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Physician Information
Physicians and Healthcare Professional Information - Early Ejaculation and Lack of Ejaculatory Control - Clinical Review of Management Options
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| Early Ejaculation, Lack of Ejaculatory Control, and Premature Ejaculation can be debilitating sexual
problems. These common problems can lead to an inability to enter or sustain relationships and can cause psychological damage to sufferers, as well as impair reproductive success. Commonly employed methods of treating these
problems include psychological therapies, topical anesthetics and the use of devices. Substantially all of these methods have significant drawbacks. For example, psychological therapies can be extremely important and while they benefit a subset of patients it does require specialized therapists who may not be available to all patients, particularly in remote areas. Furthermore, psychological therapies cannot alleviate problems resulting from non-psychological causes. Another method is topically applied anesthetic agents that decrease sensitivity of tissues, thereby diminishing sensation and sexual pleasure. Unfortunately, these topical anesthetics are also easily transferred to sexual partners and thereby decrease their sensitivity and pleasure as well. With regard to devices, consumers generally report that these are awkward, inconvenient and embarrassing to use. Furthermore these highly conspicuous devices reveal the very condition that the suffering partner may prefer to conceal. Additionally, these devices can cause local irritation to one or both partners. A rather common clinically practiced method for "treating" Early Ejaculation, Lack of Ejaculatory Control, and Premature Ejaculation is the systemic administration of psychoactive compounds such as SSRI antidepressants on an "off label" prescription basis. However, the side effects of systemic psychoactive drug administration can halt treatment or impair patient compliance. Disease states or adverse interactions with other drugs may contraindicate the use of these prescription compounds or require lower dosages that may not be effective to delay the onset of ejaculation. Additionally, the stigma of "mental illness" associated with psychoactive drug therapy can discourage patients from beginning or continuing such treatments. Systemic administration of the antidepressant fluoxetine has been reported by many researchers to show some degree of efficacy. However, the systemic administration of fluoxetine has many undesired aspects. Side effects of oral fluoxetine administration include hair loss, nausea, vomiting, dyspepsia, diarrhea, anorexia, anxiety, nervousness, insomnia, drowsiness, fatigue, headache, tremor, dizziness, convulsions, sweating, pruritis, and skin rashes. Fluoxetine interacts with a variety of drugs, often by impairing their metabolism by the liver. It has also been recognized that sertraline and other SSRI's share many of the same problems as fluoxetine; [see Martindale, The Extra Pharmacopoeia, 31st edition, at p. 333 (London: The Royal Pharmaceutical Society, 1996)]. Side effects resulting from oral sertraline administration include nausea, diarrhea, dyspepsia, insomnia, somnolence, sweating, dry mouth, tremor and mania. Rare instances of coma, convulsions, fecal incontinence and gynecomastia have occurred in patients undergoing sertraline therapy. Since substantially all of the SSRI's share the nearly the same benefit and similar side effect profiles, their practicality of use is limited by their
drawbacks. Consequently, there is a widespread unmet need for a method of delaying early ejaculation and improving ejaculatory control that requires no specialized psychological therapy. A new oral product can now be obtained discreetly and used conveniently without embarrassment, and does not involve the problems associated with prior therapeutic methods (anesthetic creams) and prescription SSRI antidepressants.
Today, there is an oral non-prescription capsule to satisfy this large unmet need.
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| The treatment of Early Ejaculation, Lack of Ejaculatory Control, and Premature Ejaculation has recently undergone somewhat of a rebirth. Physicians are now able to effectively treat most problems with targeted SSRI medications, depending upon the diagnosis. Before the advent of these antidepressant medications, mental health individuals and sexual therapists saw most of these patients. Earlier, the condition was commonly believed to be a psychological problem. At the time, treatment principally involved only behavioral therapy, which required a high degree of motivation from both partners. From a physician's perspective, the behavioral therapy typically did not achieve the success rate as reported in the standard literature of the time. One form of this therapy involved sexual foreplay to the point of ejaculation, without allowing ejaculation to occur, then slowly increasing the length of time between activity and the point of ejaculation. Previous medical therapy employed the use of topically applied local anesthetics, which were non-prescription creams or gels found in drugstores. Men would apply roughly one-half teaspoon of this "anesthetic jelly" to the penis and wear a condom. Approximately thirty minutes later, sexual relations were begun. On occasion, this treatment could be successful, but an obvious and highly unwanted side effect was vaginal and clitoral anesthesia. Before the advent of serotonin selective re-uptake inhibitors (SSRIs), another treatment option involved giving the patient intracavernosal penile injections to create a pharmacologic erection that would not go away after orgasm, thus allowing the individual to get over the fear of the problem. The utilization of serotonin selective re-uptake inhibitors has significantly changed the medical treatment of the condition. It has been widely reported that men who are on (SSRIs) to treat depression experience difficulty ejaculating, and many patients complained about this side effect. This observation prompted many physicians to use this side effect as a treatment in men with ejaculation problems. These medications, including fluoxetine, sertraline, and clomipramine tend to prolong ejaculatory latency, and for some patients, increases the time it takes to ejaculate by up to twenty to thirty minutes. It is extremely important to note that these drugs are not currently indicated for this treatment, and physicians prescribing their use, must be done with caution and only for "informed" patients since this is an "off-label" use of these prescription antidepressants. Some physicians have found that using a lower-strength dosage roughly four (4) hours prior to anticipated sexual relations can produce meaningful success rates.
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| A major problem within this area is the lack of a clear definition or diagnostic criteria. Some clinicians have defined the condition as the inability to delay orgasm until the female partner is satisfied, while others have attempted to quantify the condition by measuring the duration of intercourse or number of thrusts following penetration. The perception of control on the part of the male is an important element in most definitions. It has been proposed that men with the problem have increased penile sensitivity or a decreased threshold for the bulbocavernosus reflex. It has also been proposed, and more widely believed, that a deficiency of serotonin or an excess of dopamine and/or both might be occurring. Deferol™ was specifically designed to help promote a favorable
serotonin/dopamine ratio to assist in controlling climax.Prevalence data from non-clinical samples shows that approximately 30-40% of U.S. males have difficulties with ejaculation control at some time in their lives. Other surveys have reported that as many as 60% of men have intermittent concerns about ejaculating too rapidly. Surveys also report that approximately 40% of men ejaculate within 2-3 minutes or less after vaginal penetration. Although relatively few men seek professional treatment, it remains among the most prevalent and troublesome of all male sexual difficulties. Currently, there is no FDA-approved prescription treatment. There are over-the-counter topically applied anesthetic products that have poor patient acceptability due to inherent product drawbacks. Deferol™ helps most men "delay ejaculation, improve ejaculatory control and enhance the quality of sex lives for both partners".
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Squeeze Method.
The "squeeze method" can be used when the male feels that he is getting very close to ejaculating, he withdraws and you clamp down (usually with the thumb and two fingers) very tightly on the penis for 10 to 20 seconds. While some experts say it is better to squeeze at the base of the penis; others recommend just below the head, so you might want to experiment. Some men find that after a few seconds of this, they lose the immediate urge to ejaculate and can go for a longer period of time.
Start-Stop Method.
A sometimes helpful approach is the "start-stop method," in which your partner learns to slow down or even stop stimulation for a brief time when you are getting close to ejaculating. You and your partner should discuss this prior to sex so you know why he is suddenly changing the pace or even stopping for a moment.
Anesthetic Creams.
There are a number of topically applied anesthetic creams that are available over-the-counter for use in
Early Ejaculation and Lack of Ejaculatory Control. Examples are
Prolong®, Endure® and other creams that contain either benzocaine or a similar local anesthetic. These products do not enjoy particularly widespread use due to the local anesthetic effects that "numb" the penis and often times the vagina and clitoris, thereby detracting from the woman's pleasure as well. Because these products are intended to work by "anesthetizing the penis", men having any degree of erectile dysfunction (ED), may have their condition further compounded with difficulties of obtaining and maintaining an erection sufficiently rigid for intercourse.
Prolong Cream® is a product of Universal Nutrition Corporation. Endure® is a product of Gain, Inc.
Prescription Antidepressants.
Recently, pharmacologic treatment approaches are being increasingly used by physicians in the "medical treatment" of PE. While prescription antidepressant drugs may offer the potential for simple and cost-effective treatment of
Early Ejaculation and Lack of Ejaculatory Control, several limitations and risks should be considered:
- Treatment is likely to be effective only as long as drug administration is ongoing and most patients are reluctant to use "psychiatric medications" on a long-term basis.
- Chronic use of serotonin selective re-uptake inhibitors
(SSRI's) often cause decreased libido and/or erectile difficulties are reported to affect up to 60% of patients.
- These drugs (SSRI's) are strongly contraindicated for patients with erectile dysfunction (ED) or those with PE, sexual desire or arousal difficulties.
- Other side effects may be experienced. In particular, sedation or sleep difficulties are reported in a significant number of cases.
Although many healthcare professionals don't recommend this approach as a "first course of action", it may work for some. An urologist or a psychiatrist would be able to help your partner learn if this might be a good approach for him.
The latest development for men is a new non-prescription approach called
Deferol™, a capsule that works on the same scientific principles as the SSRI antidepressants, but without the drawbacks and side effects of those prescription medications.
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Sexual health and sexual satisfaction is an important part of an individual's overall physical and emotional well being. For many men, their ejaculation is difficult and sometimes impossible to control, and thus ejaculation occurs relatively quickly. If this occurs prior to the woman achieving sexual satisfaction, then frustration can result. This frustration can be shared by the man as well. If this frustration continues, then relationship problems can occur. If a man ejaculates before he desires or is ready, or before he can satisfy his partner, then the condition is termed Early or Premature Ejaculation (P.E.).
Deferol™ Climax Control Supplement is a product designed to allow a man to have more control over his climax. To determine the effectiveness of Deferol™, the company is currently engaged in ongoing clinical trials comparing Deferol™ to placebo using a randomized placebo-controlled double blind crossover study. This is an in-home study using only one Deferol™ capsule prior to intercourse and comparing intercourse time to that of one placebo capsule. In an effort to eliminate placebo skew, the subjects were not told one capsule was a placebo. The subjects believed both capsules they were testing were active Deferol™. Subjects were asked to measure their intercourse time, defined as the time of initial vaginal penetration with the penis until ejaculation, for each capsule taken.
Currently, 29 normal healthy males ranging in age from 18 to 44 years with intercourse times ranging from 4 minutes to 45 minutes have completed the study. Statistical analysis shows a statistically significant increase in intercourse time with Deferol™ over placebo1. This study shows Deferol™ is clinically effective as a climax control supplement under the most rigorous test of efficacy possible of just one capsule one hour prior to intercourse.
Deferol™ Climax Control Supplement would be most appealing to men with relatively short intercourse times. In an analysis of the subgroup of men with self-reported intercourse times of less than 15 minutes, one Deferol™ capsule prior to sex showed an average 40% increase in intercourse time2.
Additional studies are underway to assess the effectiveness of Deferol™. These studies involve evaluating the effectiveness of multiple doses of Deferol™ and evaluating the effectiveness of daily administration of Deferol™. Based on the current results seen with just one dose of Deferol™, the company expects even more compelling results with these studies.
1) n=29, statistically significant (P=0.006), paired t-Test 2) n=17, statistically significant (P=0.031), paired t-Test
© Copyright 2001. SureSafe Testing Labs, LLC. Dover, DE. All rights reserved. Data on file.
Summary of the Medical Literature Review of Chrysin
(March 2001)(These excerpts are not inclusive of all
information about the compound)
Chrysin has been shown to reduce anxiety levels (anxiolytic). Paladini's "laboratory described the existence of natural anxiolytic
flavonoids. The first of these was chrysin (5,7-dihydroxyflavone)…"
(Paladini, 1999). "Chrysin (5,7-di-OH-flavone) was identified in Passiflora coerulea L., a plant used as a sedative in folkloric medicine. Chrysin was found to be a ligand for the benzodiazepine receptors, both
central[ly] and peripheral[ly]"
(Medina, 1990). "The pharmacological effects of 5,7-dihydroxyflavone
(chrysin), a naturally occurring monoflavonoid that displaces [3H]flunitrazepam binding to the central benzodiazepine
(BDZ) receptors, were examined in mice. These data suggest that chrysin possesses anxiolytic actions without inducing sedation and muscle relaxation. We
[Wolfman, et.al.] postulate that this natural monoflavonoid is a partial agonist of the central BDZ receptors."
(Wolfman, 1994). "The naturally occurring flavonoid, chrysin….has been recently reported to selectively bind with high affinity to the central benzodiazepine receptor, and to exert powerful anxiolytic and other
benzodiazepine-like effects in rats. The data suggest that
chrysin,….flavonoids derivatives possessing anxioselective effects acting on central benzodiazepine receptors, may deserve clinical trials as anxiolytic agents.
(Salgueiro 1997). Current research shows "…bioflavonoid
(chrysin)-containing foods and beverages, such as grapefruit juice"
(Mitsunaga, 2000) is " a natural product present in our daily
diet,…"(Walle, 1999). Current research also shows
"Chrysin exhibited a clear anxiolytic effect. [T]he anxiolytic effect of
chrysin,…, could be linked to an activation of the GABA(A) receptor unit."
(Zanolil, 2000).Chrysin , present in fruits and vegetables
(Steerenberg, 1998), is a dietary ingredient that helps protect the body from certain cancers
(Steerenberg, 1998; Eaton, 1996; Liu, 1992), viruses (Debiaggi,
1990), allergies (Pearce, 1984), and influence the metabolism of foreign chemicals in our body
(Siess, 1982; Conney, 1980).
SUMMARY REFERENCES FOR CHRYSIN
Paladini AC, Marder M, Viola H, Wolfman C, Wasowski C,
Medina JH Flavonoids and the central nervous system: from
forgotten factors to potent anxiolytic compounds. J Pharm
Pharmacol 1999 May;51(5):519-26.
Medina JH, Paladini AC, Wolfman C, Levi de Stein M, Calvo
D, Diaz LE, Pena C Chrysin (5,7-di-OH-flavone), a
naturally-occurring ligand for benzodiazepine receptors, with
anticonvulsant properties. Biochem Pharmacol 1990 Nov
15;40(10):2227-31
Wolfman C, Viola H, Paladini A, Dajas F, Medina JH Possible
anxiolytic effects of chrysin, a central benzodiazepine
receptor ligand isolated from Passiflora coerulea. Pharmacol
Biochem Behav 1994 Jan;47(1):1-4
Salgueiro JB, Ardenghi P, Dias M, Ferreira MB, Izquierdo I,
Medina JH Anxiolytic natural and synthetic flavonoid
ligands of the central benzodiazepine receptor have no effect
on memory tasks in rats. Pharmacol Biochem Behav 1997
Dec;58(4):887-91
Mitsunaga Y, Takanaga H, Matsuo H, Naito M, Tsuruo T,
Ohtani H, Sawada Y Effect of bioflavonoids on vincristine
transport across blood-brain barrier. Eur J Pharmacol 2000
May 3;395(3):193-201
Walle UK, Galijatovic A, Walle T Transport of the
flavonoid chrysin and its conjugated metabolites by the human
intestinal cell line Caco-2. Biochem Pharmacol 1999 Aug
1;58(3):431-8
Zanolil P, Avallone R, Baraldi M Behavioral
characterisation of the flavonoids apigenin and chrysin.
Fitoterapia 2000 Aug;71 Suppl 1:S117-S123
Shin JS, Kim KS, Kim MB, Jeong JH, Kim BK Synthesis and
hypoglycemic effect of chrysin derivatives. Bioorg Med
Chem Lett 1999 Mar 22;9(6):869-74
Steerenberg PA, Garssen J, Dortant P, Hollman PC, Alink GM,
Dekker M, Bueno-de-Mesquita HB, Van Loveren H Protection of
UV-induced suppression of skin contact hypersensitivity: a
common feature of flavonoids after oral administration?
Photochem Photobiol 1998 Apr;67(4):456-61
Eaton EA, Walle UK, Lewis AJ, Hudson T, Wilson AA, Walle T Flavonoids,
potent inhibitors of the human P-form phenolsulfotransferase.
Potential role in drug metabolism and chemoprevention.
Drug Metab Dispos 1996 Feb;24(2):232-7
Liu YL, Ho DK, Cassady JM, Cook VM, Baird WM Isolation
of potential cancer chemopreventive agents from Eriodictyon
californicum. J Nat Prod 1992 Mar;55(3):357-63
Debiaggi M, Tateo F, Pagani L, Luini M, Romero E Effects
of propolis flavonoids on virus infectivity and replication.
Microbiologica 1990 Jul;13(3):207-13
Pearce FL, Befus AD, Bienenstock J Mucosal mast cells.
III. Effect of quercetin and other flavonoids on
antigen-induced histamine secretion from rat intestinal mast
cells. J Allergy Clin Immunol 1984 Jun;73(6):819-23
Siess MH, Vernevaut MF The influence of food flavonoids
on the activity of some hepatic microsomal monooxygenases in
rats. Food Chem Toxicol 1982 Dec;20(6):883-6
Conney AH, Buening MK, Pantuck EJ, Pantuck CB, Fortner JG,
Anderson KE, Kappas A Regulation of human drug metabolism
by dietary factors. Ciba Found Symp 1980;76:147-67
Summary of the Medical Literature Review of 5-HTP (March 2001)(These excerpts are not inclusive of all information about the compound)
Serotonin is a natural compound in our central nervous system that has a calming effect. 5-HTP is a natural body compound that elevates the brain's serotonin level
(Birdsall, 1998). "5-HTP is well absorbed from an oral dose, with about 70 percent ending up in the bloodstream. It easily crosses the blood-brain barrier and effectively increases central nervous system (CNS) synthesis of
serotonin. In the CNS, serotonin levels have been implicated in the regulation of… anxiety….sexual
behaviour" (Birdsall, 1998). In fact, 5-HTP has been proven in animals to extend the time before ejaculation occurs. "The administration of the
[serotonin] precursor 5-hydroxytryptophan (5-HTP) … produced a dose-dependent increase in the ejaculation latency of male rats…"(Ahlenius, 1998). High doses may cause increased bowel movements, possibly diarrhea (Sanger, 2000).
SUMMARY REFERENCES FOR 5-HTP:
Birdsall TC 5-Hydroxytryptophan: a clinically-effective
serotonin precursor. Altern Med Rev 1998 Aug;3(4):271-80
Ahlenius S, Larsson K Evidence for an involvement of
5-HT1B receptors in the inhibition of male rat ejaculatory
behavior produced by 5-HTP. Psychopharmacology (Berl) 1998
Jun;137(4):374-82
den Boer JA, Westenberg HG Behavioral, neuroendocrine,
and biochemical effects of 5-hydroxytryptophan administration
in panic disorder. Psychiatry Res 1990 Mar;31(3):267-78
Hillegaart V, Ahlenius S Facilitation and inhibition of
male rat ejaculatory behaviour by the respective 5-HT1A and
5-HT1B receptor agonists 8-OH-DPAT and anpirtoline, as
evidenced by use of the corresponding new and selective
receptor antagonists NAD-299 and NAS-181. Br J
Pharmacol 1998 Dec;125(8):1733-43
Ahlenius S, Larsson K Opposite effects of
5-methoxy-N,N-di-methyl-tryptamine and 5-hydroxytryptophan on
male rat sexual behavior. Pharmacol Biochem Behav
1991 Jan;38(1):201-5
Ahlenius S, Larsson K Antagonism by lisuride and
8-OH-DPAT of 5-HTP-induced prolongation of the performance of
male rat sexual behavior. Eur J Pharmacol 1985 Apr
16;110(3):379-81
Westenberg HG, Gerritsen TW, Meijer BA, van Praag HM Kinetics
of L-5-hydroxytryptophan in healthy subjects. Psychiatry
Res 1982 Dec;7(3):373-85
Dreshfield-Ahmad LJ, Thompson DC, Schaus JM, Wong DT
Enhancement in extracellular serotonin levels by
5-hydroxytryptophan loading after administration of WAY 100635
and fluoxetine. Life Sci 2000 Apr 14;66(21):2035-41
Perry KW, Fuller RW Extracellular 5-hydroxytryptamine
concentration in rat hypothalamus after administration of
fluoxetine plus L-5-hydroxytryptophan. J Pharm
Pharmacol 1993 Aug;45(8):759-61
Semont A, Fache M, Hery F, Faudon M, Youssouf F, Hery M Regulation
of central corticosteroid receptors following short-term
activation of serotonin transmission by 5-hydroxy-L-tryptophan
or fluoxetine. J Neuroendocrinol 2000
Aug;12(8):736-44
Meyers S Use of neurotransmitter precursors for
treatment of depression.
Altern Med Rev 2000 Feb;5(1):64-71
Byerley WF, Judd LL, Reimherr FW, Grosser BI 5-Hydroxytryptophan:
a review of its antidepressant efficacy and adverse effects.
J Clin Psychopharmacol 1987 Jun;7(3):127-37
Wa TC, Burns NJ, Williams BC, Freestone S, Lee MR Blood
and urine 5-hydroxytryptophan and 5-hydroxytryptamine levels
after administration of two 5-hydroxytryptamine precursors in
normal man. Br J Clin Pharmacol 1995 Mar;39(3):327-9
Natural Medicines Comprehensive Database : Review of the Ingredients of Deferol™
IMPORTANT NOTE: This information was extracted from the Natural Medicines Comprehensive Database 2001 edition and reviewed by our pharmacists. These excerpts are intended to be a summary of, but are not inclusive of all information about each natural component.
The Natural Medicines Comprehensive Database provides up-to-date clinical data on the natural medicines, herbal medicines, and dietary supplements used in the western world. This database is compiled by pharmacists and physicians who are part of the Pharmacist's Letter and Prescriber's Letter research and editorial staff. They evaluate natural medicines by the same scientific criteria that they have used for 15 years to evaluate regular prescription and non-prescription drugs. This is the most comprehensive, scientifically based, and practical database on natural medicines available. The data in this database are referenced by thousands of references from the peer-reviewed medical literature. Natural Medicines Comprehensive Database. Edited by Jeff M. Jellin, Forrest Batz, and Kathy Hitchens (Pharmacist's Letter/Prescriber's Letter), 1310 pp, ISBN 0-9676136-2-0, Stockton, Calif, Therapeutic Research Faculty, http://www.naturaldatabase.com, http://www.pharmacistsletter.com, 1999.
PYRIDOXINE (VITAMIN B6) inclusive of Pyridoxal 5-phosphate.(These excerpts are not inclusive of all information about the compound.) Also Known As: Adermine Hydrochloride, B Complex Vitamin, Pyridoxal, Pyridoxamine, Pyridoxine Hydrochloride. Scientific Names: Pyridoxine; Vitamin B6. People Use This For: Orally, pyridoxine is used most commonly for vitamin B6 deficiency. Effectiveness: EFFECTIVE ...when taken orally for preventing and treating vitamin B6 deficiency. Mechanism of Action: Pyridoxine is required for amino acid metabolism. It is also involved in carbohydrate and lipid metabolism. In the body, pyridoxine is converted to pyridoxal phosphate and pyridoxamine phosphate, which are coenzymes in a wide variety of metabolic reactions. These reactions include transamination of amino acids, conversion of tryptophan to niacin, synthesis of gamma-aminobutyric acid (GABA) in the CNS, metabolism of serotonin, norepinephrine and dopamine, metabolism of polyunsaturated fatty acids and phospholipids, and the synthesis of heme, a hemoglobin constituent. Pyridoxine is involved with several of the reactions important for the overall metabolism of nitrogen; therefore, pyridoxine requirements are related to the total amino acid nitrogen burden to be metabolized. Pyridoxine deficiency in adults principally affects the peripheral nerves, skin, mucous membranes, and hematopoietic system. Deficiency can occur in people with uremia, alcoholism, cirrhosis, hyperthyroidism, malabsorption syndromes, and congestive heart failure; and in those receiving certain drugs. In attention-deficit hyperactivity disorder (ADHD), some children can have low serotonin levels; however, this is controversial. It's thought that pyridoxine can increase serotonin levels and might improve symptoms in some children with low serotonin levels.Drug Interactions: LEVODOPA (Larodopa): Concomitant use accelerates peripheral metabolism of levodopa, reversing the therapeutic effects. PHENYTOIN (Dilantin), PHENOBARBITAL: Concomitant use can decrease the serum concentrations of phenytoin and phenobarbital. Drug Influences on Nutrient Levels and Depletion - SOME DRUGS CAN AFFECT PYRIDOXINE LEVELS:ANTIBIOTICS: Destruction of normal gastrointestinal flora by antibiotics can cause decreased production of B vitamins. The clinical significance of this decreased production is not known.
THEOPHYLLINE (Theo-Dur): Theophylline interferes with vitamin B6 metabolism, reducing serum vitamin B6 levels. The need for vitamin B6 supplementation has not been adequately
studied.
HYDRALAZINE (Apresoline): Hydralazine can increase vitamin B6 requirements. The need for vitamin B6 supplementation has not been adequately
studied. PENICILLAMINE (Cuprimine): Penicillamine can increase vitamin B6 requirements. The need for vitamin B6 supplementation has not been adequately
studied.
ISONIAZID (INH, Rifamate): Isoniazid can increase pyridoxine requirements. Patients receiving more than 10 mg/kg/day of INH should be supplemented with 50-100 mg of pyridoxine per day Interactions with Foods: No interactions are known to occur, and there is no known reason to expect a clinically significant interaction with pyridoxine. Interactions with Lab Tests: UROBILINOGEN: Pyridoxine can cause a false positive result in the spot test with Ehrlich's reagent. Interactions with Diseases or Conditions: No interactions are known to occur, and there is no known reason to expect a clinically significant interaction with pyridoxine. Dosage and Administration - ORAL: As a dietary supplement, 2 mg per day of pyridoxine is generally considered sufficient in individuals with normal GI absorption. For vitamin B6 deficiency in women taking oral contraceptives, the dose is 25-30 mg per day. For symptoms associated with premenstrual syndrome (PMS), the daily dose is 50-100 mg. Doses as high as 500 mg per day have been used, but daily doses over 100 mg don't appear to have additional benefit, and may increase the risk for adverse effects. For kidney stones, 25-500 mg daily has been used. The daily recommended dietary allowances (RDAs) of vitamin B6 are: Infants 0-6 months, 0.1 mg; Infants 7-12 months, 0.3 mg; Children 1-3 years, 0.5 mg; Children 4-8 years, 0.6 mg; Children 9-13 years, 1 mg; Males 14-50 years, 1.3 mg; Men over 50 years, 1.7 mg; Females 14-18 years, 1.2 mg; Women 19-50 years, 1.3 mg; Women over 50 years, 1.5 mg; Pregnant women, 1.9 mg; and Lactating women, 2 mg. The recommended maximum daily intake is: Children 1-3 years, 30 mg; Children 4-8 years, 40 mg; Children 9-13 years, 60 mg; Adults, pregnant and lactating women, 14-18 years, 80 mg; and Adults, pregnant and lactating women, over 18 years, 100 mg.
Comments: Vitamin B6 is present in many foods including cereal grains, legumes, vegetables, liver, meat, and eggs. Pyridoxine is frequently used in combination with other B vitamins in vitamin B complex formulations. Vitamin B complex generally includes vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin/niacinamide), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B12 (cyanocobalamin), and folic acid. However, some products do not contain all of these ingredients and some may include others, such as biotin, para-aminobenzoic acid (PABA), choline bitartrate, and inositol.
(These
excerpts are not inclusive of all information about the
compound.)
Also Known As: B-Complex Vitamin, Folacin, Folate,
Vitamin B9.
Scientific Names: Pteroylglutamic acid;
Pteroylmonoglutamic acid;
Pteroylpolyglutamate.
People Use This For: Orally, folic acid is used for
preventing and treating folate deficiency. It is also used for
orally for preventing neural tube defects during pregnancy,
reducing the risk of colon cancer, preventing pregnancy loss,
hyperhomocystinemia, gingival hyperplasia, memory deficit,
insomnia, depression, and peripheral neuropathy. It is also
used for reducing and for preventing signs of aging, heart
attack, and stroke.
Safety: Folic acid is generally considered safe
when used in appropriate doses. It is recommended that doses
should not exceed the tolerable upper limit of 1000 mcg per
day. Although there have been conflicting findings reported,
the majority of evidence shows that folic acid 400-1000 mcg
can significantly lower homocysteine levels in people with
elevated homocysteine levels. At least 400 mcg per day of
folate seems to be necessary to simultaneously normalize or
maintain serum folate levels and decrease plasma total
homocysteine concentrations. Folic acid supplements and folic
acid-fortified cereals appear to be more effective than folate-rich
foods for reducing plasma total homocysteine concentrations.
Although folic acid lowers homocysteine levels, it’s not
clear if this results in decreased cardiovascular morbidity
and mortality. POSSIBLY EFFECTIVE ...when used orally for reducing
the risk of colon cancer.
Mechanism of Action: Folate is the general term
that refers to the various chemical forms of the vitamin.
Folic acid, or pteroylmonoglutamic acid, is the form used in
vitamin supplements and fortified foods. Folate in food is
pteroylpolyglutamate, which has a polyglutamate side chain
with peptide linkages. Folate in food is about 40% less
bioavailable than synthetic folic acid, which is almost 100%
bioavailable. Before folate from food can be absorbed, the
polyglutamate side chain must be cleaved to form the
absorbable monoglutamate form. After folic acid is absorbed,
it is converted to tetrahydrofolate. In humans,
tetrahydrofolate-based coenzymes play a major role in
intracellular metabolism. Tetrahydrofolate plays an indirect
role in the rate-limiting step in DNA synthesis. Abnormalities
in this process that occur with folic acid deficiency cause
megaloblastic anemia. Folic acid supplementation can correct
this problem. Folic acid can also reduce damage to DNA and
prevent replication errors. Tetrahydrofolate-based coenzymes
are also involved in the conversion of homocysteine to
methionine. Supplementation with folic acid increases
conversion of homocysteine to methionine, lowering
homocysteine levels and making it useful for
hyperhomocystinemia. Hyperhomocystinemia has been linked to
cardiovascular disease, and low folic acid levels have been
associated with elevated homocysteine levels and increased
risk of acute coronary events, including myocardial
infarction. Although still poorly understood, it has been
proposed that hyperhomocystinemia may alter anticoagulant
properties of endothelial cells, cause dysfunction of vascular
endothelium, or enhance lipid peroxidation. It is thought that
folic acid supplementation might decrease the risk of
cardiovascular disease through reducing plasma homocysteine
levels. It is thought that folic acid might be beneficial for
reducing coronary events because people with low serum folate
are at an increased risk for coronary events. Early evidence
suggests that folic acid alone or in combination with other B
vitamins can reduce arterial endothelial dysfunction in people
with elevated homocysteine levels. Folic acid also seems to
play an important role in pregnancy. Low folate levels have
been associated with recurrent spontaneous pregnancy loss.
However, whether folate supplementation might be beneficial in
women with histories of early pregnancy loss has not been
studied. Folic acid supplementation also prevents neural tube
defects in the fetus. But the exact role of folic acid in this
process is not completely understood. Folic acid deficiency
might play a role in Alzheimer's disease. Preliminary evidence
indicates that low folate concentrations might be related to
atrophy of the cerebral cortex, particularly in people with
neocortical lesions related to Alzheimer's disease. Low serum
folate levels have been strongly correlated to cerebral
atrophy on autopsy. Functional and mental deterioration have
been associated with low folate levels in elderly people.
Folate deficiency has also been attributed to melancholic
depression and poor response to antidepressants. Some patients
with chronic fatigue syndrome also have decreased folic acid
levels, so some people try folic acid supplements for chronic
fatigue. Crohn's disease has also been associated with
decreased folate levels. Low red blood cell folate levels have
been associated with the development of dysplasia and cancer
in ulcerative colitis. Preliminary clinical evidence suggests
folate supplementation might protect against cancer in people
with ulcerative colitis.
Adverse Reactions: Orally, high doses of folic acid
can cause altered sleep patterns, vivid dreaming,
irritability, excitability, overactivity, confusion, impaired
judgment, exacerbation of seizure frequency and psychotic
behavior, nausea, abdominal distention, flatulence, bitter
taste in the mouth, allergic skin reactions, and zinc
depletion. In one study, these effects were observed after
administration of 15 mg per day for 30 days.
Drug Interactions: PHENYTOIN (Dilantin),
FOSPHENYTOIN (Cerebyx), PRIMIDONE (Mysoline), PHENOBARBITAL:
Folic acid can increase metabolism and reduce the serum levels
of these drugs. These drugs can also affect folic acid (see
Drug Influences on Nutrient Levels and Depletion).
Drug Influences on Nutrient Levels and Depletion -
SOME DRUGS CAN AFFECT FOLIC ACID LEVELS:
ANTIBIOTICS: Destruction of normal gastrointestinal
flora by antibiotics can cause decreased production of B
vitamins. The clinical significance of this decreased
production is not known.
CARBAMAZEPINE (Tegretol): Treatment with
carbamazepine is associated with decreased folic acid levels.
However, the necessity for folic acid supplementation to
prevent peripheral neuropathies or red cell dyscrasias has not
been adequately studied.
CYCLOSERINE (Seromycin Pulvules): Use of
cycloserine can impair dietary folic acid absorption and
reduce serum folic acid levels. The need for supplementation
has not been adequately studied.}
FUROSEMIDE (Lasix): Use of furosemide might
increase the excretion of folic acid. Long-term furosemide
therapy in people with hypertension has been associated with
decreased folic acid levels and increased homocysteine levels.
Elevated homocysteine levels are associated with
atherosclerotic vascular disease, arterial and venous
thromboembolism, coronary, cerebral, and peripheral arterial
occlusive diseases, and increased risk of myocardial
infarction in smokers. However,
the need for folic acid supplementation during furosemide
therapy has not been adequately studied.
METFORMIN (Glucophage): Metformin may reduce serum
folic acid and vitamin B12 levels. A multivitamin preparation
may be valuable in some patients.
METHOTREXATE: Methotrexate binds to dihydrofolate
reductase and prevents the conversion of folate to folic acid.
Consider folic acid supplements for prolonged methotrexate
therapy.
PENTAMIDINE (NebuPent): Treatment with pentamidine
can impair dietary folic acid absorption and reduce serum
folic acid levels. The need for folic acid supplementation
during pentamidine therapy has not been adequately studied.
PHENOBARBITAL (Luminal), PRIMIDONE (Mysoline):
These drugs can impair dietary folic acid absorption and
reduce serum folic acid levels. The need for folic acid
supplementation has not been adequately studied.
PHENYTOIN (Dilantin), FOSPHENYTOIN (Cerebyx): These
drugs can reduce serum folic acid levels. Clinical evidence
suggests that giving supplemental folic acid with the initial
dose of phenytoin might prevent folic acid deficiency.
THIAZIDE DIURETICS: These drugs might increase the
excretion of folic acid. Long-term thiazide diuretic therapy
in people with hypertension has been associated with decreased
folic acid levels and increased homocysteine levels. Elevated
homocysteine levels are associated with atherosclerotic
vascular disease, arterial and venous thromboembolism,
coronary, cerebral, and peripheral arterial occlusive
diseases, and increased risk of myocardial infarction in
smokers. The need for folic acid supplementation during
thiazide diuretic therapy has not been adequately studied.
TRIMETHOPRIM (Trimpex): Trimethoprim, including
trimethoprim contained in the combination antibiotic
trimethoprim/sulfamethoxazole (TMP/SMX, Septra) can interfere
with folic acid metabolism, reduce serum folic acid levels,
and cause mild folic acid deficiency in patients on long-term
or high-dose therapy.
Interactions with Lab Tests: MEAN CORPUSCULAR
VOLUME (MCV): Folic acid supplementation can normalize
megaloblastic anemia in cases of folic acid and vitamin B12
deficiencies. In cases of vitamin B12 deficiency or pernicious
anemia, treatment with folic acid will normalize hematological findings, but will not
prevent neurological damage.
Interactions with Diseases or Conditions -
PERNICIOUS ANEMIA: Folic acid can mask pernicious anemia by
decreasing megaloblastic anemia. This can prevent appropriate
treatment with vitamin B12 and result in neurological damage.
Patients should be warned to avoid treating undiagnosed anemia
with folic acid.
SEIZURE DISORDERS: Supplemental folic acid can
exacerbate seizures in people with seizure disorders. This was
reported in a study using 800 mcg folic acid per day in
pregnant women with seizure disorders.
Dosage and Administration - ORAL: For folate
deficiency, the typical dose is 250-1000 mcg per day. For
preventing neural tube defects, 400 mcg folic acid per day
from supplements or fortified food should be taken by women capable of becoming
pregnant and continued through the first month of pregnancy.
Women with a history of previous pregnancy complicated by such
neural tube defects usually take 4 mg per day beginning one
month before and continuing for three months after conception.
For reducing colon cancer risk, 400 mcg per day has been used.
For hyperhomocystinemia and reducing atherogenesis, 400-1000
mcg per day has been used. For decreasing blood pressure and
homocysteine levels in patients with a history of stroke or
myocardial infarction, 5 mg daily has been used. For vitiligo,
5 mg is typically taken twice daily. For the reduction of
methotrexate toxicity, 5 mg a week or 1 mg daily is used.
The adequate intakes (AI) for infants are 65 mcg for
infants 0-6 months and 80 mcg for infants 7-12 months of age.
The recommended dietary allowances (RDAs) for folate in DFE,
including both food folate and folic acid from fortified foods
and supplements are: Children 1-3 years, 150 mcg; Children 4-8
years, 200 mcg; Children 9-13 years, 300 mcg; Adults over 13
years, 400 mcg; Pregnant women 600 mcg; and Lactating women,
500 mcg. The maximum daily levels of folate not likely to pose
a risk for adverse effects are 300 mcg for children 1-3 years
of age, 400 mcg for children 4-8 years, 600 mcg for children
9-13 years, 800 mcg for adolescents 14-18 years, and 1000 mcg
for everyone over 18 years of age.
Comments: Beginning in 1998, the US
government required folic acid fortification of all cold
cereals and baking flour, which extends to breads, pastas,
bakery items, cookies, crackers, etc. (6241). Foods that are
naturally high in folate content include spinach, okra,
asparagus, legumes, beef liver, and orange and tomato
juice.Folic acid is frequently used in combination with other
B vitamins in vitamin B complex formulations. Vitamin B
complex generally includes vitamin B1 (thiamine), vitamin B2
(riboflavin), vitamin B3 niacin/niacinamide), vitamin B5 (pantothenic
acid), vitamin B6 pyridoxine), vitamin B12 (cyanocobalamin),
and folic acid. However, some products do not contain all of
these ingredients and some may include others, such as biotin,
para-aminobenzoic acid (PABA), choline bitartrate, and
inositol.
5-HTP (These excerpts are not inclusive of all information about the compound.)
Also Known As: 5HTP, 5-hydroxytryptophan, L-5-Hydroxytryptophan, L-5-HTP.CAUTION: See separate listing for L-tryptophan. Scientific Names: 5-hydroxytryptophan; L-5 hydroxytryptophan. People Use This For: Orally, 5-HTP is used for sleep disorders, depression, anxiety, migraine, fibromyalgia, binge-eating associated with obesity, attention deficit disorder (ADD). POSSIBLY EFFECTIVE ...when taken orally for depression, fibromyalgia, obesity and anxiety. Mechanism of Action: 5-HTP is an intermediate metabolite in the biosynthesis of serotonin from L-tryptophan. 5-HTP readily crosses the blood-brain barrier, increasing CNS synthesis of serotonin, which effects sleep, depression, anxiety, aggression, appetite, temperature, sexual behavior, and pain sensation. Adverse Reactions: Large doses of 5-HTP can cause nausea, vomiting, diarrhea, and anorexia. 5-HTP can exacerbate
asthma.
Drug Interactions: SEROTONIN AGONISTS: Concurrent use of 5-HTP can increase the risk of adverse effects. Serotonin agonist drugs include monoamine oxidase inhibitors (MAOIs), reserpine, SSRIs, tricyclic, and atypical antidepressants.SEROTONIN ANTAGONISTS: Concurrent use of 5-HTP can decrease the effectiveness of these drugs, which include methysergide and cyproheptadine. Interactions with Foods: No interactions are known to occur, and there is no known reason to expect a clinically significant interaction with 5-HTP. Interactions with Lab Tests: No interactions are known to occur, and there is no known reason to expect a clinically significant interaction with 5-HTP. Dosage and Administration ORAL: For depression, the typical dose of 5-HTP is 150-300 mg daily. Comments: 5-HTP is often promoted for treating insomnia.
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Mechanism of
Action
The proposed physiologic mechanism of Early Ejaculation, Lack of Ejaculatory Control, or Premature Ejaculation is thought by most sexual medicine experts to be due to either decreased serotoninergic tone or increased dopaminergic tone or a combination of both. This theory is in part due to the widespread observation by physicians and other healthcare practitioners that when men are treated for clinical depression with SSRI-type prescription antidepressants, a commonly reported "side effect" was delayed ejaculation. The prevalence of delayed ejaculation as a reported "side effect" has spawned additional research into exploring different dosing regimens of existing SSRI antidepressants to minimize the other "unwanted" side effects inherent with this class of antidepressants. A principle deterrent to chronic use of SSRI prescription antidepressants is that they often produce an unacceptable decrease in libido.
(L-5HTP) The Immediate Precursor to Serotonin L-5-Hydroxytryptophan (5-HTP) is an amino acid metabolite. The body makes 5-HTP from tryptophan (an essential amino acid) and converts it to serotonin, an important neurotransmitter (brain chemical). 5-HTP dietary supplementation helps to raise serotonin levels in the brain, which may have a positive effect on the following functions and processes: sleep, mood, anxiety, aggression, and sexual behavior. Scientists believe that low levels of serotonin in the brain cause some forms of depression. Therefore, many of the anti-depressant drugs prescribed for depression increase serotonin levels. 5-HTP is reported to be as effective as some antidepressant drugs in treating some individuals with mild to moderate depression, and people treated with 5-HTP have shown improvements in mood, anxiety, insomnia, and physical symptoms.Additional background is provided by Birdsall (1998), in a review article published in Alternative Medicine Review, August 1998, entitled 5-Hydroxytryptophan: a Clinically-Effective Serotonin Precursor. L-5-Hydroxytryptophan (5-HTP) is the intermediate metabolite of the essential amino acid L-tryptophan (LT) in the biosynthesis of serotonin. Intestinal absorption of 5-HTP does not require the presence of a transport molecule, and is not affected by the presence of other amino acids; therefore it may be taken with meals without reducing its effectiveness. Unlike L-Tryptophan, 5-HTP cannot be shunted into niacin or protein production. Therapeutic use of 5-HTP bypasses the conversion of L-Tryptophan into 5-HTP by the enzyme tryptophan hydroxylase, which is the rate-limiting step in the synthesis of serotonin. 5-HTP is well absorbed from an oral dose, with about 70 percent ending up in the bloodstream. It easily crosses the blood-brain barrier and effectively increases central nervous system (CNS) synthesis of serotonin. In the CNS, serotonin levels have been implicated in the regulation of sleep, depression, anxiety, aggression, appetite, temperature, sexual behavior, and pain sensation. Therapeutic administration of 5-HTP has been shown to be effective in treating certain conditions; including depression, anxiety and sleep disturbances.
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| Deferol™ is a clinically tested oral non-prescription alternative that
assists in
controlling early ejaculation and improving climax control in men. It is a scientifically formulated combination incorporating the following five (5) synergistic dietary compounds: L-5-Hydroxytryptophan (L-5HTP), pyridoxal-5 phosphate (active form of vitamin B-6) pyridoxine (vitamin B-6), folic acid (folate) and the naturally occurring bioflavinoid (5,7 dihydroxyflavone) also known as chrysin. In addition to the bioactive dietary ingredients, each capsule contains the following inactive ingredients: magnesium stearate, rice powder, and gelatin.
Deferol
is hormone free and preservative free.
L-5-Hydroxytryptophan (L-5HTP) provides the
serotonergic neurochemical foundation for Deferol™ and is
the immediate biological precursor for serotonin (5-HT)
formation. The FDA considers L-5HTP a dietary supplement.
L-5HTP is extracted from the seed of the African plant
Griffonia simplicifolia. It is purified and concentrated in
Deferol™. L-5HTP has substantial pharmacology and safety
data published in the medical and scientific literature.
L-5HTP is designated chemically as L-5-Hydroxytryptophan.
Synonyms: L-2-Amino-3-(5-hydroxyindolyl)propionic
acid L-5-HTP Molecular
Formula: C11H12N2O3
Molecular Weight: 220.2
CAS: 145224-90-4
Form/Aspect: White
solid Comments:
Immediate precursor of serotonin,
L-aromatic amino acid decarboxylase substrate. Soluble in
water (10 mg/ml). Light sensitive
Literature References: Merck
Index, 12th ed., No. 4895.
Deferol™ Climax Control Supplement is formulated in "DSHEA-approved" size "0" capsules containing a proprietary blend of L-5-Hydroxytryptophan in conjunction with other synergistic natural compounds for oral administration. "Deferol" is imprinted in black on the upper portion of the capsule. U.S. and International Patents Pending.
Pharmacokinetics and Pharmacodynamics of L-5HTP
(L-5-Hydroxytryptophan) is somewhat slowly absorbed after oral administration, with absolute bioavailability of about 70%. The finding of a direct proportionality between the size of the oral dose level of L-5-hydroxytryptophan and the corresponding areas under the plasma concentration curves within a dosage interval at steady state strongly indicates dose-dependent, linear pharmacokinetics of the compound. The systemic availability of L-5-hydroxytryptophan exhibited an interindividual range of 47-84%, with a mean value of 69.2%+/- 4.7 S.E.M. The absorption took place at a rather slow rate as judged from times of 1.8 to 3.3 hours elapsing from administration of the compound until occurrence of the maximum measured plasma concentrations. The kinetics of L-5-hydroxytryptophan (5-HTP) were studied in five volunteers with oral administration of 5-HTP. The biological half-life of 5-HTP ranged from 2.2 to 7.4 hours, and the plasma clearance ranged from 0.10 to 0.23 1/kg/hour.
Deferol™ contains L-5HTP and other components from only the highest quality cGMP pharmaceutical & botanical raw material suppliers and manufacturers that strictly conform to U.S.P. (US Pharmacopiea) specifications for purity. Additional quality control measures ensure that our L-5HTP raw material source produces only certified Peak "X" Free product.
Synonyms: (5,7-dihydroxyflavone) Molecular Formula: C15H10O4
Molecular Weight: 254.24 CAS: 480-40-0 Comments: Melting Point (°C): 285 to 286 UV wavelength max. (nm): 348 ELINCS/EINECS Number: 207-549-7 Merck Index: 12,2316 Beilstein Index: 18,124 Reference to Aldrich Library of FT-IR Spectra: 2(2),2508C Reference to Aldrich Library of 13C and 1H NMR Spectra: 1(2),918C Literature
References: Aldrich NMR Library (60 MHz): 2(2),98A
INCLUDING THE FOLLOWING:
Required enzymatic co-factors to ensure maximal central bioconversion of L-5HTP to serotonin that also minimize dopaminergic influence on the ejaculatory response.
Synonyms: Vitamin
B6
Molecular Formula: C8H11NO3
• HCl
Molecular Weight: 205.64
CAS: 58-56-0
Purity Grade: USP
Storage Temp: Store
at RT.
Synonyms:
Pteroylglutamic acid
Vitamin M
Molecular Formula: C19H19N7O6
Molecular Weight: 441.41
Purity Grade: USP
Storage Temp: Store at RT.
Precautions
L-5HTP, a component of Deferol™ can sometimes cause mild gastrointestinal disturbances in some people. These side effects include mild nausea, heartburn, flatulence, feelings of fullness, and rumbling sensations.
Do not take Deferol™ if any of the following applies to you: If you are taking certain antidepressant drugs, such as monoamine oxidase inhibitors (MAOIs) or selective serotonin reuptake inhibitors (SSRIs), or certain other prescription medications without first consulting your physician or other healthcare provider. Do not take Deferol™ if you are taking St. John's wort.
Potential Drug Interactions
Prescription (SSRI - type) anti-depressants that potentially could interact with Deferol™ are: Prozac® (fluoxetine), Zoloft ® (sertraline), Paxil® (paroxetine), Celexa® (citalopram), Anafranil® (clomipramine), Luvox® (fluvoxamine), and some atypical antidepressants such as Remeron® (mirtazapine), Effexor® (venlafaxine), Serzone® (nefazodone) and Desyrel® (trazodone).
Tricyclic antidepressants such as amitriptyline [e.g. Elavil®,] , nortriptyline
[Norpramin® or Aventyl®], clomipramine [e.g., Anafranil®], desipramine [e.g., Pertofrane®], doxepin [e.g., Sinequan®], imipramine [e.g., Tofranil®], protriptyline [e.g., Vivactil®], trimipramine [e.g., Surmontil®]), may interact with Deferol™.
Deferol™ could interact with monoamine oxidase inhibitors such as phenelzine [e.g., Nardil®], procarbazine [e.g., Matulane®], selegiline [e.g., Eldepryl®, tranylcypromine [e.g., Parnate®].
Disclaimer
The information on this website should not in any way be used as a substitute for the advice of a physician or other licensed health care practitioner. Neither Idist Laboratories nor its affiliates shall be liable or responsible to any person or entity for any loss or damage caused, or alleged to be have been caused, directly or indirectly by the information or ideas contained, suggested, or referenced on this web site.
Copyright© 2008 Idist Laboratories, Inc. All rights reserved. Last Update: 3/12/01 We subscribe to the HONcode principles of the Health On the Net
Foundation
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Literature Review
- Abstracts Concerning the Ingredients in Deferol™
MEDLINE
LITERATURE SEARCH OF THE TERM “5-HTP”
(FIRST
500 ARTICLES ONLY)
Current
: March 2001
Altern Med Rev 1998 Aug;3(4):271-80
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5-Hydroxytryptophan: a clinically-effective serotonin
precursor.
Birdsall TC
73541.2166@compuserve.com
5-Hydroxytryptophan (5-HTP) is the intermediate metabolite of
the essential amino acid L-tryptophan (LT) in the biosynthesis
of serotonin. Intestinal absorption of 5-HTP does not require
the presence of a transport molecule, and is not affected by
the presence of other amino acids; therefore it may be taken
with meals without reducing its effectiveness. Unlike LT,
5-HTP cannot be shunted into niacin or protein production.
Therapeutic use of 5-HTP bypasses the conversion of LT into
5-HTP by the enzyme tryptophan hydroxylase, which is the
rate-limiting step in the synthesis of serotonin. 5-HTP is
well absorbed from an oral dose, with about 70 percent ending
up in the bloodstream. It easily crosses the blood-brain
barrier and effectively increases central nervous system (CNS)
synthesis of serotonin. In the CNS, serotonin levels have been
implicated in the regulation of sleep, depression, anxiety,
aggression, appetite, temperature, sexual behaviour, and pain
sensation. Therapeutic administration of 5-HTP has been shown
to be effective in treating a wide variety of conditions,
including depression, fibromyalgia, binge eating associated
with obesity, chronic headaches, and insomnia.
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Psychopharmacology (Berl)
1998 Jun;137(4):374-82
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Evidence for an
involvement of 5-HT1B receptors in the inhibition of male rat
ejaculatory behavior produced by 5-HTP.
Ahlenius S, Larsson K
Department of Physiology and Pharmacology, Karolinska
Institute, Stockholm, Sweden. sven.ahlenius@arcus.se.astra.com
The administration of the 5-hydroxytryptamine (5-HT) precursor
5-hydroxytryptophan (5-HTP) (25 mg/kg i.p.), in combination
with an inhibitor of peripheral 5-HTP decarboxylase, produced
a dose-dependent increase in the ejaculation latency of male
rats, and this effect was enhanced by additional treatment
with the 5-HT1 receptor antagonist (-)-pindolol (2 mg/kg s.c.).
The 5-HT2A/C receptor agonist (+/-)
1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.125-0.5
mg/kg s.c.) did not by itself affect male ejaculatory
behavior, but additional treatment with (-)-pindolol (2 mg/kg
s.c.) produced a dose-dependent decrease in number of
ejaculating animals. The increased ejaculation latency
produced by 5-HTP was fully antagonized by treatment with the
5-HT1B receptor antagonist isamoltane (4 mg/kg s.c.), but not
by ritanserin (2 mg/kg s.c.) treatment. The selective 5-HT1A
receptor antagonist WAY-100635 (0.15 mg/kg s.c.) enhanced the
inhibitory actions of 5-HTP on the male rat ejaculatory
behavior, and this dose of WAY-100635 fully antagonized
8-OH-DPAT-induced facilitation (0.25 mg/kg s.c.) of the
ejaculatory behavior. WAY-100635 (0.04-0.60 mg/kg s.c.) did
not, by itself, significantly affect male rat sexual behavior.
Taken together, the results suggest an inhibitory role for
postsynaptic 5-HT1B receptors in the effects produced by 5-HTP
on male rat ejaculatory behavior. Furthermore, 5-HTP-induced
inhibition of male rat ejaculatory behavior is partially
controlled by stimulation of inhibitory 5-HT1A autoreceptors,
since the effects of 5-HTP were accentuated by treatment with
(-)-pindolol, as well as by the more selective 5-HT1A receptor
antagonist WAY-100635.
Br J Pharmacol 1998 Dec;125(8):1733-43
Facilitation and inhibition of male
rat ejaculatory behaviour by the respective 5-HT1A and 5-HT1B
receptor agonists 8-OH-DPAT and anpirtoline, as
evidenced by use of the corresponding new and selective
receptor antagonists NAD-299 and NAS-181.
Hillegaart V, Ahlenius S
Department of Pharmacology, Astra
Arcus AB, Sodertalje, Sweden. viveka.hillegaart@fyfa.ki.se
1.
Ejaculatory problems and anorgasmia are well-known
side-effects of the SSRI antidepressants, and a
pharmacologically induced increase in serotonergic
neurotransmission inhibits ejaculatory behaviour in the
rat. In the
present study the role of 5-HT1A and 5-HT1B receptors in the
mediation of male rat ejaculatory behaviour was examined by
use of selective agonists and antagonists acting at these 5-HT
receptor subtypes.
2. The 5-HT1A receptor agonist 8-OH-DPAT (0.25-4.00 micromol
kg(-1) s.c.) produced an expected facilitation of the male rat
ejaculatory behaviour, and this effect was fully antagonized
by
pretreatment
with the new selective 5-HT1A receptor antagonist
(R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5
-carboxamide hydrogen (2R,3R) tartrate monohydrate (NAD-299)
(1.0
micromol
kg(-1) s.c.). NAD-299 by itself (0.75-3.00 micromol kg(-1) s.c.)
did not affect the male rat ejaculatory behaviour. 3. The
5-HT1B receptor agonist anpirtoline (0.25-4.00 micromol kg(-1)
s.c.) produced a dose-dependent inhibition of the male rat
ejaculatory behaviour, and this effect was fully antagonized
by pretreatment with the 5-HT1B receptor antagonist isamoltane
(16 micromol kg(-1) s.c.) as well as by the new and selective
antagonist
(R)-(+)-2-(3-morpholinomethyl-2H-chromene-8-yl)oxymethylmorphol
inomethansulphonate (NAS-181) (16 micromol kg(-1) s.c.).
Isamoltane (1.0-16.0 micromol kg(-1) s.c.) and NAD-181
(1.0-16.0 micromol kg(-1) s.c.) had no, or weakly facilitatory
effects on the male rat ejaculatory behaviour. The
non-selective 5-HT1 receptor antagonist (-)-pindolol (8
micromol kg(-1) s.c.), did not antagonize the inhibition
produced by anpirtoline. 4. The present results demonstrate
opposite effects, facilitation and inhibition, of male rat
ejaculatory behaviour by
stimulation of 5-HT1A and 5-HT1B receptors, respectively,
suggesting that the SSRI-induced inhibition of male
ejaculatory dysfunction is due to 5-HT1B receptor stimulation.
Pharmacol Biochem Behav 1991
Jan;38(1):201-5
Opposite effects of
5-methoxy-N,N-di-methyl-tryptamine and 5-hydroxytryptophan on
male rat sexual behavior.
Ahlenius S, Larsson K
Department of Psychology, University
of Goteborg, Sweden.
The administration of
5-methoxy-N,N-di-methyl-tryptamine (5-MeODMT), O-2.0 mg.kg-1
SC -15 min, produced a dose-dependent facilitation of the male
rat sexual behavior, as evidenced by a decrease in the number
of intromissions to ejaculation and in the ejaculation
latency. The effects produced by 5-MeODMT (1 mg.kg-1) were
antagonized by pindolol (4 mg.kg-1 SC -30 min), but not
pirenperone (0.25 mg.kg-1 SC -30 min) or metergoline (1
mg.kg-1 SC -30 min), administration. As expected, 5-HTP (25
mg.kg-1 SC -60 min) produced an increased number of mounts and
intromissions to ejaculation and an increase in the
ejaculation latency in benserazide (25 mg.kg-1 SC -90 min)
pretreated animals. Pindolol (4 mg.kg-1) by itself produced
the same effects as seen after 5-HTP administration, and the
combination of these compounds produced additive effects.
Betaxolol (8 mg.kg-1 SC -30 min) had no effects of its own and
did not interact with 5-HTP. The
results suggest that stimulation of brain 5-HT1 or 5-HT2
receptors produces facilitation and inhibition, respectively,
of the male rat sexual behavior.
Eur J Pharmacol 1985 Apr
16;110(3):379-81
Antagonism by lisuride and 8-OH-DPAT
of 5-HTP-induced prolongation of the performance of male rat
sexual behavior.
Ahlenius S, Larsson K
Both lisuride and 8-OH-DPAT dose
dependently antagonized the 5-HTP-induced inhibition of male
rat sexual behavior. The increase in the number of
intromissions and/or the ejaculation latency produced by 5-HTP, 25 mg/kg i.p. (-60 min) in
combination with the peripheral 5-HTP decarboxylase inhibitor
benserazide, 25 mg/kg i.p. (-90 min), were antagonized by
lisuride, 0.05-0.1 mg/kg i.p. (-15 min) and by 8-OH-DPAT,
0.025-0.05 mg/kg i.p. (-15 min). Thus, in this model lisuride
and 8-OH-DPAT behave as 5-HT antagonists.
Psychiatry Res 1982 Dec;7(3):373-85
Kinetics of L-5-hydroxytryptophan in
healthy subjects.
Westenberg HG, Gerritsen TW, Meijer
BA, van Praag HM
The kinetics of L-5-hydroxytryptophan
(5-HTP) were studied in five volunteers after intravenous and
oral administration of 5-HTP following pretreatment with
carbidopa. In addition, the effect of pretreatment with carbidopa on metabolism and
disposition of 5-HTP was studied in eight subjects. The
kinetics of 5-HTP following a 20-minute linear infusion are
adequately described by a biexponential function. The biological half-life of 5-HTP ranged
from 2.2 to 7.4 hours, and the plasma clearance ranged from
0.10 to 0.23 1/kg/hour. The bioavailability of 5-HTP after
oral administration in combination with carbidopa was calculated as 48% 15 (mean
SD). The plasma concentrations of 5-HTP observed in this
study displayed an unusual double peak in most subjects after
oral administration. Pretreatment with carbidopa caused a significant increase in the extent of
absorption of unchanged 5-HTP, and a significant reduction in
the area under the plasma concentration-time curves of
5-hydroxyindoleacetic acid. Gastrointestinal side effects appeared to be related to the 5-HTP
plasma concentration.
Life Sci 2000 Apr 14;66(21):2035-41
Enhancement in extracellular serotonin
levels by 5-hydroxytryptophan loading after administration of
WAY 100635 and fluoxetine.
Dreshfield-Ahmad LJ, Thompson DC,
Schaus JM, Wong DT
The Lilly Research Laboratories, Eli
Lilly and Company, Indianapolis, IN 46285, USA. dreshfield@lilly.com
It has been demonstrated that
synthesis of serotonin (5-HT) is dependent on the
availability of precursor, as well as the activity of 5-HT
neurons. In the present series of experiments, we examined the
effects of precursor (5-HTP) loading on
extracellular hypothalamic 5-HT after administration of
fluoxetine alone or in combination with WAY 100635, a
selective 5-HT1A antagonist. In the first experiment,
fluoxetine alone (10 mg/kg i.p.) caused 5-HT levels to
significantly increase to 150% of basal levels. Subsequent
administration of 5-HTP at 10, 20, and 40 mg/kg i.p. caused
5-HT levels to further increase to a maximum value of 254%,
405%, and 618%, respectively. In the second experiment, either
vehicle or WAY 100635 (1 mg/kg/hour s.c.) was infused, then
fluoxetine (10 mg/kg i.p.) and 5-HTP (10 mg/kg i.p.) were
administered. By itself, WAY 100635 led to a slight but
significant increase in hypothalamic 5-HT levels one hour
after the start of administration (130% of basal levels). In
the WAY 100635-treated group, fluoxetine caused an increase to
240% of basal levels after one hour, which rose to 290% of
basal levels after two hours. Subsequent administration of
5-HTP further increased 5-HT levels to 580% of basal levels
after one hour. In the vehicle-treated group, fluoxetine
caused an increase of 160% of basal levels which was stable over two hours, and subsequent administration of 5-HTP led to
a slight increase in 5-HT levels of 220% after one hour. These
results suggest that combining blockade of 5-HT1A
autoreceptors with 5-HT uptake inhibition results in a synergistic
increase in synthesis and release of 5-HT when precursor is
administered.
J Pharm Pharmacol 1993
Aug;45(8):759-61
Extracellular 5-hydroxytryptamine
concentration in rat hypothalamus after administration of
fluoxetine plus L-5-hydroxytryptophan.
Perry KW, Fuller RW
Lilly Research Laboratories, Eli Lilly
and Company, Indianapolis, IN 46285.
Fluoxetine (10 mg kg-1, i.p.) caused a
three- to fourfold increase in extracellular
5-hydroxytryptamine (5-HT) concentration measured by
microdialysis in hypothalamus of freely moving rats. The
addition of L-5-hydroxytryptophan at 20 or 40 mg
kg-1, i.p. doses, magnified the increase in extracellular 5-HT
to as much as 16 times basal levels, although these doses of
L-5-hydroxytryptophan alone had only small effects on extracellular 5-HT. The
increased formation of 5-HT following L-5-hydroxytryptophan
administration appears to overcome homeostatic mechanisms that
limit the increases in extracellular 5-HT caused by uptake
inhibition.
J Neuroendocrinol 2000
Aug;12(8):736-44
Regulation of central corticosteroid
receptors following short-term activation of serotonin
transmission by 5-hydroxy-L-tryptophan or fluoxetine.
Semont A, Fache M, Hery F, Faudon M,
Youssouf F, Hery M Laboratoire des Interactions
fonctionnelles en Neuroendocrinologie,
INSERM U501, Universite de la
Mediterranee, IFR Jean-Roche, UER de Medecine Nord, Marseille, France.
Alterations of the
hypothalamic-pituitary-adrenal (HPA) axis function
characterized by a decreased negative feedback capacity are
often associated with affective disorders and are corrected by
treatment with antidepressant drugs. To gain a better
understanding of the effects of the antidepressant drug
fluoxetine, a specific serotonin (5-HT) reuptake inhibitor, on
central corticosteroid receptors, the effects of short-term
activation of serotonin transmission on central corticosteroid
receptor expression were analysed in adrenalectomized (ADX)
rats either supplemented or not with corticosterone. Serotonin
transmission was stimulated either by a single injection of
the 5-HT precursor, 5-hydroxy-L-tryptophan (5-HTP), or by a
2-day treatment with fluoxetine. In ADX rats, administration
of 5-HTP decreased hippocampal
mineralocorticoid (MR) and glucocorticoid (GR) receptor
numbers 24 h later, while their respective mRNAs were
unchanged and these effects of 5-HTP were mediated by 5-HT2
receptors. In the hypothalamus, GR mRNAs and binding sites
decreased 3 h and 24 h after 5-HTP, respectively. By contrast, fluoxetine treatment
increased hippocampal MR and GR mRNAs and MR binding sites
while GR number remained unchanged. In ADX rats supplemented
with corticosterone, 5-HTP and fluoxetine treatment had the
same effects on corticosteroid receptors compared to those
observed in non supplemented ADX rats: 5-HTP decreased
hippocampal MR and GR and hypothalamic GR while fluoxetine
treatment increased hippocampal MR. These results show that
short-term stimulation of 5-HT transmission by 5-HTP decreases hippocampal and
hypothalamic corticosteroid receptor numbers through a
corticosterone-independent mechanism. It is hypothesized that
the delayed maximal increase in extracellular 5-HT contents after fluoxetine treatment,
due to negative feedback regulations induced by the activation
of 5-HT1A and 5-HT1B autoreceptors, is not the primary cause
for the delayed normalization of
corticosteroid receptor numbers that regulates the HPA axis
functioning.
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Altern Med Rev 2000 Feb;5(1):64-71
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Use of
neurotransmitter precursors for treatment of depression.
Meyers S Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
spmeyers@lbl.gov
Insufficient activity of the neurotransmitters serotonin and
norepinephrine is a central element of the model of depression
most widely held by neurobiologists today. In the late 1970s
and 1980s, numerous studies were performed in which depressed
patients were treated with the serotonin precursors L-tryptophan
and 5-hydroxytryptophan (5-HTP), and the dopamine and
norepinephrine precursors tyrosine and L-phenylalanine. This
article briefly reviews the published research on the efficacy
of neurotransmitter precursors in treating depression,
highlights the findings of studies, and discusses issues
regarding the interpretation of those findings. The nature of
the studies makes it difficult to draw firm conclusions
regarding the efficacy of neurotransmitter precursors for
treating depression. While there is evidence that precursor
loading may be of therapeutic value, particularly for the
serotonin precursors 5-HTP and tryptophan, more studies of
suitable design and size might lead to more conclusive
results. However, the evidence suggests neurotransmitter
precursors can be helpful in patients with mild or moderate
depression.
J Clin Psychopharmacol 1987
Jun;7(3):127-37
5-Hydroxytryptophan: a review of its
antidepressant efficacy and adverse effects.
Byerley WF, Judd LL, Reimherr FW,
Grosser BI
Alterations in serotonin metabolism
may be an important factor in the etiology and treatment of
depression. In this regard, 5-hydroxytryptophan (5-HTP), a
serotonin precursor, has been given to patients with depression. Although a
review of these studies suggests that 5-HTP possesses
antidepressant properties, additional trials are clearly
indicated. Following a discussion of the pharmacology of
5-HTP, the authors highlight adverse effects associated with
its administration to depressed patients, neurologic
subjects, and normal individuals. Relatively few adverse
effects are associated with its use in the treatment of
depressed patients.
Br J Clin Pharmacol 1995
Mar;39(3):327-9
Blood and urine 5-hydroxytryptophan
and 5-hydroxytryptamine levels after administration of two
5-hydroxytryptamine precursors in normal man.
Wa TC, Burns NJ, Williams BC,
Freestone S, Lee MR
Department of Medicine, Royal
Infirmary, Edinburgh.
Six healthy male subjects received
equimolar amounts of two 5-hydroxytryptamine (5-HT)
precursors, 5-hydroxy-L-tryptophan (5-HTP) and
gamma-L-glutamyl-5-hydroxy-L-tryptophan (glu-5-HTP), on two occasions in a randomised cross-over
study. There were marked increases in urinary 5-HTP and 5-HT
excretion after infusion of both compounds. Mean urinary
excretion rate of 5-HT, which was < 0.7 nmol min-1 before
dosing, rose to a peak value of 412 92 nmol min-1 at the
end of 5-HTP infusion and 303 29 nmol min-1 after
administration of glu-5-HTP. This occurred without
significant changes in blood 5-HT levels measured in platelet-rich
plasma. These findings provide further evidence that the
increase in urine 5-HT after administration of both 5-HT
precursors is largely due to 5-HT synthesised within the
kidney.
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J Neural Transm Gen Sect
1995;102(2):91-7
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Pyridoxine effect on synthesis rate of serotonin in the monkey
brain measured with positron emission tomography.
Hartvig P, Lindner KJ, Bjurling P, Laengstrom B, Tedroff J
Uppsala University PET Centre, Uppsala, Sweden.
The influence of the co-factor pyridoxine, vitamin B6, on the
activity of aromatic amino acid decarboxylase enzyme was
studied by positron emission tomography, PET in the brain of
the Rhesus monkey using the precursor for serotonin synthesis
5-hydroxy-L-tryptophan (5-HTP) radiolabelled with 11C in the
beta-position. The rate constant for the formation of
serotonin in the corpus striatum was calculated using a two
tissue compartment model with reference area in the brain. In
baseline investigations, the mean rate constants (+/-S.D:) for
selective utilization of [11C]5-HTP to form [11C]serotonin in
the corpus striatum was 0.0080 +/- 0.0011 min(-1).
Pretreatment with intravenous pyridoxine hydrochloride 10
mg/kg bodyweight before doing a second PET study resulted in
an enhanced rate constant by a mean of 20%. The rate increase
was statistically significant. The increase varied
considerably in different monkeys from no effect to more than
60%. The effect of pyridoxine on aromatic amino acid
decarboxylase activity supported a regulatory role of
pyridoxine on the synthesis of neurotransmitter in vivo, and
may be of importance in diseases with deficiencies in
neurotransmitter function.
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Brain Res 1993 Sep 24;623(1):72-6
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Sensory responsiveness of brain noradrenergic neurons is
modulated by endogenous brain serotonin.
Shiekhattar R, Aston-Jones G
Department of Mental Health Sciences, Hahnemann University,
Philadelphia, PA 19102.
Previous results have indicated that application of serotonin
(5-HT) onto noradrenergic locus coeruleus (LC) neurons
selectively attenuates the response of these cells to
excitatory amino acids (EAAs). Other studies revealed that
certain sensory responses of LC neurons are mediated by EAA
inputs. We examined the role of endogenous 5-HT in modulating
sensory responses of LC neurons that are EAA-mediated. LC
neurons recorded in rats pretreated with the serotonin (5-HT)
depletor, p-chlorophenylalanine (PCPA), exhibited increased
responsiveness to electrical stimulation of a rear footpad.
Conversely, injection of the 5-HT precursor,
5-hydroxytryptophan (5-HTP), reversed this effect of PCPA and
attenuated this sensory response of LC neurons in drug-naive
animals. Neither treatment altered the spontaneous discharge
rate of LC neurons. These results are consistent with previous
findings indicating that 5-HT has potent but selective effects
on EAA-mediated responses of LC neurons, and in addition point
to a possible functional role for endogenous 5-HT in
controlling sensory-evoked LC activity.
J Neurol Neurosurg Psychiatry 2000
Aug;69(2):228-32
Homocysteine, folate, methylation, and
monoamine metabolism in depression.
Bottiglieri T, Laundy M, Crellin R,
Toone BK, Carney MW, Reynolds EH Department of Neurology, King's
College Hospital, London, UK.
OBJECTIVES: Previous studies suggest
that folate deficiency may occur in up to one third of
patients with severe depression, and that treatment with the
vitamin may enhance recovery of the mental state. There are, however, difficulties in interpreting
serum and red cell folate assays in some patients, and it has
been suggested that total plasma homocysteine is a more
sensitive measure of functional folate (and vitamin B12)
deficiency. Other studies suggest a link between folate
deficiency and impaired metabolism of serotonin, dopamine, and
noradrenaline (norepinephrine), which have been implicated in
mood disorders. A study of
homocysteine, folate, and monoamine metabolism has, therefore,
been undertaken in patients with severe depression. METHODS:
In 46 inpatients with severe DSM III depression, blood counts,
serum and red cell folate, serum vitamin B12, total plasma
homocysteine, and, in 28 patients, CSF folate, S-adenosylmethionine,
and the monoamine neurotransmitter metabolites 5HIAA, HVA, and
MHPG were examined. Two control groups comprised 18 healthy
volunteers and 20 patients with neurological disorders, the
second group undergoing CSF examination for diagnostic
purposes. RESULTS: Twenty four depressed patients (52%) had
raised total plasma homocysteine. Depressed patients with
raised total plasma homocysteine had significant
lowering of serum, red cell, and CSF folate, CSF S-adenosylmethionine
and all three CSF monoamine metabolites. Total plasma
homocysteine was significantly negatively correlated with red
cell folate in depressed patients, but not controls.
CONCLUSIONS: Utilising total plasma homocysteine as a
sensitive measure of functional folate deficiency, a
biological subgroup of depression with folate deficiency,
impaired methylation, and monoamine neurotransmitter
metabolism has been identified. Detection of this subgroup,
which will not be achieved by routine blood counts, is
important in view of the potential benefit of vitamin
replacement.
Nutr Rev 1997 May;55(5):145-9
Nutrition and depression: the role of folate.
Alpert JE, Fava M
Department of Psychiatry, Harvard
Medical School, Boston, MA 02114, USA.
A relationship between folate and
neuropsychiatric disorders has been inferred from clinical
observation and from the enhanced understanding of the role of
folate in critical brain metabolic pathways. Depressive symptoms are the most common
neuropsychiatric manifestation of folate deficiency.
Conversely, borderline low or deficient serum or red blood
cell folate levels have been detected in 15-38% of adults
diagnosed with depressive disorders. Recently, low folate
levels have been linked to poorer antidepressant response to
selective serotonin reuptake inhibitors. Factors contributing
to low serum folate levels among depressed patients as well as the
circumstances under which folate and its derivatives may have
a role in antidepressant pharmacotherapy must be further
clarified.
MEDLINE LITERATURE
SEARCH OF THE TERM “CHRYSIN”
Current: March 2001
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J Pharm Pharmacol 1999
May;51(5):519-26
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Flavonoids and the central nervous system: from forgotten
factors to potent anxiolytic compounds.
Paladini AC, Marder M, Viola H, Wolfman C, Wasowski C, Medina
JH
Instituto de Quimica y Fisicoquimica Biologicas, Facultad de
Farmacia y Bioquimica, Buenos Aires, Argentina.
The list of activities of plant flavonoids did not include
effects on the central nervous system (CNS) up to 1990, when
our laboratory described the existence of natural anxiolytic
flavonoids. The first of these was chrysin
(5,7-dihydroxyflavone), followed by apigenin
(5,7,4'-trihydroxyflavone) and flavone itself. Semisynthetic
derivatives of flavone obtained by introducing halogens, nitro
groups or both in its molecule, give rise to high affinity
ligands for the benzodiazepine receptor, active in-vivo;
6,3'-dinitroflavone, for example, is an anxiolytic drug 30
times more potent than diazepam. The data collected in this
paper make clear that some natural flavonoids are CNS-active
molecules and that the chemical modification of the flavone
nucleus dramatically increases their anxiolytic potency.
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Biochem Pharmacol 1990 Nov
15;40(10):2227-31
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Chrysin (5,7-di-OH-flavone), a naturally-occurring ligand for
benzodiazepine receptors, with anticonvulsant properties.
Medina JH, Paladini AC, Wolfman C, Levi de Stein M, Calvo D,
Diaz LE, Pena C
Instituto de Biologia Celular, Facultad de Medicina, Buenos
Aires, Argentina.
Chrysin (5,7-di-OH-flavone) was identified in Passiflora
coerulea L., a plant used as a sedative in folkloric medicine.
Chrysin was found to be a ligand for the benzodiazepine
receptors, both central (Ki = 3 microM, competitive mechanism)
and peripheral (Ki = 13 microM, mixed-type mechanism).
Administered to mice by the intracerebroventricular route,
chrysin was able to prevent the expression of tonic-clonic
seizures induced by pentylenetertrazol. Ro 15-1788, a central
benzodiazepine receptor antagonist, abolished this effect. In
addition, all of the treated mice lose the normal righting
reflex which suggests a myorelaxant action of the flavonoid.
The presence in P. coerulea of benzodiazepine-like compounds
was also confirmed.
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Pharmacol Biochem Behav 1994
Jan;47(1):1-4
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Possible anxiolytic effects of chrysin, a central
benzodiazepine receptor ligand isolated from Passiflora
coerulea.
Wolfman C, Viola H, Paladini A, Dajas F, Medina JH
Instituto de Biologia Celular, Facultad de Medicina, UBA,
Argentina.
The pharmacological effects of 5,7-dihydroxyflavone (chrysin),
a naturally occurring monoflavonoid that displaces
[3H]flunitrazepam binding to the central benzodiazepine (BDZ)
receptors, were examined in mice. In the elevated plus-maze
test of anxiety, diazepam (DZ, 0.3-0.6 mg/kg) or chrysin (1
mg/kg) induced increases in the number of entries into the
open arms and in the time spent on the open arms, consistent
with an anxiolytic action of both compounds. The effects of
chrysin on the elevated plus-maze was abolished by
pretreatment with the specific BDZ receptor antagonist Ro
15-1788 (3 mg/kg). In the holeboard, diazepam (1 mg/kg) and
chrysin (3 mg/kg) increased the time spent head-dipping. In
contrast, high doses of DZ (6 mg/kg) but not of chrysin
produced a decrease in the number of head dips and in the time
spent head-dipping. In the horizontal wire test, diazepam (6
mg/kg) had a myorelaxant action. In contrast, chrysin (0.6-30
mg/kg) produced no effects in this test. These data suggest
that chrysin possesses anxiolytic actions without inducing
sedation and muscle relaxation. We postulate that this natural
monoflavonoid is a partial agonist of the central BDZ
receptors.
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Pharmacol Biochem Behav 1997
Dec;58(4):887-91
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Anxiolytic natural and synthetic flavonoid ligands of the
central benzodiazepine receptor have no effect on memory tasks
in rats.
Salgueiro JB, Ardenghi P, Dias M, Ferreira MB, Izquierdo I,
Medina JH
Centro de Memoria, Departamento de Bioquimica, I.C.B.S.,
Universidade Federal do Rio Grande do Sul, Porto Alegre,
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