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Expert Column - What Every PCP Should Know: Over-the-Counter Insomnia Treatments

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Expert Column - What Every PCP Should Know: Over-the-Counter Insomnia Treatments  CME


Irina V. Zhdanova, MD, PhD   


According to various estimates, 15% to 40% of the general population suffer from transient, short-term, or chronic insomnia associated with subjective complaints of prolonged sleep latency, frequent nighttime awakenings, long periods of nighttime wakefulness, or early-morning awakening.[1,2] Because altered nighttime sleep leads to daytime fatigue and sleepiness, any type of insomnia negatively affects mood and performance, and thus increases the risk of accidents and health problems, including major depression.

Although some insomniacs consistently seek and follow medical advice in addressing their sleep problems and use prescribed therapy (pharmacologic, circadian, behavioral, or cognitive), many choose over-the-counter (OTC) sleep aids in an attempt to shorten latency to sleep or promote nighttime sleep maintenance. A rationale for using OTC sleep aids may differ; some are searching for a "quick fix" with a readily available medication, and others have found conventional hypnotics to be ineffective or their side effects intolerable. Many are also attracted by a label "dietary supplement," which is often perceived as a safer or more natural alternative to drugs.

It is critically important to know whether your patient suffers from insomnia and, if so, which medications he or she is using to combat it. The major categories of OTC sleep medications widely available in stores, pharmacies, and on the Web include antihistamines as well as hormonal and herbal preparations. In addition, some insomniacs use ethanol or marijuana as a sedative despite the disadvantages, such as dependence. OTC preparations also are frequently used in combination, which is likely to amplify both their sleep-promoting and adverse effects.


First-generation antihistamines (eg, diphenhydramine, brompheniramine, or chlorpheniramine) have been used to treat allergies for a number of years and are available without prescription. However, they can also induce sedation via central antihistaminergic and anticholinergic mechanisms,[3,4] and this effect is widely exploited.

A number of clinical studies have addressed the dose- and time-dependent properties of antihistamines and found both subjective and objective changes in sleepiness, sleep, and psychomotor performance associated with the reduction in latency to sleep onset or increase in sleep duration.[5-8] Although previous studies tended to support the use of this class of drugs to treat occasional mild-to-moderate insomnia,[9,10] more recent opinions of sleep specialists have shifted strongly against this practice.[11]

The major reason for limiting the use of antihistamines for treating insomnia is their multiple side effects, including changes in sleep architecture, notably a reduction in rapid eye movement (REM) sleep caused by their anticholinergic effects; a reduction in cognitive functions;[12] day-after sedation; an increased risk of accidents;[13] the development of tolerance;[14] and interference with other medications. The side effects of antihistamines appear to be especially risky for elderly patients, almost 50% of whom use sleep medications occasionally or on a regular basis and who often choose OTC sleep aids.[15]Adverse Effects of Diphenhydramine

A recent study, involving 1627 individuals aged 65 and over, found that between 1989 and 1996 the use of prescription sedative-hypnotics (primarily benzodiazepines) rose from 1.8% to 3.1%, whereas OTC sedative-hypnotic use (primarily diphenhydramine) increased from .4% to 7.6%, and reached 8.17% by 1998.[16] This study also highlighted a significant association of diphenhydramine use and cognitive impairment in elderly individuals without dementia.

In a Yale University (New Haven, Connecticut) hospital study, 114 (27%) of 426 hospitalized medical patients aged 70 years or older received diphenhydramine during hospitalization.[17] Although at baseline these patients demonstrated similar characteristics (age, sex, delirium risk, and Mini-Mental State Examination scores) to those of patients who did not receive diphenhydramine, the ones who received diphenhydramine showed a significantly greater risk for delirium symptoms, disorganized speech, and altered consciousness during hospitalization. A diphenhydramine dose-response relationship was demonstrated for most adverse outcomes.

In view of the antihistamine-induced side effects, it is especially disturbing that a large number of OTC preparations contain diphenhydramine under a score of brand names,* which can confuse patients. Furthermore, many OTC medications include diphenhydramine as a second active ingredient (eg, Tylenol PM, Aspirin PM, Acetaminophen PM, Alka-Seltzer Plus, etc). Typical doses of diphenhydramine in these preparations are 25-50 mg per tablet or capsule, and, in most cases, 2 tablets are the recommended dose, 3-4 times per day. Syrup, elixir, spray, cream, and gel forms of diphenhydramine are also widely available.

The Swiss Toxicological Information Centre has recently studied the dose-dependent toxicity of diphenhydramine in 282 patients with acute diphenhydramine poisoning.[18] They found that mild toxicity symptoms (somnolence, anticholinergic signs, tachycardia, and nausea/vomiting) accounted for 55% to 64% of the cases and were associated with doses under 300 mg. Moderate symptoms (isolated and spontaneously resolving agitation, confusion, hallucinations, and electrocardiogram disturbances) were documented in 22% to 27% of those who ingested more than 300 mg of diphenhydramine. Severe symptoms (delirium/psychosis, seizures, and coma) manifested in 14% to 18% of the patients after ingestion of nearly 1 g of the drug. Thus, combining several tablets of an OTC "cold" medication with a topical cream for allergy could place a patient at health risk.

Recognizing the complexities of the OTC antihistamine market, in 2002 the US Food and Drug Administration (FDA) ruled that drug products containing diphenhydramine should carry warnings, advising consumers not to use oral OTC diphenhydramine products with any other product containing diphenhydramine, including products used topically.[19] Overall, occasional use of low-dose antihistamines for acute sedation may be relatively safe, but using them frequently to control sleep is not a good idea.

*40 Winks, Aid to Sleep, Aler-Dryl, Allergia-C, Allergy Medicine Antihistamine, AllerMax, Altaryl, Anti-Histamine, Antihist, Antihistamine, Antihistamine Allergy, Antituss, Banaril, Banophen, Beldin, Belix, Benadryl, Benadryl Allergy, Benadryl DF, Benadryl Dye-Free Allergy, Benadryl Ultratab, Benahist-10, Benahist-50, Benoject-50, Bydramine, Calm-Aid, Child Allergy, Complete Allergy, Complete Allergy Relief, Compoz Nighttime Sleep Aid, Diphedryl, Diphen, Diphen AF, Diphen Cough, Diphenadryl, Diphendryl, Diphenhist, Diphenhydramine Hydrochloride, Diphenyl, Diphenylin, DPH, Dytan, Dytuss, Genahist, Hydramine, Hydramine Compound, Hydramine Cough Syrup, Hyrexin, Nervine, Night Time Sleep-Aid, Nu-Med, Nytol Caplet, Pardryl, Phendry, Q-Dryl, Quenalin, Scot-Tussin Allergy Relief Formula, Siladryl, Siladryl DAS, Siladyl SA, Silphen Cough, Simply Sleep, Sleep, Sleep Aid, Sleep Tab II, Sleep Tabs, Sleep-ettes, Sleep-eze-3, Sleepinal, Sominex, Sominex Maximum Strength Caplet, Somnicaps, Total Allergy, Trux-adryl, Tusstat, Twilite, Uni-Hist, Unisom Sleepgels Maximum Strength, Valu-Dryl, Wehdryl(


The onsets of sleepiness, sleep quantity, and sleep quality depend not only on the duration of prior wakefulness, the so-called homeostatic mechanism of sleep regulation, but also on the time of day when an attempt to initiate sleep is taking place. The latter reflects circadian mechanisms of sleep regulation and is linked to the biological clock structure, the suprachiasmatic nucleus of the hypothalamus.

The neuroendocrine system is likely to play a major role in both homeostatic and circadian sleep processes. However, so far we know very little about hormonal mechanisms of sleep regulation. An exception is melatonin, the principal hormone of the circadian system, released nightly into the cerebrospinal fluid and blood circulation by the pineal gland. The ability of high doses of melatonin to induce sleepiness was reported over 40 years ago, during an unrelated clinical trial.[20] More recently, low-dose melatonin (.1-.5 mg, orally) was found to promote objectively documented sleep.[21-25] Of importance, these low doses induced circulating melatonin levels within those normally observed in human blood (50-150 pg/mL). The latter suggests that melatonin may normally play a role in homeostatic sleep regulation, acutely promoting sleep onset and maintenance at night, in addition to its ability to shift a circadian phase of sleep, resulting from its effects on the "biological clock."

Melatonin does not appear to significantly affect nighttime sleep quantity and quality in healthy individuals but can help them to fall asleep during the day.[21-25] It was shown to be especially helpful for insomnias associated with neurologic disorders in children.[26-31] The results of melatonin administration to elderly insomniacs are more variable, ranging from mild but significant improvements in their sleep[32-34] to a lack of therapeutic effect.[35,36] Of note, sensitivity to the effects of melatonin on sleep is not uniform among individuals and may decline with age or as a result of neurodegenerative diseases.[37,38] Melatonin coadministration can also facilitate the effects of common hypnotics, helping to reduce their effective dose and side effects or attenuating drug withdrawal.[39] A combination of circadian and homeostatic effects of melatonin with its surprisingly low toxicity and lack of significant effects on sleep architecture and day-after performance at high pharmacologic doses makes it a popular compound among insomniacs.Sleep Effects

The nature of melatonin's effect on sleep, which is only starting to emerge, is such that it promotes a behavioral state resembling quiet wakefulness, which predisposes to normal sleep initiation, rather than sleepiness or profound drowsiness. A comparison of the effects of melatonin on human performance with those of conventional hypnotics (such as temazepam, zaleplon, and zopiclone) has shown that melatonin administration induces a smaller or no deficit in performance on a range of neurobehavioral tasks, despite a similar duration of subjective sleepiness.[40,41] However, stimuli that would interfere with normal sleep, eg, turning lights on, changing to an upright position, or the necessity of conducting a task requiring a high level of attention or motivation, will temporarily interfere with the effect of melatonin on the sleep process. Under such circumstances, a person would typically feel quite alert rather than sedated, despite the high circulating melatonin levels. Once the interference is removed, the ability to fall asleep faster under the influence of melatonin is restored.

It is important to distinguish between the circadian and acute effects of melatonin, because timing of administration may be crucial. Morning melatonin treatment can delay the onset of evening sleepiness by delaying the phase of the circadian rhythms, whereas administering melatonin in the evening can advance the circadian rhythms by 30-60 minutes per day, including time of sleep onset. By contrast, acute sleep-promoting effects of melatonin can manifest at different times of the day and, in insomniacs, at night, within 30 minutes after treatment.

Melatonin's short 20- to 40-minute half-life makes it possible to choose different approaches when using it to treat insomnia. Near-physiological doses of the hormone (.2-.5 mg) can be administered at bedtime to shorten sleep latency or to entrain the free-running circadian rhythms in individuals with circadian sleep disorders. Low melatonin doses (.1-.2 mg) can also be administered in the middle of the night, upon early awakening, in order to reinitiate sleep and prolong an overall sleep period.Preparations

It should be noted that despite melatonin being sold in the United States under the label of a dietary supplement, no meaningful amount of this pineal hormone is ever consumed through food intake. Normally, mammals rely on their own pineal glands to produce melatonin from tryptophan and to release it into the circulation. This process is precisely regulated, synchronizing melatonin secretion with both nighttime and darkness. Environmental light can suppress nocturnal melatonin production, whereas darkness during the day does not stimulate it.

In the United States, melatonin is available OTC in both immediate- and slow-release preparations and at a large variety of doses, typically from .1 to 5 mg. No major side effects have been documented after ingestion of high melatonin doses, and some researchers and practitioners choose to use them, hoping to augment melatonin efficacy. A few dose-dependency studies, however, failed to show significant improvement in the sleep-promoting effects of melatonin after the blood melatonin levels exceed those normally observed at night.[21-23, 25,34]

Slow-release melatonin preparations have a potential to mimic a physiological pattern of overnight melatonin production, prolonging their sleep-promoting effects. However, unless optimally designed, such preparations, as well as immediate-release doses higher than .5 mg, may result in increased daytime melatonin levels and thus alter a circadian signal provided by this hormone, which would provoke insomnia rather than treating it.[42]


Many herbs or herb-based preparations appear to have some sedative properties. These include valerian (Valeriana officinalis), hops (Humulus lupulus), skullcap (Scutellaria lateriflora), passionflower (Passiflora incarnata), lemon balm (Melissa officinalis), and kava (Piper methysticum).[43] Of these, valerian is the most popular and well-studied phytosedative. It has been and continues to be used in many cultures and is widely believed to have calming and relaxing effects that can also help to initiate sleep and ease anxiety in insomniacs.

Several recent reviews provide detailed information from clinical trials involving valerian.[44,45] Repeated administration of valerian was typically found to be beneficial to insomniacs, reducing time to sleep onset and promoting sleep maintenance.[46-49] By contrast, single-dose-treatment studies produced controversial results, some demonstrating sleep improvement in insomniacs,[49-51] others finding no difference between valerian and placebo.[52] These inconsistent outcomes may be related to both mild effects of valerian on sleep and individual sensitivity to its effects, or they may reflect differences in formulations, populations, and methodological approaches used to test these effects.

Gamma-aminobutyric acid (GABA)ergic and adenosine-ergic mechanisms of valerian's effects on sleep have been proposed, but remain to be further elucidated. Valerian root contains a number of biologically active substances, including valepotriates (iridoid esters), valeric acid, alkaloids, and free amino acids (including GABA). The role of each of these components in the sedative effects of valerian remains largely unknown, and a combined action of several of them and their correct proportions may be required. The nature of valerian preparations, however, suggests that their constituents may differ, depending on when and where the plants were harvested.Preparations and Treatment Duration

Because some components of valerian are not water-soluble, valerian extracts and tinctures are prepared with alcohol or alcohol-free (eg, glycerite) bases. Powdered valerian is available in capsule or tablet forms or as valerian tea. Typically, valerian preparations are taken about 30 minutes before bedtime, and the dose depends on the type of preparation. For example, 1-3 g of dried root can be used as valerian tea or 150-600 mg of valerian extract can be added to a small glass of water. Typically, individualized doses are established empirically, and a wide range of valerian doses appears to be well tolerated. That said, some individuals may experience a paradoxical reaction to this herb, associated with anxiety, tachycardia, and insomnia, and thus a gradual increase in dose should be recommended to first-time users.

The treatment duration depends on the specific symptoms of sleep disorder, and herbalists recommend a 2- to 3-week break after a 4- to 6-week period of valerian treatment. Perhaps shorter courses should be recommended to those who are initiating this treatment, before they acquire personal experience in using a specific valerian preparation. Until now, clinical trials have not documented valerian-withdrawal symptoms. However, a recent study suggests that valerian can have a positive effect on withdrawal from benzodiazepines.[53]

Valerian is often used in preparations containing multiple herbs that are traditionally believed to provide sedative or hypnotic effects. Interactions between different ingredients of these plants and their possible synergistic effects are very likely. However, representative placebo-controlled studies involving these other herbs (eg, passionflower, hops, lemon balm, or kava) and their combinations remain to be conducted. Possible toxic effects of individual herbs or their combinations also cannot be excluded. For example, repeated reports of liver damage linked to kava intake prompted European and North American regulatory agencies, including the FDA, to warn consumers of the risk involved in using this herb.Regulatory Issues

In addition to safety issues typical for any standardized medication, such as dose-response, toxicity, or interactions with other drugs, OTCs marked as "dietary supplements" pose an additional challenge. According to current US regulations, premarket evaluation and approval by the FDA are not required for the marketing of so-called "generally regarded as safe" (GRAS) ingredients, unless claims are made for specific disease prevention or treatment. GRAS status can result from a history of safe use before 1958, self-declaration by the manufacturer, or affirmation by the FDA. Furthermore, the FDA, rather than a manufacturer, has the burden to prove that a specific GRAS substance is unsafe.[54]

Dietary supplements are not required to be standardized in the United States but must comply with food Good Manufacturing Practice regulations, which are primarily concerned with safety and sanitation rather than dietary-supplement quality.[55,56] Such products are only infrequently tested for manufacturing consistency and batch-to-batch composition may vary considerably.


Although scores of sleep aid are on the OTC market, for the most part they represent 3 products: diphenhydramine, melatonin, and valerian. They are sold separately or in combination with other biologically active substances, including nonsteroidal anti-inflammatory drugs (with diphenhydramine), vitamins (with melatonin), or herbs (with valerian or melatonin).

All these substances can facilitate sleep onset or maintenance, with different potencies for different individuals. However, each of these sleep aids should be used by patients with appropriate caution, at the right time, with minimal effective doses, and (importantly) without combining several preparations containing the same active ingredient.

This program was supported by an independent educational grant from Takeda.


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This is a part of article Expert Column - What Every PCP Should Know: Over-the-Counter Insomnia Treatments Taken from "Atarax Hydroxyzine 25Mg" Information Blog

Are we emotionally what we eat?

appetite reduction Negative emotions can send us rushing to the biscuit tin or hiding our horrors in a tub of ice-cream - with up to 43% of people using food to alter their mood, according to a survey by the Priory Clinic.

Others binge and vomit or develop anorexia as a way of trying to gain some sort of control over runaway feelings.

BBC News Online spoke to the experts to try to find out why so many of us have this up and down relationship with what, on its most fundamental level, is just a means of fuelling our bodies.

According to Deanne Jade, principle of the National Centre for Eating Disorders, our complex relationship with food starts right back in the cradle.

"A baby's blood sugar falls if they are hungry and they get in a dire emotional state. They scream and cry, are fed and feel better.


"So very early on we learn to associate stress reduction with eating and drinking.

"Secondly, the chemicals we gain from food have a strong impact not only on our appetite but also on our emotional brains, so the connections between food and mood become intricately connected in a very complex way."

Because of this complex relationship, people might say they are hungry and genuinely believe it, when in fact they are sad. They will also feel sad and miserable when they are hungry because of the deficiency of certain neurochemicals, which carry messages in the brain.

"For example, when we eat we get changes in serotonin, endorphins and dopamine levels in the brain. These are very powerful chemicals, which also affect mood.

"Sugar, for example, causes serotonin flows and serotonin is a chemical used in certain anti-depressants, such as Prozac, which cause the user to feel more balanced and equitable.

"People who are low in serotonin in the brain do generally feel better when they eat sugar, but that's not true of people who have adequate levels of serotonin."

So could that mean we can become addicted to certain foods? The notion has certainly sparked vigorous debate in recent months.

Jane Ogden, a reader in health psychology at King's College, London, believes it depends on your definition of addiction.

She says: "If addiction means you have no control over something, then this could apply to food, but if you take the classic definition of addiction, which means you get withdrawal and tolerance, then I'm not sure it can really apply to eating behaviour."

She adds: "Ideally, if we were purely biological beings, we would only eat when we were hungry, but food intake isn't like that.

"Food becomes a central part of the currency of social life and also the individual's day-to-day emotional life.

"It is no longer is about whether you are hungry or not but takes on a range of other meanings. It becomes part of social negotiation and about celebration and special occasions, about relationships and power.

"The family meal has a whole context which has got very little to do with hunger and satiety and a lot more to do with communication within families and the way you show whether you care about people or how you are bonded.

"Then on an individual level, food has also taken on the role of comfort and distraction from boredom. If we were animals it would have only a very basic meaning but because we are social beings it is inevitable food is going to have a much bigger role in people's lives. "

So how does all this apply to people with anorexia or bulimia?

"Starving causes people to feel high and spaced out and separated from their emotions," says Mrs Jade.

"When you starve, you don't feel the normal range of emotions. You feel kind of insulated from them. It doesn't mean you don't get depressed and miserable - you can get severely depressed - but we are talking about a narrowing of emotional range.

"There are many reasons why starving is alluring to some people. It makes them feel special, powerful, maybe more sexy, maybe less sexy, and it makes them feel they can transcend the normal things that other people need. It makes them feel very, very much in control.

"What is common to people with eating disorders is that body image and feelings about their body are a very big part of their self-esteem."


With binge eating, it has been proved that an unhealthy diet leads to chemical disturbances in the brain, setting up a cycle, so we become depressed, irritable or aggressive, then eat more of the very food that makes us feel that way.

Studies have shown that antisocial behaviour can be connected to having too much sugar and refined carbohydrates and a shortage of vitamins B11, B1 and minerals such as iron, selenium and magnesium and omega-3 fatty acids, found especially in oily fish such as salmon, sardines and mackerel.

A study published in the July 2002 issue of the British Journal of Psychiatry indicates that the simple use of nutritional supplements can significantly reduce behavioural problems among prisoners.

The research, carried out by a team led by C Bernard Gesch of Oxford University, was a trial of nutritional supplements on 231 young adults, comparing disciplinary offences before and during supplementation.

Those receiving the active capsules, rather than a placebo, committed an average of 26.3% fewer offences.

So in times of stress some people will eat more and some will eat less. It apparently comes down to something called biochemical individuality.

It also has a lot to do with the fact that we're all different. Our emotional response to food is formed in childhood, due to many things - the way our parents feed us, and our own experiences around food, which are very personal.


And as well as our chemistry and our individuality, the way we experience emotion and how we handle it also play a part.

To treat eating problems, the National Centre for Eating Disorders tries to regulate food intake, so people are at least protected on the chemical side. The centre also tries to help people become better at dealing with their own emotions without hiding behind food or drugs.

"If I got up in the morning, had a cup of black coffee, went to work and had a diet coke and had no protein until my evening meal, then washed it down with tea and biscuits, I'd be in a pretty bad emotional state by the end of the day as well," says Mrs Jade.

"And that is absolutely and totally to do with the food you don't eat, as well as the food you do eat. A lot of people are absolutely all over the place emotionally, simply because they have a desperately poor diet."

This is a part of article Are we emotionally what we eat? Taken from "Buy Acomplia Tablet" Information Blog

Dermatological Drug Dosage in the Elderly


Changes in Pharmacodynamics

Pharmacodynamic considerations include receptor number and affinity, signal transduction mechanisms, cellular responses, and homeostatic regulation.[59] Sensitivity to certain drugs may be either increased or decreased in the elderly, e.g., sensitivity to benzodiazepines is greater in older patients,[60] as is the response to some opioids and anticoagulants.

Conversely, the elderly seem to be less responsive to certain β-adrenoceptor agonists and antagonists.[27] Simons, et al. studied H1-receptor sensitivity to hydroxyzine by measuring changes in suppression of histamine-induced wheal and flare and suggested an enhanced suppression of H1-receptor activity in the elderly.[24]  Printer- Friendly Email This

Skin Therapy Lett.  2006;11(8):1-7.  ©2006
This is a part of article Dermatological Drug Dosage in the Elderly Taken from "Atarax Hydroxyzine 25Mg" Information Blog

Sunday, July 6, 2008

International Approvals: NovoRapid, Fentanyl, Atriance


International Approvals

International Approvals: NovoRapid, Fentanyl, Atriance

Yael Waknine

September 24, 2007 — The European Commission (EC) has approved insulin aspart subcutaneous injection for use in the elderly and patients with renal or hepatic impairment; the Japanese Ministry of Health, Labor, and Welfare has approved fentanyl citrate 0.1- and 0.25-mg injections for use in pediatric patients aged 2 years and younger; and the EC has approved nelarabine intravenous infusion for the treatment of refractory and relapsed T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma.

Insulin Aspart (NovoRapid) for Use in Elderly Patients in EU

On September 20, the European Commission approved an expanded indication for insulin aspart subcutaneous injection (NovoRapid, Novo Nordisk), allowing its use for the treatment of types 1 and 2 diabetes in the elderly and in patients with renal or hepatic impairment.

According to the International Diabetes Federation, approximately 20% of the world's elderly population has diabetes, and that figure is steadily rising, the company said in a news release. Insulin aspart is the only rapid-acting, modern insulin approved for use in this population.

Insulin aspart previously was approved by the EC for use in children aged 2 years and older and pregnant women. Marketed as NovoLog in the United States, it has been approved by the US Food and Drug Administration for the control of hyperglycemia in diabetic patients, with the caveats that its benefits should justify the risk to the fetus during pregnancy and that lower doses may be required in the setting of renal or hepatic impairment.

Fentanyl Injection for Use in Children Aged Less Than 2 Years in Japan

On August 28, the Japanese Ministry of Health, Labor, and Welfare (MHLW) approved an expanded indication for fentanyl citrate 0.1- and 0.25-mg injections (Daiichi Sankyo Company, Ltd), allowing use of the drug in pediatric patients aged 2 years and younger.

According to a company news release, the approval was based on data from a physician-led phase 3 trial that demonstrated the drug's safety in children and infants.

Fentanyl injection is approved by the MHLW and the US Food and Drug Administration (FDA) for use as a short-term analgesic during anesthetic periods, induction/maintenance, and immediate postoperative period; as a narcotic analgesic supplement in general/regional anesthesia; and as an anesthetic agent with oxygen in high-risk patients. It also may be used with a neuroleptic as an anesthetic premedication, for the induction of anesthesia, and as an adjunct in the maintenance of general/regional anesthesia.

Although the FDA does not contraindicate use of fentanyl injection in children aged less than 2 years, the safety labeling states that rare cases of unexplained clinically significant methemoglobinemia have occurred in premature neonates undergoing emergency anesthesia and surgery that included combined use of fentanyl, pancuronium, and atropine. A direct cause between use of these drugs and methemoglobinemia has not been established.

Nelarabine Injection (Atriance) for Refractory T-ALL and T-LBL in EU

On August 28, the European Commission approved nelarabine intravenous injection (Atriance, GlaxoSmithKline) for the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) in patients who have not responded to or have relapsed after treatment with at least 2 chemotherapy regimens. The approval is valid in all 27 member states of the European Union, with identical national licenses usually issued in Norway, Iceland, and Liechtenstein.

Nelarabine is a prodrug of arabinosylguanine with T-cell selectivity. The nucleoside analog is converted into arabinosylguanine nucleotide triphosphate, which inhibits DNA synthesis and induces apoptosis.

The approval was based on complete response rates induced by nelarabine therapy; randomized trials demonstrating increased survival or other clinical benefits have not been conducted.

Data from 2 multicenter, phase 2 clinical studies of single-agent therapy of nelarabine in relapsed/refractory patients (28 adults, 39 children) showed that 21% of adults and 23% of children achieved a complete response (defined as the disappearance of all detectable signs of disease) both with and without full hematologic recovery. One adult and 4 children went on to receive a stem cell transplant; median overall survival after nelarabine therapy was 21 and 13 weeks in adults and children, respectively.

These findings were supported by those of a German ALL Study Group trial (n = 57), in which 47% of patients treated with nelarabine achieved remission and 74% of those demonstrating complete response were transferred to a stem cell transplant.

Hematologic toxicity was the most common moderate-to-severe (grade 3 – 4) nelarabine-associated adverse event. As with other cytotoxic agents, nelarabine is associated with treatment-limiting neurologic adverse events; close monitoring of patients is recommended, and dosing should be discontinued if neurologic events of grade 2 or greater severity occur.

The recommended regimen for nelarabine in adults is 1500 mg/m², administered intravenously over 2 hours on days 1, 3, and 5 and repeated every 21 days. Pediatric patients should be given 650 mg/m² intravenously over 1 hour daily for 5 consecutive days, repeated every 21 days.

Nelarabine (marketed as Arranon) previously was approved for this indication by the US Food and Drug Administration in October 2005.
This is a part of article International Approvals: NovoRapid, Fentanyl, Atriance Taken from "Atarax Hydroxyzine 25Mg" Information Blog

Efficacy of Granisetron for Treatment of Postoperative Nausea


Patients and Methods

After obtaining approval from our institutional ethics committee and informed consent from each patient, we studied women who were American Society of Anesthesiologist physical status I (no organic, physiological, biochemical or psychiatric disturbances) and who experienced nausea lasting >10 minutes and/or vomiting within the 3 hours after recovery from general anaesthesia for breast surgery. Breast surgery included partial mastectomy, partial mastectomy with axillary dissection, modified radical mastectomy, and modified radical mastectomy with axillary dissection.

We excluded patients who had gastrointestinal disease, those who had a history of motion sickness and/or previous PONV, those who had taken antiemetics within 24 hours before surgery, and those who were pregnant, menstruating or taking hormonal therapy.

Patients were randomly assigned to study groups according to a computer-generated table of random numbers. Placebo or granisetron at four different doses (10 µg/kg, 20 µg/kg, 40 µg/kg and 80 µg/kg) was administered intravenously when patients experienced nausea lasting >10 minutes and/or vomiting within 3 hours after anaesthesia. Identical syringes containing each drug were prepared by personnel not otherwise involved in this study.

For preanaesthetic medication, patients received oral diazepam 5mg, as is routine in our institution. Anaesthesia was induced with intravenous propofol 2 mg/kg and intravenous fentanyl 2 µg/kg; intravenous vecuronium bromide 0.15 mg/kg was used to facilitate tracheal intubation. After tracheal intubation, anaesthesia was maintained with isoflurane 1.0–3.0% (inspired concentration) and nitrous oxide (N2O) 66% in oxygen, with controlled ventilation adjusted using an anaesthetic/respiratory gas analyzer to keep an end-tidal CO2 concentration of 35–40mm Hg. Neuromuscular block was achieved with vecuronium bromide and was antagonized by administering intravenous atropine 0.02 mg/kg and neostigmine 0.04 mg/kg at the end of surgery. The trachea was extubated when the patient was awake. Rectal temperature was monitored and maintained at 36.5–37.0°C using a warming pad. Postoperative analgesia was provided with indometacin 50mg administered rectally when the patient complained of pain. To maintain the integrity of our results, no patients received any intraoperative PONV prophylaxis.

The patients were observed for a 24-hour period after administration of the study drug in order to assess efficacy. All episodes of emetic symptoms (nausea, retching and vomiting) were recorded by nursing staff blinded to the study group allocation of the patient. These nurses observed the patients at intervals according to normal ward routine. Nausea was defined as a subjectively unpleasant feeling associated with an awareness of the urge to vomit; retching was defined as the labored, spasmodic, rhythmic contraction of the respiratory muscles without the expulsion of the gastric contents; and vomiting was defined as the forcing of gastric contents from the mouth.[3] Complete control of established PONV was defined as no emetic symptoms and no need for rescue antiemetic medication. If more than two episodes of vomiting occurred within the 24-hour period after study drug administration, a rescue antiemetic (e.g. domperidone rectally) was given, as is common practice in our institution. The details of any other adverse effects were recorded by the nurses who interviewed the patients.Statistical Analysis

Based on previously published data,[1,2] complete control of established PONV (which was regarded as the primary end-point) in patients receiving placebo would be 50%. An improvement from 50% to 90% with the use of granisetron would be considered clinically significant. To provide 80% power (beta = 0.2) to detect such an absolute difference using a test at a = 0.05, a sample size of 20 patients per group was required. Patient demographic data were analyzed by ANOVA with Bonferroni's correction for multiple comparison (continuous variables) and the Chi-square (χ2) test (discrete variables). The numbers of patients having complete control of established PONV (no emetic symptoms and no rescue medication), experiencing nausea, retching, vomiting or requiring a rescue antiemetic, and the incidence of adverse events were compared with Fisher's exact probability test. A p-value of <0.05 was considered to be significant.  Printer- Friendly Email This

Clin Drug Invest.  2006;26(4):203-208.  ©2006 Adis Data Information BV
This is a part of article Efficacy of Granisetron for Treatment of Postoperative Nausea Taken from "Atarax Hydroxyzine 25Mg" Information Blog

Effective Strategies for Managing Late-Stage Primary Biliary Cirrhosis?

atarax Question

When a patient with primary biliary cirrhosis (PBC) begins to exhibit markedly abnormal liver function tests and is experiencing increasing pruritis that is not relieved by an H1 blocker, hydroxyzine, or cholestyramine, what other therapies may be beneficial? The patient is unable to tolerate doxepin.

Charla Bright, PA-C

Response from  Mary P. Ettari, MPH, PA-C 
A PA in family practice with Medical Partners of Martin County, Stuart, Florida. She is immediate past-president of the Florida Academy of Physician Assistants, past secretary of the American Academy of Physician Assistants, and presently a trustee of the PA Foundation.

PBC is an autoimmune disorder characterized by pruritis and fatigue. The cause is unknown but the mechanism of the disease produces a chronic inflammatory reaction in the liver that damages the interlobular bile ducts, leading to progressive cholestasis and finally cirrhosis.[1]

The disease affects mainly middle-aged women between the ages of 35 and 60 but can affect all ages and races. At least 30% of patients are initially asymptomatic. The diagnosis is usually made during routine bloodwork.[2]

The clinical course of the disease is divided into 4 stages. Stage I is characterized by lymphocytic destruction of the interlobular ducts, and during stage II, there is bile ductular proliferation. Stages III and IV have worsening fibrosis, with cirrhosis occurring in stage IV.[3]

Most cases of PBC are diagnosed on the basis of abnormal liver function tests (LFTs), which lead to further investigation and the ultimate diagnosis of PBC. The most common symptoms are fatigue and pruritis. Additional symptoms are xanthelasma on the eyelids, xanthoma on the palms of the hands and heels, neuropathy, and asymptomatic urinary tract infections (UTIs). As the disease worsens, the patient may develop esophageal varices, osteopenia and osteoporosis, and hepatocellular carcinoma. About 50% of patients present with an enlarged nontender liver, 25% with splenomegaly, 10% with hyperpigmentation, and fewer than 10% with jaundice alone.[2]

The presence of antimitochondrial antibody (AMA) in the serum is a hallmark in the diagnosis of PBC, although not all patients test positive.[3] Additionally, elevations of alkaline phosphatase, gammaglutamyl transpeptidase, and 5'-nucleotidase may be found. These enzymes may be substantially elevated; a less dramatic elevation of the serum aminotransferase may be seen. The conjugated fraction of hyperbilirubinemia may also be elevated.[1]

Medications used in the therapy of PBC are ursodeoxycholic acid 12-15 mg/kg each day in divided doses.[1] Treatment with immunosuppressive agents such as azathioprine and cyclosporine have not improved survival. A clinical trial evaluating methotrexate is currently being evaluated. Colchicine may improve liver function in terms of prothrombin time and serum albumin, but no large-scale studies have yet been done to show improved survival.[1]

Other strategies used to control pruritus include avoiding nylon or wool next to the skin, avoiding hot showers, and not getting overheated in bed at night. Ultraviolet light helps some, but sunburn must be avoided. The old standby of bicarbonate of soda in a cool bath is soothing, as is a post shampoo rinse of bicarbonate of soda. Avoidance of perfumed soaps, bath gels, and powder may also lessen pruritis.[4]

Liver transplantation remains the only cure for PBC and has a survival rate of greater than 70%.Posted 03/13/2001


Heathcote J. Primary biliary cirrhosis. In: Harrison's Online. New York, NY: McGraw-Hill Companies, Inc. 2000. Available at: R, Beers MH, Fletcher AJ, Bogin RM, eds. The Merck Manual. Whitehouse Station, NJ: Merck and Co., Inc. 2000. Available at: J. Update on Primary biliary cirrhosis. Can J Gastroenterol. 2000;14:43-48.That dreaded itch. The PBC Foundation. Available at:

Medscape Family Medicine/Primary Care.  2001;3(1) ©2001 Medscape

This is a part of article Effective Strategies for Managing Late-Stage Primary Biliary Cirrhosis? Taken from "Atarax Hydroxyzine 25Mg" Information Blog

Friday, July 4, 2008

Medical Cannabis Is A Blunt Tool


IF anecdotes and ancient medicine are to be trusted, cannabis is a wonder drug. Yet results of clinical trials have been mixed and its use in modern medicine remains limited. Now it seems the reasons may be practical as much as political and cultural: there are fundamental problems with how our bodies respond to the stuff.

Some compounds in cannabis, including THC and cannabidiol, interfere with a natural signalling system throughout our brains, nerves and immune system. This system, which produces its own cannabis-like compounds called endocannabinoids, plays a role in many medical conditions including pain, epilepsy, multiple sclerosis, Parkinson's disease, depression and schizophrenia.

Because the system is so widespread, smoking or ingesting cannabis is bound to have varied effects, including its influence on the mind. Now it seems that even with purified cannabis extracts, changing the amount, time or place of a dose could produce completely opposite effects on the body, according to evidence presented at the Federation of European Neuroscience Societies (FENS) meeting in Vienna earlier this month. This could explain why the medical benefits have proved so difficult to harness.

In one study, Vincenzo Di Marzo of the National Research Council in Pozzuoli, Italy, boosted levels of an endocannabinoid called andandamide in rats engineered to develop an Alzheimer's-like disease. This appeared to protect the rats from memory loss and nerve degeneration. But if the rise was prolonged, cannabinoids became ineffective or even damaging.

Beat Lutz of the University of Mainz in Germany found a similar paradox in models of epilepsy in mice. Anandamide is synthesised during epileptic fits, providing a natural calming effect. "If we apply cannabinoids we should protect from seizures," says Lutz. "But no, we actually get worsening of seizures in mice."

He believes he has found the reason. The main class of cannabinoid receptor, called CB1 receptors, occurs in two distinct populations of neurons, those that excite neighbouring neurons and those that inhibit them - so cannabinoids can have opposite effects depending on which neurons they hit. David Baker, a multiple sclerosis expert at University College London has found the same problem in MS. Mice that have been engineered to have a condition like MS and no CB1 receptors suffer much worse nerve damage than those with normal CB1 receptors, suggesting that cannabinoids are involved in protecting against the nerve damage seen in MS. But other experiments in mice have shown that cannabinoid signalling also prompts release of stress hormones called glucocorticoids that can kill neurons.

The greatest anecdotal evidence for the medical benefits of cannabis comes from its painkilling properties, and animal models have produced promising results. Yet even here new evidence suggests that an endocannabinoid called NADA binds not only to cannabinoid receptors but to a completely different class of receptor as well, where it mimicks the effect of a pain-producing chemical called capsaicin, says J. Michael Walker of Indiana University in Bloomington, who also presented his research at FENS. This may explain why human trials of cannabis for the treatment of pain have produced mixed results.

"The problem with cannabis is that there's no way of targeting the drug to any particular place," says Baker.

The answer will be to manipulate the system from within, he says. New ways of amplifying natural cannabinoid release include reuptake inhibitors that prolong this release just as Prozac does for serotonin. Such methods look promising for a range of conditions from pain and cancer to nerve degeneration and MS.

Other methods now being tried in the lab include the manipulation of enzymes that make and deliver endocannabinoids, as well as compounds that stimulate and block them. Drugs that bind to CB1 receptors and alter their efficiency are also being discovered, says Roger Pertwee, director of pharmacology at GW Pharmaceuticals, based in Porton Down Science Park, Wiltshire, UK. His company developed Sativex, the first pharmaceutical cannabis extract to gain clinical approval.

Ironically, the first offshoot of endocannabinoid research to gain clinical approval, last month, has the opposite effect to cannabis: Acomplia (rimonabant), an appetite suppressant, works by blocking CB1 receptors (New Scientist, 8 July, p 5).


scientific publication

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This is a part of article Medical Cannabis Is A Blunt Tool Taken from "Buy Acomplia Tablet" Information Blog