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Constantin Tamvakopoulos - One of the best experts on this subject based on the ideXlab platform.
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Determination of Melanotan‐II in rat plasma by liquid chromatography/tandem mass spectrometry: determination of pharmacokinetic parameters in rat following intravenous administration
Rapid Communications in Mass Spectrometry, 2020Co-Authors: S Mock, Xiaolan Shen, Constantin TamvakopoulosAbstract:A method is described for the determination of Melanotan-II (MT-II), a synthetic cyclic heptapeptide analog of α-melanocyte-stimulating hormone (α-MSH), in rat plasma by liquid chromatography/tandem mass spectrometry (LC/MS/MS). The analyte is recovered from plasma by solid-phase extraction (SPE) and subsequently analyzed by LC/MS/MS. A SPE procedure using OASIS 96-well plates is used for extraction of MT-II from rat plasma. Using the described approach a limit of quantitation of 5 ng/mL was achieved in rat plasma. This level of sensitivity allowed the determination of pharmacokinetic parameters, following intravenous administration of MT-II in rat. Copyright © 2002 John Wiley & Sons, Ltd.
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A liquid chromatographic/tandem mass spectroscopic method for quantification of the cyclic peptide Melanotan-II. Plasma and brain tissue concentrations following administration in mice
Rapid Communications in Mass Spectrometry, 2020Co-Authors: Sophia Hatziieremia, Nikolaos Kostomitsopoulos, Vagelis Balafas, Constantin TamvakopoulosAbstract:Melanotan-II (MT-II), a synthetic analogue of the natural melanocortin peptide, α-melanocyte-stimulating hormone (α-MSH), is well known for the anorexic effects it elicits in rodents. These effects are, at least partly, associated with agonistic action on the centrally located melanocortin receptors, MC3R and MC4R. Whether MT-II exerts this effect via brain penetration still remains unclear. In order to address this question we administered MT-II in rodents at efficacious doses and then employed a sensitive methodology for the determination of MT-II in plasma and brain samples. MT-II was extracted from mouse plasma and brain tissue by acetonitrile precipitation followed by liquid chromatography/tandem mass spectrometry (LC/MS/MS) analysis. The described assay improved significantly previously reported MT-II levels of quantification in rat plasma and brain. The lower limits of quantification (LLOQs) of 0.5 ng/mL and 2.5 ng/g were obtained in 50 µL plasma and 100 µL brain homogenate, respectively. The calibration curve was linear over the concentration range of 0.5–500 ng/mL for plasma and 2.5–250 ng/g for brain tissue. The method was successfully applied in measuring levels of MT-II in plasma and brain tissue following intraperitoneal (ip) administration of 1 mg/kg of peptide in mice. Following administration of MT-II, clearance from plasma was rapid. The sensitivity of the assay allowed the determination of low concentrations of MT-II (11.4 ± 5.5 ng/g) in brain homogenate at 30 min after dosing. However, the brain concentrations when compared with the high plasma levels of MT-II at the same time point confirmed the low penetrability of the peptide in mouse brain. Copyright © 2007 John Wiley & Sons, Ltd.
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a liquid chromatographic tandem mass spectroscopic method for quantification of the cyclic peptide Melanotan II plasma and brain tissue concentrations following administration in mice
Rapid Communications in Mass Spectrometry, 2007Co-Authors: Sophia Hatziieremia, Nikolaos Kostomitsopoulos, Vagelis Balafas, Constantin TamvakopoulosAbstract:Melanotan-II (MT-II), a synthetic analogue of the natural melanocortin peptide, α-melanocyte-stimulating hormone (α-MSH), is well known for the anorexic effects it elicits in rodents. These effects are, at least partly, associated with agonistic action on the centrally located melanocortin receptors, MC3R and MC4R. Whether MT-II exerts this effect via brain penetration still remains unclear. In order to address this question we administered MT-II in rodents at efficacious doses and then employed a sensitive methodology for the determination of MT-II in plasma and brain samples. MT-II was extracted from mouse plasma and brain tissue by acetonitrile precipitation followed by liquid chromatography/tandem mass spectrometry (LC/MS/MS) analysis. The described assay improved significantly previously reported MT-II levels of quantification in rat plasma and brain. The lower limits of quantification (LLOQs) of 0.5 ng/mL and 2.5 ng/g were obtained in 50 µL plasma and 100 µL brain homogenate, respectively. The calibration curve was linear over the concentration range of 0.5–500 ng/mL for plasma and 2.5–250 ng/g for brain tissue. The method was successfully applied in measuring levels of MT-II in plasma and brain tissue following intraperitoneal (ip) administration of 1 mg/kg of peptide in mice. Following administration of MT-II, clearance from plasma was rapid. The sensitivity of the assay allowed the determination of low concentrations of MT-II (11.4 ± 5.5 ng/g) in brain homogenate at 30 min after dosing. However, the brain concentrations when compared with the high plasma levels of MT-II at the same time point confirmed the low penetrability of the peptide in mouse brain. Copyright © 2007 John Wiley & Sons, Ltd.
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determination of Melanotan II in rat plasma by liquid chromatography tandem mass spectrometry determination of pharmacokinetic parameters in rat following intravenous administration
Rapid Communications in Mass Spectrometry, 2002Co-Authors: S Mock, Xiaolan Shen, Constantin TamvakopoulosAbstract:A method is described for the determination of Melanotan-II (MT-II), a synthetic cyclic heptapeptide analog of α-melanocyte-stimulating hormone (α-MSH), in rat plasma by liquid chromatography/tandem mass spectrometry (LC/MS/MS). The analyte is recovered from plasma by solid-phase extraction (SPE) and subsequently analyzed by LC/MS/MS. A SPE procedure using OASIS 96-well plates is used for extraction of MT-II from rat plasma. Using the described approach a limit of quantitation of 5 ng/mL was achieved in rat plasma. This level of sensitivity allowed the determination of pharmacokinetic parameters, following intravenous administration of MT-II in rat. Copyright © 2002 John Wiley & Sons, Ltd.
R Dorr - One of the best experts on this subject based on the ideXlab platform.
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Melanocortin Peptide Therapeutics: Historical Milestones, Clinical Studies and Commercialization
Peptides, 2006Co-Authors: Me Hadley, R DorrAbstract:The melanocortins (MCs) are a family of multifunctional peptidergic hormones. Several superpotent, prolonged acting, enzymatically resistant, MC analogs have been designed and synthesized to help clarify the nature and role of MCs and their receptors (MCRs) in physiological functions. Two of these analogs, a linear peptide, Melanotan I, and a cyclic truncated peptide, Melanotan II (MTI and MTII, respectively) have been patented and tested clinically for studies on tanning of the skin (MTI) and for diagnosis and treatment of male erectile dysfunction (MTII). A new MTII analog, PT-141 (Palatin Technologies) has initial phase I/II trials and is scheduled to enter pivotal stage III clinical trials leading to commercialization. MTI may provide a therapeutic tan with the potential to lower the risk of skin cancer. PT-141 may improve sexual functionality in both males and females.
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Melanocortin receptor agonists, penile erection, and sexual motivation: human studies with Melanotan II
International Journal of Impotence Research, 2000Co-Authors: H Wessells, N Levine, Me Hadley, R Dorr, V HrubyAbstract:We review our experience with Melanotan II, a non-selective melanocortin receptor agonist, in human subjects with erectile dysfunction (ED). Melanotan II was administered to 20 men with psychogenic and organic ED using a double-blind placebo-controlled crossover design. Penile rigidity was monitored for 6 h using RigiScan. Level of sexual desire and side effects were reported with a questionnaire. In the absence of sexual stimulation, Melanotan II led to penile erection in 17 of 20 men. Subjects experienced a mean of 41 min Rigiscan tip rigidity>80%. Increased sexual desire was reported after 13/19 (68%) doses of Melanotan II vs 4/21 (19%) of placebo ( P
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Effect of an alpha-melanocyte stimulating hormone analog on penile erection and sexual desire in men with organic erectile dysfunction
Urology, 2000Co-Authors: H Wessells, Me Hadley, R Dorr, Victor J Hruby, D. A. N. Gralnek, N LevineAbstract:Abstract Objectives. To assess the safety, erectogenic properties, and effect on sexual desire of Melanotan II, a synthetic melanotropic initiator of erection, in men with erectile dysfunction and organic risk factors. Methods. Ten subjects were enrolled in a double-blind, placebo-controlled, crossover study. Melanotan II (0.025 mg/kg) and vehicle were each administered twice by subcutaneous injection; real-time RigiScan monitoring and a visual analog were used to quantify the erections during a 6-hour period. The level of sexual desire and side effects were recorded with a questionnaire. Results. Melanotan II initiated subjectively reported erections in 12 of 19 injections versus only 1 of 21 doses of placebo. The mean rigidity score of the responders was 6.9 on a scale of 0 to 10. The mean duration of tip rigidity greater than 80% was 45.3 minutes with Melanotan II versus 1.9 for placebo ( P = 0.047). The level of sexual desire after injection was significantly higher after Melanotan II administration than after placebo. Nausea and stretching/yawning occurred more frequently with Melanotan II, and 4 of 19 injections were associated with severe nausea. Conclusions. The erectogenic properties of Melanotan II are not limited to cases of psychogenic erectile dysfunction; men with a variety of organic risk factors developed penile erections. The finding of increased sexual desire warrants further investigation of centrally acting agents on disorders of sexual desire.
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melanocortin receptor agonists penile erection and sexual motivation human studies with Melanotan II
International Journal of Impotence Research, 2000Co-Authors: H Wessells, N Levine, Me Hadley, R Dorr, V HrubyAbstract:Melanocortin receptor agonists, penile erection, and sexual motivation: human studies with Melanotan II
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SYNTHETIC MELANOTROPIC PEPTIDE INITIATES ERECTIONS IN MEN WITH PSYCHOGENIC ERECTILE DYSFUNCTION: DOUBLE-BLIND, PLACEBO CONTROLLED CROSSOVER STUDY
The Journal of Urology, 1998Co-Authors: H Wessells, Me Hadley, R Dorr, Victor J Hruby, Kevin Fuciarelli, John Hansen, N LevineAbstract:AbstractPurpose: We evaluated the erectogenic properties of a new cyclic alpha-melanocyte-stimulating hormone analogue, Melanotan-II, to treat men with psychogenic erectile dysfunction.Materials and Methods: Ten men with erectile dysfunction of no known organic cause were entered in a double-blind, placebo controlled crossover study in which the erectogenic properties of Melanotan-II and a vehicle placebo were compared using real-time RigiScan [double dagger] monitoring. The presence, duration and rigidity of erections were recorded during a 6-hour period.Results: In 8 of 10 men treated with Melanotan-II clinically apparent erections developed. Mean duration of tip rigidity greater than 80% was 38.0 minutes with Melanotan-II and 3.0 with placebo (p = 0.0045). Transient side effects of nausea, stretching and yawning and decreased appetite were reported more frequently after injections of Melanotan-II than placebo but none required treatment.Conclusions: Melanotan-II is a potent initiator of erections in me...
Me Hadley - One of the best experts on this subject based on the ideXlab platform.
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Melanocortin Peptide Therapeutics: Historical Milestones, Clinical Studies and Commercialization
Peptides, 2006Co-Authors: Me Hadley, R DorrAbstract:The melanocortins (MCs) are a family of multifunctional peptidergic hormones. Several superpotent, prolonged acting, enzymatically resistant, MC analogs have been designed and synthesized to help clarify the nature and role of MCs and their receptors (MCRs) in physiological functions. Two of these analogs, a linear peptide, Melanotan I, and a cyclic truncated peptide, Melanotan II (MTI and MTII, respectively) have been patented and tested clinically for studies on tanning of the skin (MTI) and for diagnosis and treatment of male erectile dysfunction (MTII). A new MTII analog, PT-141 (Palatin Technologies) has initial phase I/II trials and is scheduled to enter pivotal stage III clinical trials leading to commercialization. MTI may provide a therapeutic tan with the potential to lower the risk of skin cancer. PT-141 may improve sexual functionality in both males and females.
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Discovery that a melanocortin regulates sexual functions in male and female humans
Peptides, 2005Co-Authors: Me HadleyAbstract:Melanocortins (MCs) are multifunctional peptide hormones that regulate a diversity of physiological functions. MCs have been implicated in sexual function in animals. We document here that a MC analog, Melanotan II (MTII), can enhance sexual function in human males (erectile activity) and females (increased levels of sexual desire and genital arousal). Unlike other sexual-enhancement drugs, MTII works at the level of the brain, thus eliciting a rather natural sexual response with minimal or no undesirable side effects. The actions of the peptide were discovered accidentally while studying the effects of the peptide and related analogs on human skin pigmentation (tanning).
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Melanocortin receptor agonists, penile erection, and sexual motivation: human studies with Melanotan II
International Journal of Impotence Research, 2000Co-Authors: H Wessells, N Levine, Me Hadley, R Dorr, V HrubyAbstract:We review our experience with Melanotan II, a non-selective melanocortin receptor agonist, in human subjects with erectile dysfunction (ED). Melanotan II was administered to 20 men with psychogenic and organic ED using a double-blind placebo-controlled crossover design. Penile rigidity was monitored for 6 h using RigiScan. Level of sexual desire and side effects were reported with a questionnaire. In the absence of sexual stimulation, Melanotan II led to penile erection in 17 of 20 men. Subjects experienced a mean of 41 min Rigiscan tip rigidity>80%. Increased sexual desire was reported after 13/19 (68%) doses of Melanotan II vs 4/21 (19%) of placebo ( P
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Effect of an alpha-melanocyte stimulating hormone analog on penile erection and sexual desire in men with organic erectile dysfunction
Urology, 2000Co-Authors: H Wessells, Me Hadley, R Dorr, Victor J Hruby, D. A. N. Gralnek, N LevineAbstract:Abstract Objectives. To assess the safety, erectogenic properties, and effect on sexual desire of Melanotan II, a synthetic melanotropic initiator of erection, in men with erectile dysfunction and organic risk factors. Methods. Ten subjects were enrolled in a double-blind, placebo-controlled, crossover study. Melanotan II (0.025 mg/kg) and vehicle were each administered twice by subcutaneous injection; real-time RigiScan monitoring and a visual analog were used to quantify the erections during a 6-hour period. The level of sexual desire and side effects were recorded with a questionnaire. Results. Melanotan II initiated subjectively reported erections in 12 of 19 injections versus only 1 of 21 doses of placebo. The mean rigidity score of the responders was 6.9 on a scale of 0 to 10. The mean duration of tip rigidity greater than 80% was 45.3 minutes with Melanotan II versus 1.9 for placebo ( P = 0.047). The level of sexual desire after injection was significantly higher after Melanotan II administration than after placebo. Nausea and stretching/yawning occurred more frequently with Melanotan II, and 4 of 19 injections were associated with severe nausea. Conclusions. The erectogenic properties of Melanotan II are not limited to cases of psychogenic erectile dysfunction; men with a variety of organic risk factors developed penile erections. The finding of increased sexual desire warrants further investigation of centrally acting agents on disorders of sexual desire.
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melanocortin receptor agonists penile erection and sexual motivation human studies with Melanotan II
International Journal of Impotence Research, 2000Co-Authors: H Wessells, N Levine, Me Hadley, R Dorr, V HrubyAbstract:Melanocortin receptor agonists, penile erection, and sexual motivation: human studies with Melanotan II
Sophia Hatziieremia - One of the best experts on this subject based on the ideXlab platform.
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A liquid chromatographic/tandem mass spectroscopic method for quantification of the cyclic peptide Melanotan-II. Plasma and brain tissue concentrations following administration in mice
Rapid Communications in Mass Spectrometry, 2020Co-Authors: Sophia Hatziieremia, Nikolaos Kostomitsopoulos, Vagelis Balafas, Constantin TamvakopoulosAbstract:Melanotan-II (MT-II), a synthetic analogue of the natural melanocortin peptide, α-melanocyte-stimulating hormone (α-MSH), is well known for the anorexic effects it elicits in rodents. These effects are, at least partly, associated with agonistic action on the centrally located melanocortin receptors, MC3R and MC4R. Whether MT-II exerts this effect via brain penetration still remains unclear. In order to address this question we administered MT-II in rodents at efficacious doses and then employed a sensitive methodology for the determination of MT-II in plasma and brain samples. MT-II was extracted from mouse plasma and brain tissue by acetonitrile precipitation followed by liquid chromatography/tandem mass spectrometry (LC/MS/MS) analysis. The described assay improved significantly previously reported MT-II levels of quantification in rat plasma and brain. The lower limits of quantification (LLOQs) of 0.5 ng/mL and 2.5 ng/g were obtained in 50 µL plasma and 100 µL brain homogenate, respectively. The calibration curve was linear over the concentration range of 0.5–500 ng/mL for plasma and 2.5–250 ng/g for brain tissue. The method was successfully applied in measuring levels of MT-II in plasma and brain tissue following intraperitoneal (ip) administration of 1 mg/kg of peptide in mice. Following administration of MT-II, clearance from plasma was rapid. The sensitivity of the assay allowed the determination of low concentrations of MT-II (11.4 ± 5.5 ng/g) in brain homogenate at 30 min after dosing. However, the brain concentrations when compared with the high plasma levels of MT-II at the same time point confirmed the low penetrability of the peptide in mouse brain. Copyright © 2007 John Wiley & Sons, Ltd.
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a liquid chromatographic tandem mass spectroscopic method for quantification of the cyclic peptide Melanotan II plasma and brain tissue concentrations following administration in mice
Rapid Communications in Mass Spectrometry, 2007Co-Authors: Sophia Hatziieremia, Nikolaos Kostomitsopoulos, Vagelis Balafas, Constantin TamvakopoulosAbstract:Melanotan-II (MT-II), a synthetic analogue of the natural melanocortin peptide, α-melanocyte-stimulating hormone (α-MSH), is well known for the anorexic effects it elicits in rodents. These effects are, at least partly, associated with agonistic action on the centrally located melanocortin receptors, MC3R and MC4R. Whether MT-II exerts this effect via brain penetration still remains unclear. In order to address this question we administered MT-II in rodents at efficacious doses and then employed a sensitive methodology for the determination of MT-II in plasma and brain samples. MT-II was extracted from mouse plasma and brain tissue by acetonitrile precipitation followed by liquid chromatography/tandem mass spectrometry (LC/MS/MS) analysis. The described assay improved significantly previously reported MT-II levels of quantification in rat plasma and brain. The lower limits of quantification (LLOQs) of 0.5 ng/mL and 2.5 ng/g were obtained in 50 µL plasma and 100 µL brain homogenate, respectively. The calibration curve was linear over the concentration range of 0.5–500 ng/mL for plasma and 2.5–250 ng/g for brain tissue. The method was successfully applied in measuring levels of MT-II in plasma and brain tissue following intraperitoneal (ip) administration of 1 mg/kg of peptide in mice. Following administration of MT-II, clearance from plasma was rapid. The sensitivity of the assay allowed the determination of low concentrations of MT-II (11.4 ± 5.5 ng/g) in brain homogenate at 30 min after dosing. However, the brain concentrations when compared with the high plasma levels of MT-II at the same time point confirmed the low penetrability of the peptide in mouse brain. Copyright © 2007 John Wiley & Sons, Ltd.
Francois Giuliano - One of the best experts on this subject based on the ideXlab platform.
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the melanocortin agonist Melanotan II enhances proceptive sexual behaviors in the female rat
Pharmacology Biochemistry and Behavior, 2006Co-Authors: Annesophie Rossler, Jacques Bernabe, Laurent Alexandre, James G Pfaus, Francois GiulianoAbstract:Abstract Melanocortins have been reported to play a role in the control of both male and female sexual behavior. The present study examined the effects of Melanotan-II (MT-II), a cyclic peptide analogue of alpha-melanocyte stimulating hormone on appetitive and consummatory aspects of female sexual behavior, including aspects of sexual proceptivity (solicitations, hops and darts, ear wiggling, pacing) and receptivity (lordosis). One group of ovariectomized Long-Evans rats ( n = 7) was primed subcutaneously with estradiol benzoate (EB) and progesterone (P) (10 μg and 500 μg respectively) and another group ( n = 7) with EB (10 μg) and oil (EB alone). Paced mating tests were performed with sexually experienced males in unilevel chambers, which were bisected by a Plexiglas divider containing three holes, through which only the female could pass. MT-II (1 and 3 mg/kg) or saline was injected intravenously 10 min before each 30-min paced mating test. Each female received the 3 treatments. In females primed with EB + P both doses of MT-II increased the number of hops and darts and ear wiggling significantly, but did not alter pacing or lordosis. With EB alone, no effect of MT-II was observed on any of the parameters measured. These results suggest that P can interact with MT-II to increase proceptive behaviors. Because hops and darts are essentially solicitations, made in close proximity to the male, that indicate a desire on the part of females to receive mounts and intromissions, these data suggest that activation of melanocortin receptors may represent a promising mode of action for the treatment of women with hypoactive sexual desire.
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Melanotan II investigation of the inducer and facilitator effects on penile erection in anaesthetized rat
Neuroscience, 2006Co-Authors: Francois Giuliano, Pierre Clement, S Droupy, Laurent Alexandre, Jacques BernabeAbstract:Abstract The effects of Melanotan-II, a non-specific agonist of melanocortin receptors, on erection and its possible sites of action were investigated in anesthetized rats. Delivered i.v. (0.1, 0.3 and 1mg/kg) or within the paraventricular nucleus of the hypothalamus (0.1 and 1μg), Melanotan-II exerted a dose-dependent inducer activity on erection by eliciting erectile events and shortening latency of the first erectile event to occur. Erectile events were of higher amplitude in rats treated with Melanotan-II i.t. (0.2μg) delivered at the L6–S1 level than in animals treated with the vehicle i.t. delivered. Erectile responses elicited by cavernous nerve stimulation were increased after i.v. Melanotan-II (1mg/kg), thereby exerting facilitator effect on erection. In contrast, Melanotan-II injected within the corpus cavernosum (1μg) did not display any facilitator activity. To investigate the neural pathways involved in the facilitator effect of Melanotan-II, we performed acute spinalization (T8 level) and differential selective nerve transections. Neither spinalization nor bilateral transection of pelvic nerves or dorsal penile nerves impaired facilitator activity of i.v. Melanotan-II (1mg/kg). Conversely, the facilitator effect of Melanotan-II was abolished after acute removal of the lumbar paravertebral sympathetic chain. These results lead to the conclusion that central and peripheral melanocortin pathways are recruited by Melanotan-II, depending on its route of delivery, to exert both inducer and facilitator activities on erection.
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the use of telemetry technology to test the proerectile effect of Melanotan II mt II in conscious rats
European Urology, 2005Co-Authors: Francois Giuliano, Pierre Clement, S Droupy, Laurent Alexandre, Annesophie Rossler, Jacques BernabeAbstract:Abstract Objective: The aim of this study is to demonstrate that monitoring, by means of telemetry technology, the increases in intracavernosal pressure (ICP) in freely moving rats using Melanotan-II (MT-II) as a proerectile inducer compound is a relevant experimental model to investigate the effects of pharmacological agents on erection. Methods: Adult rats were implanted in the corpus cavernosum with a pressure sensor which permitted telemetric monitoring of ICP in freely moving animals following MT-II (0.1, 0.3 and 1mg/kg) or saline i.v. injections. ICP was also measured after MT-II (0.1, 0.3 or 1mg/kg) or saline i.v. delivery in anesthetized rats. Results: In conscious rats, MT-II (1mg/kg) significantly increased overall erectile activity compared to saline. In anesthetized rats, MT-II-induced increase in overall erectile activity was not statistically significant but displayed a similar pattern. Conclusions: The use of telemetry technology allowed to collect quantifiable and reliable data regarding the proerectile activity of MT-II in physiological conditions. The telemetry model appears suitable for investigating the potential inducer proerectile properties of pharmacological agents.
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Central nervous system agents in the treatment of erectile dysfunction: How do they work?
Current Urology Reports, 2001Co-Authors: Julien Allard, Francois GiulianoAbstract:Drugs acting within the central nervous system (CNS) that reduce the sympathetic antierectile flow and enhance the parasympathetic proerectile flow to the penis may restore penile erection in cases of erectile dysfunction of both psychogenic and organic origin. The best characterized of such drugs is the dopaminergic agonist apomorphine, which acts on the hypothalamus and, perhaps, the autonomic nuclei in the spinal cord. Other drugs that target the CNS and have been registered and tested are the α_2 -adrenoceptor antagonists yohimbine and delequamine, the α ?-melanocyte-stimulating hormone agonist Melanotan II, and the serotonin reuptake inhibitor trazodone. Androgens also may influence sexual behavior by acting within the CNS, notably by modifying the neurotransmitter system targeted by these drugs. Our knowledge of the mode of action of CNS drugs comes mainly from experi-ments on rodents. Consequently, explanations regarding the way they work in humans are only speculative.