intact. The thermal pain threshold was only slightly affected by OVX. Estradiol and corticosterone were lower in OVX females than Intact ones. These data indicate that long-term depletion of gonadal hormones in female rats modulates the pain-induced behavioral responses related to supraspinal neural circuits (licking of the injected paw) rather than more spinally mediated responses such as formalin-induced flinching and withdrawal latency in the plantar test.
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PMID:Long-term ovariectomy changes formalin-induced licking in female rats: the role of estrogens. 1264 52

Estradiol (E(2)) and/or progesterone (P) to the amygdala may influence stress-induced analgesia following predator odor, trimethylthiazoline (TMT), exposure. Ovariectomized (ovx) rats were administered subcutaneous (SC) or intra-amygdala vehicle, E(2), P, or E(2)+P. The effects on performance in a test of pain sensitivity, the tailflick task, was observed in animals that experienced an acute exposure to TMT or no odor (control) in a small chamber. Rats that were exposed to TMT had increased tailflick latencies compared to rats not exposed to TMT, this was partially attenuated by the opiate antagonist naloxone. Systemic E(2), P, or E(2)+P increased tailflick latencies compared to vehicle administration to ovx rats. Ovx rats administered E(2)+P to the amygdala had increased tailflick latencies compared to control rats. These data suggest that following exposure to predator odor, pain sensitivity in the tailflick task is decreased and that E(2) and/or P may have actions in the amygdala to produce similar anti-nociceptive effects.
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PMID:Anti-nociception following exposure to trimethylthiazoline, peripheral or intra-amygdala estrogen and/or progesterone. 1294 97

Although numerous clinical practice guidelines for pain management have been published throughout the last 12 years, inadequate pain relief remains a significant health care issue. Several patient-controlled analgesia (PCA) modalities are currently available for the treatment of acute postoperative pain, including intravenous (IV) PCA, epidural (PCEA), and oral PCA. Although PCEA and IV PCA are both commonly used modalities, IV PCA is considered the standard of care for postoperative pain management. Limitations of this modality do exist, however. Consequently, noninvasive PCA systems are under development to circumvent many of these limitations, including the fentanyl hydrochloride patient-controlled transdermal system (PCTS); (IONSYS Ortho-McNeil Pharmaceutical, Raritan, NJ) and a number of patient-controlled intranasal analgesia (PCINA) delivery systems. The objective of this article is to review the PCA modalities currently in use and to discuss those in development for the treatment of acute postoperative pain.
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PMID:Patient-controlled modalities for acute postoperative pain management. 1610 6

Dapoxetine [LY 210448], a selective serotonin reuptake inhibitor (SSRI), is structurally related to fluoxetine with antidepressant activity. Dapoxetine is the D-enantiomer of LY 243917 and is 3.5 times more potent as a serotonin reuptake inhibitor than the L-enantiomer. Dapoxetine was in phase I clinical trials in the US with Eli Lilly as an antidepressant, but no recent development has been reported for this indication. However, development is underway for the treatment of premature ejaculation, with phase III trials for this indication being completed in the US. The phase II trial for the treatment of premature ejaculation was conducted by PPD GenuPro, a subsidiary of PPD, which was established from a collaboration between Eli Lilly and PPD for the development of drugs to treat genitourinary disorders. Both Lilly and PPD had an option to re-license dapoxetine upon completion of phase II trials, but neither company exercised its option, and the rights remained with PPD GenuPro. In December 2003, PPD Inc. acquired from Eli Lilly and Co. the patents for dapoxetine for development in the field of genitourinary disorders. As part of the transaction, PPD and Lilly terminated their existing license agreement for dapoxetine. In December 2000, PPD GenuPro granted an exclusive, worldwide license for dapoxetine to ALZA Corporation, a wholly owned subsidiary of Johnson & Johnson. ALZA will be responsible for development, manufacturing and commercialisation of dapoxetine for urological indications, including premature ejaculation. It will make initial, milestone and royalty payments to PPD GenuPro, a portion of which will be paid to originator Eli Lilly. PPD Inc. received a milestone payment relating to the ongoing development of dapoxetine for premature ejaculation in July 2003. In December 2003, PPD and ALZA amended the dapoxetine license to allow PPD to receive a fixed-sum cash payment apon NDA approval. In return for this, ALZA will not have to make sales-based payments for a period of time following the approval of dapoxetine. If dapoxetine is approved by the US FDA for premature ejaculation, the drug will be marketed in the US by Ortho-McNeil Pharmaceutical, Inc. In December 2004, ALZA Corporation submitted a new drug application to the FDA for dapoxetine hydrochloride in the treatment of premature ejaculation. If approved by the FDA, dapoxetine hydrochloride will be marketed in the US by Ortho-McNeil Pharmaceutical, Inc. Johnson & Johnson plans to support the launch of dapoxetine for premature ejaculation with a 'responsible' direct-to-consumer advertising campaign. In May 2005, Johnson & Johnson presented data from two phase III trials involving dapoxetine for the treatment of premature ejaculation, during the 100th Annual Scientific Meeting of the American Urological Association (AUA-2005). Results on drug interactions and pharmacodynamics of dapoxetine were also presented during this meeting. Dapoxetine also appears to be a useful adjunct to morphine, lowering the threshold for analgesia, although the compound itself has negligible analgesic activity. In December 2003, PPD, Inc. acquired from Eli Lilly and Company the patents for dapoxetine for development in the field of genitourinary disorders. Under the terms of the agreement with Lilly, PPD will pay Lilly 65 million US dollars in cash. PPD will also pay Lilly a royalty on net sales of dapoxetine in excess of a certain threshold of annual net sales. As part of the transaction, PPD and Lilly terminated their existing license agreement for dapoxetine.
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PMID:Dapoxetine: LY 210448. 1612 1

Previous research has indicated the importance of sex in mediating the larger magnitude of mu-opioid receptor agonist-induced analgesia in male relative to female rodents. Whereas manipulations involving the adult activational effects of gonadal hormones minimally alter these analgesic sex differences, manipulations involving neonatal organizational effects of gonadal hormones have previously been shown to profoundly affect morphine analgesia. Thus, adult male rats neonatally castrated on the first day after birth displayed reductions in morphine analgesia relative to sham-operated males, and adult female rats neonatally treated with testosterone propionate on the first day after birth displayed enhancements in morphine analgesia relative to vehicle-treated females. Because neonatal androgenization in female rats produces an anovulatory syndrome that could change their adult hormonal milieu, the present study examined whether adult ovariectomy altered the magnitude of systemic morphine analgesia (1-5 mg/kg) in neonatal androgenized female rats relative to neonatal vehicle-treated female rats as well as gonadal steroid hormone replacement with estradiol benzoate. Intact male rats displayed significantly greater magnitudes and potencies (2- to 2.3-fold leftward shift) of systemic morphine analgesia than female rats treated neonatally with either vehicle (1-5 mg/kg) or testosterone (1.7-5 mg/kg). In turn, neonatal androgenized female rats displayed significantly greater magnitudes of systemic morphine (1, 5 mg/kg) analgesia than vehicle-treated female rats accompanied by a smaller 20% leftward shift in potency. Adult ovariectomy minimally affected morphine analgesia in neonatal vehicle-treated females, while significantly reducing the magnitude (1 mg/kg), but not the potency of morphine analgesia in neonatal androgenized female rats. Estradiol replacement therapy significantly increased the magnitude of morphine analgesia in both groups at some doses, but only changed the potency (20-30%) in females treated neonatally with vehicle. Taken together, these data suggest a limited organizational-activational gonadal hormone interaction in the mediation of systemic morphine analgesia in female rats.
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PMID:Organizational manipulation of gonadal hormones and systemic morphine analgesia in female rats: effects of adult ovariectomy and estradiol replacement. 1615 18

Inadequate pain control in the postoperative period not only contributes to patient discomfort, but also causes physiological changes that may result in increased risk of myocardial ischaemia, deep vein thrombosis and pulmonary embolism. These events complicate postoperative recovery and may lead to longer hospital stays as well as increased healthcare costs. Patient-controlled analgesia (PCA) has emerged as an effective way for patients to manage their pain, allowing self-administration of small doses of analgesics to maintain a certain level of pain control. PCA is most commonly delivered via an intravenous (IV) or epidural route, and while patient satisfaction is higher with PCA than with conventional methods of analgesic administration, the invasiveness, costs and risk of errors associated with currently available modalities may limit their utility. These systems also require significant healthcare resources, as nurses must manually program the pumps to deliver the correct amount of medication. Several new PCA modalities are being developed to address these limitations. These systems deliver drug through a variety of routes, including nasal transmucosal and transdermal. Most notably, a self-contained, credit card-sized, transdermal PCA system is currently in the final stages of development. The fentanyl HCl patient-controlled transdermal system (PCTS; IONSYS, Ortho-McNeil Pharmaceutical, Inc., Raritan, NJ) uses an imperceptible, low-intensity direct current to transfer fentanyl on demand across the skin into the systemic circulation. This compact system is patient-activated, can be applied to the patient's upper arm or chest, and is designed to manage moderate-to-severe pain requiring opioid analgesia. The system delivers a preprogrammed amount of fentanyl HCI over 10 minutes, for a total of 80 doses, or for 24 hours, whichever occurs first. The on-demand dosing and pharmacokinetics of this system differentiate it from the passive transdermal formulation of fentanyl designed for the management of chronic pain. Clinical studies have shown that the fentanyl HCl PCTS is effective in the management of acute postoperative pain. These studies have also demonstrated that the system is safe and well tolerated by patients.
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PMID:The fentanyl HCl patient-controlled transdermal system (PCTS): an alternative to intravenous patient-controlled analgesia in the postoperative setting. 1615 10

Clinical and preclinical studies have found sex-specific differences in the discrimination and perception of inflammatory stimuli. The emerging picture suggests that the biological basis of these differences resides in the regulatory activity of gonadal hormones in the central nervous system. This study describes the effects of ovarian hormones in inflammatory pain processes. Ovariectomized rats received estradiol and/or progesterone, and the number of paw flinches was measured after 1, 2.5 or 5% formalin administration. Both estradiol and progesterone altered the number of flinches only after 1% formalin administration. Estradiol significantly reduced the overall number of flinches during Phase II of the formalin nociceptive response while progesterone attenuated Phase I of the response. After co-administration of estradiol and progesterone, progesterone reversed estradiol's analgesic effect in Phase II, however, estradiol did not reverse progesterone's analgesic activity in Phase I. To determine if estradiol effects are receptor-mediated, tamoxifen (selective estrogen receptor mediator, 15 mg/kg) or alpha-estradiol (an inactive isomer of estradiol, 20 microg) were utilized. Tamoxifen decreased the number of formalin-induced flinches during Phase II while alpha-estradiol did not affect any formalin-induced responses. When co-administered with estradiol, tamoxifen failed to reverse estradiol's effect, suggesting both tamoxifen and estradiol activate similar intracellular mechanisms. Although Western blot analysis detected the presence of estradiol alpha and beta and progesterone B receptors in the spinal cord, hormone replacement treatments had no effects on the levels of these receptors. We postulate that the mechanisms by which estradiol and progesterone induce analgesia occur through the activation of their receptor at the spinal cord level.
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PMID:Estradiol and progesterone differentially regulate formalin-induced nociception in ovariectomized female rats. 1625 5

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