Author: Lohela, Terhi J ; Rauhala, Pekka V ; Niemi, Mikko ; Copie, Radu G ; Kurkela, Mika ; Lilius, Tuomas O ; Kari, Melina Farzaneh ; Rosenholm, Marko ; Blomqvist, Kim

The synergistic antinociceptive effects of α₂-adrenergic agonists and intrathecal (i.t.) opioids were initially linked to pharmacodynamics. However, the α₂-agonist dexmedetomidine also enhances brain delivery of CSF-administered drugs by increasing glymphatic influx. Here, fadolmidine, a hydrophilic α₂-agonist designed for spinal analgesia, was studied for its sedative, antinociceptive, and pharmacokinetic effects with co-administered lumbar intrathecal morphine. Subcutaneous and i.t. dexmedetomidine served as comparators. Forty-eight male Sprague-Dawley rats received i.t. lumbar catheters. Sedative effects of i.t. fadolmidine (1-10 μg) and i.t. dexmedetomidine (1-10 μg) were assessed by open field and rotarod tests. The antinociceptive effects of morphine alone (1.5 μg i.t.) and co-administered with i.t. fadolmidine (3 and 10 μg) were evaluated using the tail-flick test. Effects of i.t. fadolmidine and subcutaneous dexmedetomidine (0.2 mg/kg) on morphine concentration within CNS were assessed by liquid chromatography-tandem mass spectrometry at 60 minutes. While i.t. dexmedetomidine was sedating, i.t fadolmidine was not. The antinociceptive effects of other treatment regimens weaned at latest after 90 minutes, whereas the combination of fadolmidine 10 μg i.t. and morphine 1.5 μg i.t. provided antinociception until the end of the measurement period (maximum possible effect of 77.5 ± 11.5 vs saline 10.6 ± 11.1, p = 0.0002 at 120 minutes). Subcutaneous dexmedetomidine effectively targeted lumbar morphine towards the injection site resulting in a 3335-fold (95% CI: 929-11978) lower brain-to-injection site ratio, versus a 355-fold (95% CI: 196-641) difference with saline. By improving spinal opioid targeting, α₂-adrenergic agonists dexmedetomidine and fadolmidine may reduce supraspinal side effects, enabling safe and efficacious intrathecal analgesia.

01 Oct 2021·The Journal of Sexual MedicineQ2 · MEDICINE

Sexual Incentive Motivation and Copulatory Behavior in Male Rats Treated with the Adrenergic α2-Adrenoceptor Agonists Tasipimidine and Fadolmidine: Implications for Treatment of Premature Ejaculation

Q2 · MEDICINE

Article

Author: Paredes, Raúl G. ; Ågmo, Anders ; Chu, Xi ; Lehtimäki, Jyrki ; Ventura-Aquino, Elisa

ABSTRACTBackgroundPremature ejaculation is the most common sexual dysfunction in young men, and it often leads to reduced relationship satisfaction and quality of life.AimTo determine the role of central and peripheral α2-adrenoceptors in the control of ejaculation and sexual incentive motivation in rats.MethodsSexual incentive motivation was studied in a large arena in which a male subject could choose between approaching and remaining close to a sexually receptive female or another male. Sexual behavior was studied in standard observation cages in which a male was allowed to freely interact with a receptive female for 30 minutes. Two highly selective agonists at the α2-adrenoceptors, tasipimidine and fadolmidine, were administered before the tests. Low peripheral doses of fadolmidine have been reported to have effects mainly outside of the central nervous system, whereas at large doses also the central effects are evident.OutcomesThe time spent close to the receptive female in relation to the time spent with the male and measures of ambulatory activity were obtained from the test for sexual incentive motivation, while the habitual parameters of sexual behavior were recorded with the copulation test.RESULTSTasipimidine prolonged ejaculation latency and the interintromission interval at the dose of 200 µg/kg when data from fast-ejaculating rats were used. No other sexual parameter was modified. A dose of 100 µg/kg was ineffective. There was no consistent effect on sexual incentive motivation, although modest sedation was observed. Fadolmidine, a drug that does not easily penetrate the blood–brain barrier, had no effect on sexual incentive motivation at any of the doses used (3, 30, and 100 µg/kg). The largest dose had clear sedative effects. The lower doses had no systematic effect on sexual behavior, not even when only fast or very fast ejaculating males were analyzed.Clinical TranslationThe findings are relevant to the search for treatments for premature ejaculation that are specific enough to selectively delay ejaculation.Strengths & LimitationsThe procedures used here are standard in the field and yield the most reliable data. Whether the effects observed in male rats are directly transferrable to men can only be determined through clinical studies.CONCLUSIONThe observation that drugs acting at central but not peripheral α2-adrenoceptors prolong ejaculation latency without affecting any other parameter of sexual behavior or sexual incentive motivation suggests that this kind of drug may be suitable for treating premature ejaculation.

01 Aug 2021·Pharmacology Research & PerspectivesQ4 · MEDICINE

Effects of fadolmidine, an α₂‐adrenoceptor agonist, as an adjuvant to spinal bupivacaine on antinociception and motor function in rats and dogs

Q4 · MEDICINE

ArticleOA

Author: Haapalinna, Antti ; Leino, Tiina ; Salonen, Jarmo S. ; Viitamaa, Timo ; Pesonen, Ullamari

Abstractα2‐Adrenoceptor agonists such as clonidine and dexmedetomidine are used as adjuvants to local anesthetics in regional anesthesia. Fadolmidine is an α2‐adrenoceptor agonist developed especially as a spinal analgesic. The current studies investigate the effects of intrathecally administered fadolmidine with a local anesthetic, bupivacaine, on antinociception and motor block in conscious rats and dogs. The antinociceptive effects of intrathecal fadolmidine and bupivacaine alone or in combination were tested in the rat tail‐flick and the dog's skin twitch models. The durations of motor block in rats and in dogs were also assessed. In addition, the effects on sedation, mean arterial blood pressure, heart rate, respiratory rate and body temperature were evaluated in telemetrized dogs. Concentrations of fadolmidine in plasma and spinal cord were determined after intrathecal and intravenous administration in rats. Co‐administration of intrathecal fadolmidine with bupivacaine increased the magnitude and duration of the antinociceptive effects and prolonged motor block without hypotension. The interaction of the antinociceptive effect was synergistic in its nature in rats. Concentration of fadolmidine in plasma was very low after intrathecal dosing. Taken together, these studies show that fadolmidine as an adjuvant to intrathecal bupivacaine provides enhanced sensory‐motor block and enables a reduction of the doses of both drugs. The results indicate that co‐administration of fadolmidine with intrathecal bupivacaine was able to achieve an enhanced antinociceptive effect without hypotension and could thus represent a suitable combination for spinal anesthesia.

News (Medical) associated with Fadolmidine Hydrochloride

15 Apr 2017

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Recro Pharma Inc REPH Pharmaceuticals Healthcare Deals and Alliances Profile [Updated: 21022017] Prices from USD $250

Summary Recro Pharma Inc Recro Pharma is a specialty pharmaceutical company that develops nonopioid therapeutics for the treatment of pain. The company's product candidates include dexmedetomidine, meloxicam and fadolmidine. Its dexmedetomidine is used in the treatment of chronic pain and cancer breakthrough pain. Recro Pharma's fadolmidine is used for treating postoperative pain and neuropathic pain. The company's meloxicam is a NSAID with preferential COX2 inhibition and used for treatment of symptoms of osteoarthritis and rheumatoid arthritis. It markets its products through its sales offices. Recro Pharma is headquartered in Malvern, Pennsylvania, the US. Recro Pharma Inc REPH Pharmaceuticals Healthcare Deals and Alliances Profile provides you comprehensive data and trend analysis of the company's Mergers and Acquisitions MAs, partnerships and financings. The report provides detailed information on Mergers and Acquisitions, Equity/Debt Offerings, Private Equity, Venture Financing and Partnership transactions recorded by the company over a five year period. The report offers detailed comparative data on the number of deals and their value categorized into deal types, subsector and regions. GlobalData derived the data presented in this report from proprietary inhouse Pharma eTrack deals database, and primary and secondary research. Scope Financial Deals Analysis of the company's financial deals including Mergers and Acquisitions, Equity/Debt Offerings, Private Equity, Venture Financing and Partnerships. Deals by Year Chart and table displaying information encompassing the number of deals and value reported by the company by year, for a five year period. Deals by Type Chart and table depicting information including the number of deals and value reported by the company by type such as Mergers and Acquisitions, Equity/Debt Offering etc. Deals by Region Chart and table presenting information on the number of deals and value reported by the company by region, which includes North America, Europe, Asia Pacific, the Middle East and Africa and South and Central America. Deals by Subsector Chart and table showing information on the number of deals and value reported by the company, by subsector. Major Deals Information on the company's major financial deals. Each such deal has a brief summary, deal type, deal rationale; and deal financials and target Company's major public companies key financial metrics and ratios. Business Description A brief description of the company's operations. Key Employees A list of the key executives of the company. Important Locations and Subsidiaries A list and contact details of key centers of operation and subsidiaries of the company. Key Competitors A list of the key competitors of the company. Key Recent Developments A brief on recent news about the company. Reasons to Buy Get detailed information on the company's financial deals that enable you to understand the company's expansion/divestiture and fund requirements The profile enables you to analyze the company's financial deals by region, by year, by business segments and by type, for a five year period. Understand the company's business segments' expansion / divestiture strategy The profile presents deals from the company's core business segments' perspective to help you understand its corporate strategy. Access elaborate information on the company's recent financial deals that enable you to understand the key deals which have shaped the company Detailed information on major recent deals includes a summary of each deal, deal type, deal rationale, deal financials and Target Company's key financial metrics and ratios. Equip yourself with detailed information about the company's operations to identify potential customers and suppliers. The profile analyzes the company's business structure, locations and subsidiaries, key executives and key competitors. Stay uptodate on the major developments affecting the company Recent developments concerning the company presented in the profile help you track important events. Gain key insights into the company for academic or business research Key elements such as break up of deals into categories and information on detailed major deals are incorporated into the profile to assist your academic or business research needs. Note*: Some sections may be missing if data is unavailable for the company.

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KEGG	Wiki	ATC	Drug Bank
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Indication	Highest Phase	Country/Location	Organization	Date
Pain, Postoperative	Phase 2	-	Orion Oyj	-
Neuralgia	Preclinical	United States	Orion Oyj	-
Pain, Postoperative	Preclinical	United States	Societal CDMO, Inc.	-

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