Phytochemical info of Passiflora,Passiona Flower,Passion Flower Extract.:
Product Name:
Synonym:
Definition: Passion Flower Extract are majorly composed of
Chemical information disclosed as following table:
Research update of Passiflora,Passiona Flower,Passion Flower Extract,Flavonoids.:
Passiflora: a review update.:
J Ethnopharmacol. 2004; 94(1):1-23 (ISSN: 0378-8741)Dhawan K; Dhawan S; Sharma A.Department of Drugs Control Administration, Government of Haryana State, Sector-6, Panchkula 134109, India. kdd@glide.net.in
This review describes the morphology, microscopy, traditional and folklore uses, phyto-constituents, pharmacological reports, clinical applications and toxicological reports of the prominent species of the genus Passiflora. Flavonoids, glycosides, alkaloids, phenolic compounds and volatile constituents have been reported as the major phyto-constituents of the Passiflora species. A few species of Passiflora have been used for curing various ailments, the most important being Passiflora incarnata Linneaus which possesses significant CNS depressant properties. The studies performed by the authors with the newly isolated benzoflavone (BZF) moiety from P. incarnata have been discussed. In the concluding part, various virgin areas of research on the species of this genus have been highlighted with a view to explore, isolate and identify the medicinally important phyto-constituents which could be utilized to alleviate various diseases affecting the mankind.
Hypnotic activities of chamomile and passiflora extracts in sleep-disturbed rats.:
Biol Pharm Bull. 2005; 28(5):808-10 (ISSN: 0918-6158)
In the present study, we investigated hypnotic activities of chamomile and passiflora extracts using sleep-disturbed model rats. A significant decrease in sleep latency was observed with chamomile extract at a dose of 300 mg/kg, while passiflora extract showed no effects on sleep latency even at a dose of 3000 mg/kg. No significant effects were observed with both herbal extracts on total times of wakefulness, non-rapid eye movement (non-REM) sleep and REM sleep. Flumazenil, a benzodiazepine receptor antagonist, at a dose of 3 mg/kg showed a significant antagonistic effect on the shortening in sleep latency induced by chamomile extract. No significant effects were observed with chamomile and passiflora extracts on delta activity during non-REM sleep. In conclusion, chamomile extract is a herb having benzodiazepine-like hypnotic activity.
Evaluation of anxiolytic activity of spray dried powders of two South Brazilian Passiflora species.:
Phytother Res. 2006; 20(5):348-51 (ISSN: 0951-418X).Reginatto FH; De-Paris F; Petry RD; Quevedo J; Ortega GG; Gosmann G; Schenkel EP.Faculdade de Farm??cia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. flavio@saude.upf.br
The Passiflora extracts have been used in folk medicine because of its reputed sedative and anxiolytic properties. The present study aimed to compare the potential anxiolytic activity of two Passiflora spray-dried powders obtained from P. alata and P. edulis, known in Brazil as 'maracuj??'. Male adult Swiss rats were treated with 200, 400 and 800 mg/kg of spray-dried powders p.o. and anxiolytic activity was evaluated using the elevated plus-maze test. The spray-dried powders showed anxiolytic activity in doses of 400 and 800 mg/kg. Our results support the potential anxiolytic effect of Passiflora spray-dried powders (P. alata and P. edulis).
Preliminary evaluation of inhibition of matrix-metalloprotease MMP-2 and MMP-9 by Passiflora edulis and P foetida aqueous extracts.:
Fitoterapia. 2003; 74(3):302-4 (ISSN: 0367-326X).Puricelli L; Dell'Aica I; Sartor L; Garbisa S; Caniato R.Dipartimento di Biologia, V le G Colombo 3, Padova 35131, Italy.
Fruit's decoctions of Passiflora edulis and P. foetida var. albiflora were evaluated for the inhibition of activity of gelatinase MMP-2 and MMP-9, two metallo-proteases involved in the tumour invasion, metastasis and angiogenesis. Both water extracts, at different concentrations, inhibited the enzymes.
Drug/substance reversal effects of a novel tri-substituted benzoflavone moiety (BZF) isolated from Passiflora incarnata Linn.--a brief perspective.:
Addict Biol. 2003; 8(4):379-86 (ISSN: 1355-6215).Dhawan K.University Institute of Pharmaceutical Sciences, Panjab Univesity, Chandigarh, India. kdd@glide.net.in
The present work is a mini-review of the author's original work on the plant Passiflora incarnata Linn., which is used in several parts of the world as a traditional medicine for the management of anxiety, insomnia, epilepsy and morphine addiction. A tri-substituted benzoflavone moiety (BZF) has been isolated from the bioactive methanol extract of this plant, which has been proposed in the author's earlier work to be responsible for the biological activities of this plant. The BZF moiety has exhibited significantly encouraging results in the reversal of tolerance and dependence of several addiction-prone psychotropic drugs, including morphine, nicotine, ethanol, diazepam and delta-9-tetrahydrocannabinol, during earlier pharmacological studies conducted by the author. In addition to this, the BZF moiety has exhibited aphrodisiac, libido-enhancing and virility-enhancing properties in 2-year-old male rats. When administered concomitantly with nicotine, ethanol and delta-9-tetrahydrocannabinol for 30 days in male rats, the BZF also prevented the drug-induced decline in sexuality in male rats. Because the BZF moiety isolated from P. incarnata is a tri-substituted derivative of alpha-naphthoflavone (7,8-benzoflavone), a well-known aromatase-enzyme inhibitor, the mode of action of BZF has been postulated to be a neurosteroidal mechanism vide in which the BZF moiety prevents the metabolic degradation of testosterone and upregulates blood - testosterone levels in the body. As several flavonoids (e.g. chrysin, apigenin) and other phytoconstituents also possess aromatase-inhibiting properties, and the IC50 value of such phytomoieties is the main factor determining their biochemical efficacy, by altering their chemical structures to attain a desirable IC50 value new insights in medical therapeutics can be attained, keeping in view the menace of drug abuse worldwide.
Wien Med Wochenschr. 2002; 152(15-16):404-6 (ISSN: 0043-5341)Krenn L.Institut f??r Pharmakognosie, Universit??t Wien, Althanstrasse 14, A-1090 Wien. Liselotte.Kren@univie.ac.at
Extracts and fluid extracts from the aerial parts from Passiflora incarnata L. are widely used as components of herbal sedatives. Many pharmacological investigations confirm the sedative effects of Passiflorae herba. From some of the studies also anxiolytic effects can be deduced. As Passionflower is mainly used in combinations, clinical studies of the single drug are not available. Based on pharmacological data, the experiences of traditional use and the use in combinations Passiflora extracts are an important factor in the phytotherapy of tenseness, restlessness and irritability with difficulty in falling asleep.
Quantification of the flavonoid glycosides in Passiflora incarnata by capillary electrophoresis.:
Planta Med. 2003; 69(5):452-6 (ISSN: 0032-0943)Marchart E; Krenn L; Kopp B.Institute of Pharmacognosy, University of Vienna, Vienna, Austria.
Capillary electrophoresis has been applied for the separation and quantification of the flavonoids in Passiflorae herba. Separations were performed using 25 mM sodium borate with 20 % methanol (pH 9.5). For the quantification quercetin 3-O-arabinoside was used as internal standard. The method was applied to the determination of the flavonoid glycosides in 10 different commercial samples of the drug and showed similar flavonoid patterns, but differences concerning the single and total amounts of flavonoids. The total flavonoid contents determined with the new method correlated satisfactorily with those achieved by the spectrophotometric assay according to the European Pharmacopoeia.
Toxicity of Passiflora incarnata L.:
J Toxicol Clin Toxicol. 2000; 38(1):63-6 (ISSN: 0731-3810).Fisher AA; Purcell P; Le Couteur DG.The Canberra Hospital, Garran, Australia.
BACKGROUND: Herbal medicines may have significant adverse effects which are not suspected or recognized. CASE REPORT: A 34-year-old female developed severe nausea, vomiting, drowsiness, prolonged QTc, and episodes of nonsustained ventricular tachycardia following self-administration of a herbal remedy, Passiflora incarnata L., at therapeutic doses. The possible association of symptoms with passiflora was not recognized for several days. She required hospital admission for cardiac monitoring and intravenous fluid therapy. CONCLUSIONS: Passiflora incarnata was associated with significant adverse effects in this patient. It is important to ask specifically about the use of herbal medicines in patients with undiagnosed illnesses.
Plants and the central nervous system.:
Pharmacol Biochem Behav. 2003; 75(3):501-12 (ISSN: 0091-3057).Carlini EA.Department of Psychobiology, Paulista School of Medicine, Federal University of S??o Paulo, Rua: Botucatu, 862 Ed. Ci??ncias Biom??dicas, 1o andar, CEP 04023-062, S??o Paulo, SP, Brazil. carlini@psicobio.epm.br
This review article draws the attention to the many species of plants possessing activity on the central nervous system (CNS). In fact, they cover the whole spectrum of central activity such as psychoanaleptic, psycholeptic and psychodysleptic effects, and several of these plants are currently used in therapeutics to treat human ailments.Among the psychoanaleptic (stimulant) plants, those utilized by human beings to reduce body weight [Ephedra spp. (Ma Huang), Paullinia spp. (guaran??), Catha edulis Forssk. (khat)] and plants used to improve general health conditions (plant adaptogens) were scrutinized.Many species of hallucinogenic (psychodysleptic) plants are used by humans throughout the world to achieve states of mind distortions; among those, a few have been used for therapeutic purposes, such as Cannabis sativa L., Tabernanthe iboga Baill. and the mixture of Psychotria viridis Ruiz and Pav. and Banisteriopsis caapi (Spruce ex Griseb.) C.V. Morton. Plants showing central psycholeptic activities, such as analgesic or anxiolytic actions (Passiflora incarnata L., Valeriana spp. and Piper methysticum G. Forst.), were also analysed.Finally, the use of crude or semipurified extracts of such plants instead of the active substances seemingly responsible for their therapeutic effect is discussed.
Passionflower fruit-a "new" source of lycopene?.:
J Med Food. 2005; 8(1):104-6 (ISSN: 1096-620X).Mourvaki E; Gizzi S; Stefania G; Rossi R; Rufini S.Department of Clinical and Experimental Medicine, Division of Pharmacology, University of Perugia, Perugia, Italy.
Many population studies have established a link between dietary intake of the carotenoid antioxidant lycopene and a reduced risk of chronic diseases. Unlike most carotenoids, lycopene occurs in a few places in the diet. Besides tomatoes and tomato products, major sources of lycopene, other lycopene-rich foods include watermelon, pink grapefruit, pink guava, and papaya. Dried apricots and pureed rosehips contain relatively large amounts, too. In our study we found that passionflower fruit (skin and pericarp) contains a great amount of lycopene, whereas the content of other carotenoids is very low, and almost inexistent. This edible fruit could be an alternative source of a potential important nutrient for those people who do not eat tomatoes and tomato products.
Phytochemicals as means to induce sleep.:
Z Arztl Fortbild Qualitatssich. 2001; 95(1):33-4 (ISSN: 1431-7621)Volz HP.Psychiatrische Klinik der Friedrich-Schiller-Universit??t Jena. volz@landgraf.med.uni-jena.de
Phytopharmacons are widely used in Germany. Whereas St. John's wort extracts are prescribed for the treatment of mild forms of depression and kava-kava for unspecified anxiety syndromes, hop, balm, lavender, passiflora and valerian are traditionally administered against nervousness and sleep disturbances. Controlled clinical trials are only available for valerian. However, no sleep inducing potential of valerian was observed, only a certain positive effect on daytime mood. Therefore, the mentioned phytopharmacons cannot be recommended for the treatment of sleep disturbances.
Nature medicine as intoxicant.:
Tidsskr Nor Laegeforen. 1997; 117(8):1140-1 (ISSN: 0029-2001).Solbakken AM; R??rbakken G; Gundersen T.Aust-Agder sentralsykehus, Arendal.
Documentation is often scarce about adverse effects of herbal products used in alternative medicine. Five patients were admitted to hospital with altered consciousness after taking the herbal product Relaxir, a remedy for insomnia and restlessness, produced mainly from the fruit from the passion flower (Passiflora incarnata). Relaxir is thought to have an intoxicating and sedative effect and may also potentiate the effect of other drugs. It is questionable that herbal products liable to cause intoxication are sold without restriction.
Clinical Update - Management of Insomnia in the Primary Care Practice.:
In part 1 of this review in the last edition of Current Perspectives in Insomnia, Volume 1, we introduced 2 patients who were having trouble sleeping and discussed the approach to diagnosis in the primary care setting. Part 2 addresses management strategies.
Stepwise Treatment for Insomnia
The first patient is a 35-year-old woman who works as a corporate attorney. She doesn't smoke, has about 2 or 3 drinks a week, and is recently engaged to be married. She reports difficulty concentrating and daytime fatigue. These symptoms worsen during times of stress, such as when she is faced with deadlines. She goes to bed at about 11 pm but reports that she lies awake for hours staring at her alarm clock. She finally falls asleep at about 2 am.
The second patient is a 45-year-old man who is as an emergency department nurse. He works 12-hour shifts -- from 8 to 8, rotating from night to day on a 3-week schedule. He has osteoarthritis in his right shoulder from an old sports injury. He says he treats the shoulder pain with over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs), as needed. He also said he uses antacid medication for frequent heartburn. He reports having difficulty falling asleep when he is working the night shift and notes that his reflux also worsens when he works nights.
Generally, he reports good sleep quality when working the day shift, except when his shoulder pain worsens.
Treatment of insomnia should, insofar as possible, be directed at identifiable causes or those factors that perpetuate the disorders, such as temperament and lifestyle, ineffective coping and defense mechanisms, inappropriate use of alcohol or other substances,maladaptive sleep-wake schedules, and excessive worry about poor sleep. The harder these individuals try to sleep, the worse the problem becomes. Typically, these patients keep themselves awake wrestling with their apprehensions: "If I don't get to sleep right now, I'll make a bad impression tomorrow."
Many patients may benefit from an initial trial of behavioral therapy for insomnia.
Treatments for Psychophysiologic Insomnia
The 3 main, contemporary behavioral treatments of insomnia are:
Sleep-hygiene techniques;
Stimulus control instructions; and Sleep-restriction therapy.
All 3 approaches attempt to correct sleep-preventing associations and to provide education about sleep to the patient.
Sleep-Hygiene Techniques:
In 1977, Dr. Peter Hauri reviewed the existing sleep literature and translated the findings into a basic set of sleep-promoting rules. Since that time, these "rules" have formed the basis for sleep-hygiene techniques, which, in turn, are incorporated in both stimulus control instructions and sleep-restriction therapy:
Rule 1: Limit time in bed, which leads to decreased sleep-onset latency.
Rule 2: Never try to sleep, because actively pursuing sleep increases arousal, which decreases the likelihood of sleep. Rather than trying to sleep, patients are told to engage in a relatively monotonous activity, such as reading or watching television
Rule 3: Remove time pressure by moving the alarm clock to another room.
Rule 4: Exercise in the late afternoon or early evening. The timing of the exercise is crucial because it relates to circadian rhythms. People sleep better when the body's core temperature decreases as part of the circadian rhythm. Exercise causes the body's core temperature to rise, which is then followed by a temperature drop about 5-6 hours after exercise. The goal of the late afternoon-early evening exercise is to create an artificial temperature trough at bedtime to aid sleep.
Rule 5: Avoid all stimulants and alcohol.
Rule 6: Regularize bedtime and wake-up time.
Rule 7: Eat a light bedtime snack. There are 2 possible mechanisms by which the bedtime snack may be useful: Digestive hormones may have a sedative effect and/or the conversion of tryptophan into serotonin may promote sleep.
One difference in Hauri's approach is the recommendation to experiment with napping. Although many sleep researchers caution that daytime napping is counterproductive when attempting to entrain sleep patterns, Hauri suggests that elderly patients may actually benefit from daytime napping. He notes, however, that napping should be carefully monitored with sleep diaries and suggests that a 1-week trial is sufficient to determine whether naps will benefit overall sleep quality.
Stimulus Control Instructions:
Stimulus control, which was first proposed by Dr. Richard Bootzin in 1972, uses a set of 6 tools that provide a logical basis for good sleep. Patients are first instructed to attempt sleep only when sleepy, rather than following a strict timetable for sleep. This first rule is aimed at eliminating frustration that comes from unsuccessful sleep attempts while sensitizing the patient to his/her internal cues of sleepiness, such as head nods or droopy eyes.
The second instruction requires that the bedroom and bed be restricted to sleep alone -- no television, radio, music, or discussions of daily events.The third instruction or rule requires that the patient get out of bed if he/ she is unable to sleep. Again, this short-circuits frustration and arousal caused by unsuccessful attempts at sleep. Rather than tossing and turning, patients are told to leave the bedroom and engage in relatively unstimulating tasks. They are instructed to return to the bedroom only when they feel sleepy again. This instruction is often the most difficult to carry out because many insomniacs have a developed a pattern of clinging to the bed at all costs.
The fourth rule is simply a repeat of the third instruction. If the sleep attempt is not successful following step 3, the patient is told to again leave the bed, engage in nonstimulating activities, and return to bed only when sleepy. This process, according to Bootzin, may be repeated several times during the night.The fifth instruction is to get up at the same time every morning regardless of the quality of sleep during the night. This avoids a common practice among insomniacs -- seeking to make up for a lack of nighttime sleep by sleeping later in the morning, a practice that worsens sleep latency the following night. The sixth and final rule is to avoid all daytime napping. These last 2 instructions are designed to help regulate the body's sleep rhythm and deprive the patient of sleep. Sleep deprivation, in turn, is likely to decrease sleep latency while strengthening the association of sleep with the sleep environment, ie, the bedroom at night.
Sleep-Restriction Therapy:Spielman and coworkers expand on the concept of sleep deprivation as a means of decreasing sleep-onset latency, increasing periods of deep sleep, and reducing awakenings. In their sleep-restriction therapy approach, the first step is determination of the maximum allowable time in bed, which is determined by averaging the patient's estimated total nightly sleep time over a 1-week period. Note, however, that the total allowable sleep time is never set below 4.5 hours. The wake-up time is predetermined on the basis of the time the patient normally awakens to start the day. Bedtime is determined by subtracting the total allowable sleep time from the wake-up time. Thus, for example, if a patient's wake-up time is 7 am and his/her maximum allowable sleep time is 5 hours, then bedtime is 2 am.
The patient is put on this restricted sleep schedule for 5 days, during which time the patient is told to keep a careful log of time spent in bed and time spent awake in bed. Using the log data, the patient's mean estimate of sleep efficiency (mean total sleep time/mean total time in bed) is calculated. If the mean sleep efficiency is 90% or more, bedtime is adjusted to add 15 minutes to the total allowable sleep time. However, if sleep efficiency is less than 85%, bedtime is adjusted to reduce the total allowable sleep time by 15 minutes. The new schedule is then followed for 5 days, again with close monitoring of time in bed and total sleep time. This schedule is followed -- making adjustments every 5 days -- until the patient achieves a sleep efficiency of more than 90% for 7 hours a night.
Throughout the sleep-manipulation period, daytime napping, lying down, or (in some cases) monotonous sleep-inducing activities are avoided.
Pharmacologic Interventions
Although behavioral approaches are effective for many patients, they do not work for all. Thus, for patients with transient insomnia, a trial of brief pharmacologic therapy is recommended (Table 1).
Table 1. Pharmacotherapy for Treatment of Transient Insomnia
Condition
Type of Drug
Drug
Comments
Non-anxiety-related insomnia
Benzodiazepines
Temazepam (Restoril)
Intermediate-acting and may be useful for patients with sleep-continuity problems
Anxiety-related insomnia
Benzodiazepines
Triazolam (Halcion)
Shorter-acting; increased risk for tolerance and rebound insomnia
Anxiety-related insomnia
Benzodiazepines
Flurazepam (Dalmane)
Longer-acting; may be useful for patients with daytime anxiety
Anxiety-related insomnia
Benzodiazepines
Clonazepam (Klonopin)
Longer-acting
Anxiety-related insomnia
Nonbenzodiazepines
Zolpidem (Ambien)
Short-acting
Anxiety-related insomnia
Nonbenzodiazepines
Buspirone (Buspar)
Antianxiety effect takes at least 4 weeks
Anxiety-related insomnia
Sedative antidepressants
Nortriptyline (Aventyl)
Sedating; may help with generalized anxiety disorder
Anxiety-related insomnia
Sedative antidepressants
Doxepine (Sinequan)
Sedating
Anxiety-related insomnia
Sedative antidepressants
Trazodone (Desyrel)
Side effects, including daytime sedation, orthostatic hypotension, and possible priapism
Adapted from Weilburg JB. Approach to the patient with insomnia. In: Goroll AH, Lawrence A, eds. Primary Care Medicine: Office Evaluation and Management of the Adult Patient. 3rd ed. JB Lippincott Co; 1995
After behavioral interventions have been exhausted, the 35-year-old lawyer with insomnia who experienced daytime fatigue and difficulty concentrating is likely to benefit from a pharmacologic approach, if depression is ruled out as a comorbid condition. Generally, we rely on the newer agents -- the nonbenzodiazepines, such as zolpidem or zaleplon --because they appear to be less likely to lead to tolerance, which is a problem with some of the older agents.
Moreover, it is likely that more pharmacotherapy options will be available in the near future. Two new nonbenzodiazepine agents are poised to enter the market. The first of these, eszopiclone is a nonbenzodiazepine that acts on the gamma-aminobutyric acid (GABA) receptor complex, the target of benzodiazepines, but at a different site.
In a phase 3 trial of the drug, Krystal and colleagues reported that 60% of patients taking eszopiclone (n = 593) completed the 6-month treatment, whereas 56.6% of patients (n = 195) in the placebo arm completed treatment. Moreover, patients taking eszopiclone reported significant and sustained improvements in sleep latency, wake time after sleep onset, the number of awakenings, the number of nights awakened per week, total sleep time, and the quality of sleep as compared with placebo (P < .003). Monthly ratings of next-day function, alertness, and sense of physical well-being were also significantly better with the use of eszopiclone than with placebo ( < .002). There was no evidence of tolerance, and the most common, adverse events were unpleasant taste and headache.
In March 2004, the US Food and Drug Administration (FDA) issued conditional approval for eszopiclone, which is likely to be available by midsummer.The second new agent expected to come to market soon is indiplon. In studies reported at the 2003 American Psychiatric
Association Annual Meeting, Roth reported that indiplon improved sleep latency by polysomnography as well as self-report in a placebo-controlled trial. These were healthy young people without insomnia, however.
Indiplon's manufacturer is seeking FDA approval for both immediate-release and modified-release formulations and is requesting no time restrictions on the labeling of both formulations, which would differ from zolpidem ( which is restricted to 7-10 days of use).
Although these therapeutic options are often effective, a subset of patients is not helped by these available therapies. For those patients, complementary medicine may be an option (see Table 2). Often, patients are already experimenting with over-the-counter "natural" remedies, so it is helpful to become acquainted with these options.
Table 2. Available Complementary Medicines for Insomnia
Complementary Agent
Comments
Valerian
Purported sedative and sleep aid used since medieval times
Skullcap, blue pimpernel, mad weed
Purported herbal remedy for insomnia, efficacy not established
Passion flower
Purported herbal remedy for restlessness and insomnia, efficacy not established
Chamomile
Purposed remedy for insomnia used by ancient Egyptians, efficacy not established
Melatonin
Hormone synthesized by pineal gland. Hypnotic and circadian effects documents. Safety and efficacy for treatment of sleep disorders not established by randomized, clinical trials.
Adapted from Attele AS, Xie JT, Yuan CS. Treatment of insomnia: an alternative approach. Altern Med Rev. 2000;5:249-259
Of this list, melatonin is single compound for which there is some evidence of efficacy, although that evidence is not conclusive. For example, in a study of 7 totally blind individuals, administration of 10 mg of melatonin an hour before bedtime was associated with improved sleep efficiency (less waking time after initial onset of sleep) as compared with placebo. Additionally, the same researchers report that titrating down to .05 mg of melatonin daily for 3 months maintained synchronization of the circadian system. These studies are typical of the intriguing, yet suggestive nature of melatonin research. Nonetheless, it is well recognized that melatonin plays a role in regulating the sleep-wake system.
Thus, it is not surprising that melatonin continues to be the subject of study.
Although the efficacy of melatonin has not been confirmed in large, placebo-controlled, randomized trials, its potential utility for regulating the circadian system has led to the development of agonists for the melatonin system. One of these, ramelteon (formerly TAK-375), is a selective melatonin ML-1 receptor agonist, which is being developed for treatment of transient and chronic insomnia. Ramelteon specifically targets the brain's ML-1 receptors, located, which are located in the suprachiasmatic nucleus (described in part 1 of this review).In preclinical studies, ramelteon was found to be 15 times more potent than melatonin, with an average half-life of 1-2 hours.Roth and Walsh studied ramelteon in 400 normal sleepers ages 35-60. Volunteers were randomized to 16 mg of ramelteon, 64 mg of ramelteon, or placebo 30 minutes before bedtime. Latency to sleep onset was reduced by 50% in both groups that received the active study drug. Moreover, both doses increased sleep time by an average of 15 minutes as compared with placebo. There was no psychomotor impairment 30-60 minutes after waking among the placebo patients or patients who received 16 mg of the study drug, but patients receiving 64 mg, while having no functional impairment, did have a small, but statistically significant impairment in perception of function. Patients receiving high-dose ramelteon claimed they were less alert and had difficulty concentrating in the morning.
A recent, double-blind, placebo-controlled, crossover study enrolled 107 volunteers who met the Diagnostic Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) definition of primary insomnia, meaning insomnia not secondary to medical or psychiatric illness and not a primary sleep disorder. Most patients had experienced insomnia for more than a year. Participants were treated in the sleep laboratory for 2 consecutive nights. Patients were required to have a latency to sleep onset of 20 minutes or longer and to have at least 60 minutes of wake time during an 8-hour recording period. Ramelteon was studied at 4 mg, 6 mg, 16 mg, and 32 mg.
All doses of ramelteon reduced sleep latency by about 40% as compared with placebo. The drug also increased polysomnography-measured sleep time by more than 10 minutes. Moreover, there were no adverse effects on alertness or ability to concentrate in the morning.
However, although ramelteon appears to be a promising compound, it is not yet approved for clinical use. Moreover, the pipeline drugs eszopiclone and indiplon are also not yet available.
Rational Management Approaches
The primary care physician is left with several, well-proven treatment strategies on the basis of these essential principles:
Careful history taking, including the use of a 2-week sleep-wake log as well as assessment of sleep hygiene.
Refer patients for sleep laboratory assessment when sleep apnea, narcolepsy, or periodic limb movement disorder is suspected.
Assess for psychiatric problems and for medical problems, especially thyroid disorders and congestive heart failure.
Consider, the 2 "patients" introduced at the outset. Both require a careful assessment of sleep hygiene, but it is unlikely that either patient will require referral for sleep laboratory assessment.
After history and physical -- including an Folstein Mini-Mental State (MMS) exam to rule out depression -- the 35-year-old lawyer should be initiated on a trial of behavior therapy, starting with sleep-hygiene techniques. If, however, the behavioral approach is not effective, this patient is a good candidate for a brief pharmacologic intervention, usually with a nonbenzodiazepine agent.
The 45-year-old nurse may be the more challenging patient because he may require a more intense sleep-entraining program to overcome the circadian disturbance associated with shift work. Moreover, pain is a clear contributor to this patient's sleep problems. Remember, treat the pain and the sleep disorder is likely to benefit.
Funding Information:This report is supported by an unrestricted educational grant from Takeda.
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Bootzin RR. Stimulus control treatment for insomnia. Programs and abstracts of the 80th Annual Convention of the American Psychological Association; September 2, 1972; Honolulu, Hawaii.
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Sack RL, Brandes RW, Kendall AR, et al. Entrainments of free-running circadian rhythms by melatonin in blind people. New Engl J Med. 2000;343:1070-1077. Abstract Uchikawa O, Fukatsu K, Tokunoh R, et al. Synthesis of a novel series of tricyclic indan derivatives as melatonin receptor agonists. J Med Chem. 2002;45:4222-4239. Abstract Roth T, Walsh JK. Phase II study of the selective ML-1 receptor agonist TAK-375 in a first night effect model of transient insomnia. Programs and abstracts of the American Professional Sleep Societies; June 5-7, 2003; Chicago, Illinois. Abstract 0739L.
Erman M, Seiden D, Zammit G. Phase II study of the selective ML-1 receptor agonist TAK-375 in subjects with primary chronic insomnia. Program and abstract of the American Professional Sleep Societies; June 5-7, 2003; Chicago, Illinois. Abstract 0748L.
Sleep Disorder Self-Treatment With Herbs.:
New York (MedscapeWire) Jun 12 ¡ª In the June 2 issue of Sleep Medicine Reviews, researchers at the University of Illinois at Chicago (UIC) College of Pharmacy and College of Nursing discuss the propensity of people with sleep disorders to self-treat using herbs. UIC researchers also review the most commonly used herbal stimulants and sedatives, and they recommend a course of action to the medical and research communities.
Difficulties with sleep and wakefulness are found in up to 38% of the world population. Thirty-eight percent of US adults in 1998 reported that daytime sleepiness interferes with their daily activities at least a few days a month. At least 10% to 15% of these respondents reported using over-the-counter medications or a dietary supplement to help them stay awake during the day.
"Healthcare providers have largely ignored this phenomenon in the past, but it is now becoming necessary for providers to educate themselves and their patients in the wise and unwise use of these agents," said Charlotte Gyllenhaal, UIC College of Pharmacy research assistant professor and lead author of the article.
The researchers reviewed caffeine and caffeine-containing herbs, ephedrine-containing herbs, yohimbe and ginseng for their ability to combat fatigue, as well as valerian, German chamomile, kava, lavender, hops, lemon balm, and passion flower for their ability to improve sleep.
They note that caffeine is widely used to control sleepiness, but more research is needed on its use in sleep disorders. They express safety concerns about ephedra and ephedrine, used in stimulants and weight loss products, and yohimbe, used in stimulant and body-building preparations. They note that there is some inconclusive experimental evidence for the use of Asian and Siberian ginseng to treat fatigue.
Experimental evidence also supports the efficacy of the herbal sedatives valerian and kava, which have received the most research attention. Both herbs in small studies decreased sleep onset time and promoted deeper sleep. The researchers note that German chamomile, lavender, hops, lemon balm, and passion flower are reputed to be mild sedatives but need much more experimental examination.
The UIC team calls on researchers and medical professionals to address the use of herbs to treat sleep disorders by:
systematically gathering data about the use of herbals by people with sleep disorders;
exploring herb-drug interactions, especially in relation to elderly patients who take many prescription medications and frequently complain of sleep problems;
continuing basic research into the identity of active compounds and their stability in a variety of preparations;
conducting large-sample, double-blind, placebo-controlled trials of herbal sedatives;
examining the prevalence of adulteration and contamination in herbs, especially those imported from areas where there is little manufacturing regulation;
exploring the activity of herbal sedatives in sleep initiation vs sleep maintenance; and
asking patients nonjudgmental questions about their use of herbal preparations to aid sleep and wakefulness and incorporating their answers into their medication history.
DHEA: Dehydroepiandrosterone.:from American Journal of Health-System Pharmacy
Uses:Clinically substantiated (yet still controversial) uses of DHEA include replacement therapy in patients with low serum DHEA levels secondary to chronic disease, adrenal exhaustion, or corticosteroid therapy; treating systemic lupus erythematosus (SLE), improving bone density in postmenopausal women; improving symptoms of severe depression; improving depressed mood and fatigue in patients with HIV infection; and increasing the rate of reepithelialization in patients undergoing autologous skin grafting for burns.Other possible uses (with some supporting clinical studies) include enhancing the immune response and sense of well-being in the elderly, decreasing certain cardiovascular risk factors, and treating male erectile dysfunction. Use of DHEA to slow or reverse the aging process, improve cognitive function, promote weight loss, increase lean muscle mass, or slow the progression of Parkinson's disease and Alzheimer's disease is clinically unsubstantiated.
Pharmacology:In women, the synthesis of DHEA and DHEAS occurs almost exclusively in the adrenal cortex, whereas in men the testes secrete approximately 5% of DHEAS and 10-25% of DHEA.Minute amounts are synthesized de novo in the brain. In young adults the adrenal cortex secretes approximately 4 mg of DHEA and 25 mg of DHEAS per day.During gestation, large amounts of DHEA and DHEAS are secreted by the fetal adrenal glands. At birth, output drops to negligible amounts in both sexes and remains that way until five to seven years of age. At the onset of adrenarche, the adrenal glands gradually resume DHEA and DHEAS production, which accelerates through puberty. DHEA and DHEAS output is maximal between the ages of 20 and 30 years and then starts a decline of approximately 2% per year, leaving a residual of 10-20% of the peak production by the eighth or ninth decade of life.
DHEA and DHEAS are interconvertible by sulfohydrolases in peripheral and adrenal tissues.Some 64-74% of the DHEAS produced each day is converted to DHEA, but only 13% of the DHEA produced is metabolized to DHEAS.In humans, the brain-to-plasma ratios for DHEA and DHEAS are 4-6.5 and 8.5, respectively, indicating a neuroendocrine role for these hormones.
DHEA and DHEAS serve as the precursors of approximately 50% of androgens in men, 75% of active estrogens in premenopausal women, and 100% of active estrogens after menopause.There appears to be a sex-specific response to DHEA replacement therapy in humans. In postmenopausal women (ages 50-65), supraphysiological doses of 100 mg of DHEA per day have predominantly androgenic effects, increasing testosterone levels approximately 300% over baseline levels.In older men (mean ¡À S.D. age, 58.8 ¡À 5.1 years), 100 mg/day did not affect testosterone or dihydrotestosterone levels, but 17 beta-estradiol and estrone levels were increased over baseline by 37% and 225%, respectively (p < 0.0001 for both).It has been hypothesized that the increase in serum estrogens may provide a mechanism for beneficial cardiovascular effects in men; however, clinical studies addressing the possible cardioprotective effects of DHEA have been inconclusive.
Several mechanisms of action of DHEA and DHEAS other than their role as precursors of the sex hormones have been proposed. In the central nervous system, both DHEA and DHEAS appear to affect neurotransmitter receptors. In rodents, DHEAS binds to the -aminobutyric acid (GABA)/benzodiazepine-receptor complex (GABA-RC) and acts as a negative noncompetitive modulator of GABA-RC. DHEA, on the other hand, appears to have GABA-agonist effects on the GABA-RC. DHEA selectively enhances the neuronal response to N-methyl- D-aspartate.Also, DHEA and DHEAS appear to have neurotrophic effects, increasing the number of neurofilament-positive neurons and regulating the motility and growth of corticothalamic projections in cultured mouse embryo brain cells.
Supraphysiological oral doses of DHEA (100-300 mg/day) in humans have been found to inhibit the synthesis of thromboxane A 2 in activated platelets, reduce plasma plasminogen activator inhibitor type 1 and tissue plasminogen activator antigen, increase serum levels of insulin-like growth factor 1 (IGF-1), and increase cyclic guanosine monophosphate and nitric oxide synthesis (either directly or via increased levels of IGF-1).These effects suggest that DHEA may be beneficial in improving circulation in the microvasculature and regulating some of the risk factors of cardiovascular disease, such as platelet aggregation and ischemia. Clinical studies in this area have been equivocal, with a majority showing an inverse relationship between DHEA or DHEAS levels and cardiovascular morbidity and mortality in men but not in women.However, a recently published five-year epidemiologic cohort study found no statistically significant correlation between serum DHEA or DHEAS levels and the development of atherosclerosis in men or women.
DHEA may play a positive role in modulation of the immune response. Clinical studies in elderly persons have demonstrated that oral DHEA doses of 50 mg/day increase IGF-1 levels (p < 0.01) and cause functional activation of T cells (increases in CD8+ and CD56+ cells [natural killer cells] and enhanced cytotoxic activity).Serum levels of interleukin- 6 (a proinflammatory cytokine involved in the pathogenesis of osteoporosis, rheumatoid arthritis, atherosclerosis, Alzheimer's disease, Parkinson's disease, and beta-cell malignancies) increase significantly with age and are inversely correlated with serum DHEA and DHEAS levels (p < 0.001). In addition, DHEA, DHEAS, and androstenedione inhibit the production of interleukin-6 by peripheral blood mononuclear cells in a concentration-dependent manner (p < 0.001).
Pharmacokinetics:
Oral absorption of DHEA is excellent. The volume of distribution is 17.0-38.5 L for DHEA and 8.5-9.3 L for DHEAS. DHEA and DHEAS are converted into several active metabolites, including androstenedione, testosterone, estrone, estradiol, and estriol (Figure 1). The elimination half-life of DHEA is 15-38 minutes, whereas the half-life of DHEAS is 7-22 hours. Renal excretion accounts for 51-73% of the elimination of DHEAS and its metabolites.
Figure 1 (click image to zoom) . Synthesis of dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), and other steroids. The listing of more than one enzyme indicates a multistep process. aro = aromatase, DOC = deoxycorticosterone, HSD = hydrosteroid dehydrogenase, HSO = hydrosteroid oxidoreductase, HSS = hydrosteroid sulfatase, KSR = ketosteroid reductase, R = reductase, scc = side-chain cleavage, SH = sulfohydrolase, P-S = pregnenolone sulfate, THDOC = tetrahydrodeoxycorticosterone, THP = tetrahydroprogesterone. Reprinted from reference 3, with permission.
Clinical Studies:
To date, clinical studies of DHEA in patients with specific diseases have yielded generally inconclusive results. Most of the studies were open label or had very small samples. Most of the studies discussed below were randomized, double-blind, placebo-controlled trials in which the oral dosage was 300 mg/day. Tummala and Svec demonstrated that incremental increases in serum DHEA and DHEAS levels appear to plateau at an oral DHEA dosage of 300 mg/day and inferred that doses greater than this have little additional therapeutic value.
Postmenopausal Bone Density:
In a randomized, double-blind, placebo-controlled study by Baulieu et al.,[10] 280 healthy men and women ages 60-79 years were given DHEA 50 mg/day orally for 12 months. Increases in bone mineral density (p < 0.05) and decreases in biochemical markers of bone turnover (p < 0.01 for serum C-terminal peptide and p < 0.05 for serum bone alkaline phosphatase) were observed at 12 months in women older than 70 but not in any other subgroup.
Systemic Lupus Erythematosus:
DHEA supplementation has shown promise for the treatment of SLE. In a randomized, double-blind trial,women with SLE received DHEA 200 mg/day for three months. In the DHEA group, the SLE Disease Activity Index score and both the patients' and the physicians' overall assessments of disease activity decreased, whereas small increases were seen in the placebo group. However, significance was achieved only for the visual-analogue- scale component of the index (p = 0.022). Lupus flares occurred less frequently in the treatment group than in the placebo group (three versus eight flares, p = 0.053), and a nonsignificant decrease in prednisone requirements was noted in the treatment group (from a mean ¡À S.D. daily dose of 12.4 ¡À 3.2 mg to 9.1 ¡À 2.3 mg, compared with an increase from 5.3 ¡À 1.37 mg to 7.3 ¡À 2.9 mg in the placebo group). Serum titers of antibodies to double-stranded DNA and levels of complement components C3 and C4 did not change significantly between the groups.
Well-being and Cognition:
In a randomized, placebo-controlled, crossover trial, 30 patients ages 40-70 years were given 50 mg of DHEA orally daily.9 Within two weeks, this dose restored serum DHEA levels in both men and women to those found in young adults. With DHEA treatment, 67% of the men and 84% of the women perceived an increase in physical and psychological well-being. However, the study has been criticized for its use of an open-ended questionnaire for self-assessment of well-being.
At present, there are no rigorous data to support an improvement in memory or other aspects of cognitive function after DHEA replacement therapy. Low endogenous levels of DHEA and DHEAS do not appear to be associated with an increased risk of dementia.
Depression:
The possible relationship between depression and serum DHEA and DHEAS levels is intriguing; however, more research is needed. Some authors have suggested that abnormal diurnal variations in serum DHEA and DHEAS levels, as well as abnormally high cortisol- to-DHEA ratios, may be causative factors in depression in adults and depression with comorbid panic or phobic disorders in adolescents.
In a randomized, double-blind trial by Wolkowitz et al., 22 patients who had major depression (a Hamilton Rating Scale for Depression [HAM-D] score of 16 or greater) and who were either medication free or stabilized on antidepressant regimens received DHEA (30 mg/day for weeks 1 and 2, 60 mg/day for weeks 3 and 4, and 90 mg/day for weeks 5 and 6) or placebo. At the end of the six weeks, the mean decrease in the HAM-D score was 30.5% in the treatment group and 5.3% in the placebo group (p < 0.04). Five of 11 patients in the treatment group were considered responders (at least a 50% decrease in HAM-D score), compared with none of the 11 patients in the placebo group.
Effects in HIV-Infected Patients:
In a recent open-label trial evaluating the effect of DHEA on depressed mood and fatigue, 45 HIV-positive patients (39 men and 6 women) received oral DHEA doses of 200-500 mg/day for eight weeks. Of the 32 patients who completed the trial, 23 (72%) had an improvement in mood and 26 (81%) had a reduction in fatigue. There was a significant increase in body cell mass and libido but no effect on CD4+ lymphocyte counts or testosterone levels in men. The positive effects on mood, fatigue, and body cell mass continued for an additional four weeks in a subsequent double-blind phase of the study. Christeff et al. have noted an inverse relationship between serum DHEA and DHEAS levels and the immunologic deterioration in HIV patients, which suggests a role for DHEA and other androgens in the normal functioning of the immune system.
Effects on Physical Variables:
A randomized, double-blind, placebo-controlled crossover trial by Morales et al. looked at the effects of oral DHEA 100 mg/day in 16 subjects 50-65 years of age. Baseline levels of serum DHEA, DHEAS, androstenedione, testosterone, and dihydrotestosterone were at or below the low end of the range for young adults. In both sexes, DHEA 100 mg/day restored serum DHEAS to levels at or slightly above the upper limit of the young-adult range. In women, androstenedione, testosterone, and dihydrotestosterone were increased to three to five times baseline levels (p < 0.001 for each hormone), or to levels above the sex-specific ranges for young adults, whereas in men only androstenedione was significantly increased above baseline (p < 0.05). Serum IGF-1 levels increased by a mean ¡À S.D. of 16% ¡À 6% (p = 0.04) in men and 31% ¡À 12% in women (p = 0.02). In men but not women, fat body mass decreased by 6.1% ¡À 2.6% (p = 0.02), and there were increases in knee muscle strength (15.0% ¡À 3.3%, p = 0.02) and lumbar back strength (13.9% ¡À 5.4%, p = 0.01). No changes in basal metabolic rate, bone mineral density, urinary pyridinoline cross-links, fasting insulin, glucose, cortisol, or lipids were observed in either sex.
Dosage:
Physiological replacement dosages of oral DHEA in healthy people older than 40 years are in the range of 20-50 mg/day for men and 10-30 mg/ day for women. These dosages are usually adequate to increase serum DH-EAS to the levels found in adults 20-30 years of age and to bestow the reported benefits of a heightened sense of well-being in both sexes, increased bone mineral density in postmenopausal women, and amelioration of erectile dysfunction in men. Higher dosages may be necessary for increasing suppressed DHEA and DHEAS levels secondary to chronic disease, adrenal exhaustion, and corticosteroid therapy. Replacement doses of DHEA are usually taken once daily in the morning.
It is imperative that serum DHEAS concentration be measured before DHEA replacement therapy is started. The serum DHEAS level should be checked at least annually to ensure that it is in the normal range. To minimize adverse effects and maximize benefits, it is suggested that replacement dosages in healthy adults be adjusted to maintain serum levels of DHEAS in the second or third quartile of sex-specific, young-adult ranges.
Pharmacologic dosages of 200 mg/day have been successfully used in patients with SLE. Dosages of 200-500 mg/day have been used in HIV-positive patients with depressed mood and fatigue. It is not known what effect long-term physiological or supraphysiological doses of DHEA may have on suppression of the zona reticularis of the adrenal cortex; however, there does not appear to be feedback inhibition of DHEA or DHEAS secretion by the hypothalamic-pituitary axis.
Adverse Effects:
Increased facial sebum production, acneiform dermatitis, and mild hirsutism have been reported in women taking DHEA in physiological or supraphysiological dosages (25-200 mg/ day). Hepatitis was reported in a postmenopausal woman with preexisting high titers of antinuclear antibodies who received a single oral dose of 150 mg of DHEA; causality could not be established. A supraphysiological dosage of DHEA (100 mg/day) was shown to increase androstenedione, testosterone, and dihydrotestosterone levels threefold to fivefold in postmenopausal women.The long-term effects of these increases in androgen levels in women are not known. A nested case-control study by Dorgan et al. found that postmenopausal women (not taking DHEA or hormone replacement therapy) whose levels of endogenous DHEAS were in the highest quartile had a significantly higher risk of breast cancer (risk ratio, 2.8 [95% confidence interval 1.1-7.4]) than women whose levels of endogenous DHEAS were in the lowest quartile.
Drug Interactions:
Calcium-channel blockers and metformin increase levels of endogenous DHEAS, whereas corticosteroids and insulin significantly decrease them.Supraphysiological dosages of DHEA can increase serum triazolam levels because of an inhibition of metabolism.Theoretically, aromatase inhibitors, such as chrysin (5.7-dihydroxyflavone), an extract from the plant Passiflora coerula, can increase levels of androgens, including DHEA and DHEAS, in both men and women. Kroboth et al. published an excellent review of the effects of disease, diet, exercise, and medications on endogenous DHEA and DHEAS levels.
Contraindications:
DHEA supplementation is contraindicated in patients with a history of sex hormone-responsive cancers, such as breast, ovarian, endometrial, and prostate cancer. Women with a family history of postmenopausal, estrogen- sensitive cancers and men with benign prostatic hypertrophy or a family history of prostate cancer should carefully weigh the risks and benefits of DHEA replacement therapy with their physician. If replacement therapy is deemed necessary, close monitoring of serum DHEAS and its androgenic and estrogenic metabolites should be performed frequently. DHEA supplementation should be avoided during pregnancy and lactation.
Conclusion:
Clinical data suggest that DHEA may have a role in hormone replacement therapy in patients with low endogenous DHEA and DHEAS levels due to chronic diseases, adrenal exhaustion, corticosteroid therapy, and advancing age. However, as a potent steroid precursor, DHEA can significantly increase androgen levels in women and may enhance the progression of estrogen and testosterone-sensitive cancers. Supplementation with DHEA should never be undertaken without direct medical supervision. The long-term effects of DHEA supplementation are unknown.
Scientific References:
1.The passion-flower......Her fashioning did wait...
2.Research update of Passiflora,Passiona Flower,Passion Flower Extract,Flavonoids.
Claims & Warning:
Claims: Information this web site presented is meant for Nutritional Benefit and as an educational starting point only, for use in maintenance and promotion good health in cooperation with a common knowledge base reference...Furthermore,it based solely on the traditional and historic use or legend of a given herb from the garden of Adonis. Although every effort has been made to ensure its accurate, please note that some info may be outdated by more recent scientific developments......
Pharmakon Warning: The order of knowledge is not the transparent order of forms and ideas,as one might be tempted retrospectively to interpret it; it is the antidote....(Dissemination,Plato's Pharmacy,II.The Ingredients:Phantasms,Festivals,and Paints;138cf. Jacques Derrida.).
And as it happens,the technique of imitation,along with the production of the simulacrum,has always been in Plato's eyes manifestly magical,thaumaturgical:......and the same things appear bent and straight to those who view them in water and out,or concave and convex,owing to similar errors of vision about colors, and there is obviously every confusion of this sort in our souls.And so scene painting (skiagraphia) in its exploitation of this weakness of four nature falls nothing short of witchcraft (thaumatopoia), and so do jugglery and many other such contrivances.(Republic X,602c-d;cf.also 607c).
seminal trace...Passion Flower Extract,Flavonoids.2%4%CAS.NO.008057-62-3.Passiflora incarnata extract,Passiflora extract,Passionflower extract....
Phytochemical info of Passiflora,Passiona Flower,Passion Flower Extract.:
Passiflora: a review update.:
Scientific References:
Claims & Warning:
