Nicholas Perricone /'p?r?ko?n/, MD, is a board certified dermatologist, nutritionist who has written several books, primarily on the subjects of weight loss and maintaining the appearance of youth. Perricone is an Adjunct Professor of Medicine at Michigan State University's College of Human Medicine, from which he received his MD. He has over 40 U.S patents and appeared in two special programs on PBS. Perricone sells his own line of skin care products.

According to PEERtrainer, Perricone presents himself as a radical in the dermatological community, repeatedly encouraging his audience to challenge the status quo. He compares his work relating diet to skin care with Ignaz Semmelweis's work on hand washing and the spread of disease in the 1800s.

Perricone takes a staunchly anti-Botox stance. He argues that an anti-inflammatory diet plus nutritional supplements and topical anti aging products can produce a better result in fighting the aging process. In an interview with Marie Claire magazine, Perricone writes that "Botox is a neurotoxin that paralyzes the muscle. After people use it, they start losing volume in their face, and that accelerates the appearance of aging."

Perricone is also known for advocating "beauty from the inside out," as reported in Goop, Gwyneth Paltrow's lifestyle newsletter.

Books

Perricone's books all take a similar three-tiered approach to skin problems: diet, supplements, and topicals. The books share some general recommendations, but each contains unique material.

• Forever Young: The Science of Nutrigenomics for Glowing, Wrinkle-Free Skin and Radiant Health at Every Age. Atria Books, 2010.
• Ageless Face, Ageless Mind: Erase Wrinkles and Rejuvenate the Brain. Ballantine Books, 2007.
• Dr. Perricone's 7 Secrets to Beauty, Health, and Longevity: The Miracle of Cellular Rejuvenation. Ballantine Books, 2006.
• The Perricone Weight-Loss Diet: A Simple 3-Part Plan to Lose the Fat, the Wrinkles, and the Years. Ballantine Books, 2005.
• The Perricone Promise: Look Younger, Live Longer in Three Easy Steps. Warner Books, 2004.
• Dr. Nicholas Perricone's Programme: Grow Young, Get Slim, in Days!. Thorsons, 2004.
• The Clear Skin Prescription : The Perricone Program to Eliminate Problem Skin. HarperCollins, 2004.
• The Acne Prescription: The Perricone Program for Clear and Healthy Skin at Every Age. HarperCollins, 2003.
• The Perricone Prescription: A Physician's 28-Day Program for Total Body and Face Rejuvenation. Harper, 2002.
• The Wrinkle Cure: The Formula for Stopping Time. Vermilion, 2001.
• The Wrinkle Cure: Unlock the Power of Cosmeceuticals for Supple, Youthful Skin. Rodale, 2000.

References

External links

• Dr. Perricone's official website
• A Skeptical View of the Perricone Prescription

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Bupropion (/bju:'pro?pi.?n/ bew-PROH-pee-on) (BAN) or bupropion hydrochloride (USAN, BAN), also known as amfebutamone (INN), is a drug of the aminoketone family primarily used as an antidepressant and smoking cessation aid. Marketed as Wellbutrin and other trade names, it is one of the most frequently prescribed antidepressants in the United States, although in many English-speaking countries, including the United Kingdom, Australia and New Zealand, this is an off-label use. It is also widely used, in a formulation marketed as Zyban, to aid people who are trying to quit smoking. Bupropion is consumed in tablet form and is available only by prescription in most countries.

Clinically, bupropion serves as an atypical antidepressant fundamentally different from most commonly prescribed antidepressants such as selective serotonin reuptake inhibitors (SSRIs). It is an effective antidepressant on its own, but is also popular as an add-on medication in cases of incomplete response to first-line SSRI antidepressants. In contrast to many other antidepressants, it does not cause weight gain or sexual dysfunction. The most important side effect is an increase in risk for epileptic seizures, which caused the drug to be withdrawn from the market for some time and then caused the recommended dosage to be reduced.

Bupropion is known to affect several different biological targets, and its mechanism of action is only partly understood. It has been widely described in the literature as a weak norepinephrine-dopamine reuptake inhibitor (NDRI). However, this is not entirely accurate. There is evidence that bupropion induces the release of norepinephrine and dopamine in addition to inhibiting their reuptake, similarly to other cathinones like amfepramone (diethylpropion). Moreover, studies with humans via the oral administration route have demonstrated that bupropion does not significantly affect dopamine levels in the brain at clinically-used doses, indicating that its in vitro capacity to inhibit the reuptake and induce the release of dopamine is not involved in its clinical effects. This finding can be reasonably explained by extensive first-pass metabolism of bupropion into metabolites with differing pharmacology - namely, selective noradrenergic action without dopaminergic effect. In addition to its monoaminergic actions, bupropion and its metabolites act as non-competitive antagonists of several neuronal nicotinic acetylcholine receptors (nACh receptors), a property which appears to be importantly involved in both the antidepressant effects of bupropion and its efficacy in smoking cessation. Chemically, bupropion belongs to the class of aminoketones and is similar in structure to stimulants such as cathinone and amfepramone, and to phenethylamines in general.

Bupropion was synthesized by Nariman Mehta and patented by Burroughs Wellcome in 1969, which later became part of what is now GlaxoSmithKline. It was first approved for clinical use in the United States in 1989. It was originally called by the generic name amfebutamone, before being renamed in 2000. Its chemical name is 3-chloro-N-tert-butyl-?-ketoamphetamine. It is a substituted cathinone (?-ketoamphetamine), and by extension, a substituted amphetamine.

Medical uses

Depression

Bupropion is one of the most widely prescribed antidepressants, and the available evidence indicates that it is effective in clinical depression -- as effective as several other widely prescribed drugs, including fluoxetine (Prozac) and paroxetine (Paxil), although trends favoring the efficacy of escitalopram (Lexapro), sertraline (Zoloft) and venlafaxine (Effexor) over bupropion have been observed. Mirtazapine (Remeron), on the other hand is significantly more effective than bupropion. Bupropion has several features that distinguish it from other antidepressants: for instance, unlike the majority of antidepressants, it does not usually cause sexual dysfunction. Bupropion treatment also is not associated with the somnolence or weight gain that may be produced by other antidepressants.

In depressed people who experience symptoms of sleepiness and fatigue, bupropion has been found to be more effective than selective serotonin reuptake inhibitors (SSRIs) in alleviating these symptoms. There appears to be a modest advantage for the SSRIs over bupropion in the treatment of anxious depression.

According to surveys, the addition to a prescribed SSRI is a common strategy when people do not respond to the SSRI, even though this is not an officially approved indication. The addition of bupropion to an SSRI (most commonly fluoxetine or sertraline) may result in an improvement in some people who have an incomplete response to the first-line antidepressant.

In some countries (including Australia, New Zealand and the UK) this is an off-label use. Bupropion was approved by the U.S. Food and Drug Administration (FDA), in 2006, for the prevention of seasonal affective disorder.

Smoking cessation

The next most common use is as an aid for smoking cessation where it reduces the severity of nicotine cravings and withdrawal symptoms. A typical bupropion treatment course lasts for seven to twelve weeks, with the patient halting the use of tobacco about ten days into the course. Bupropion approximately doubles the chance of quitting smoking successfully after three months. One year after treatment, the odds of sustaining smoking cessation are still 1.5 times higher in the bupropion group than in the placebo group.

The evidence is clear that bupropion is effective at reducing nicotine cravings. Whether it is more effective than other treatments is not as clear, due to a limited number of studies. The evidence that is available suggests that bupropion is comparable to nicotine replacement therapy, but somewhat less effective than varenicline (Chantix).

In Australia and the UK smoking cessation is the only licensed indication of bupropion.

Attention deficit hyperactivity disorder

There have been numerous reports of positive results for bupropion as a treatment for attention deficit hyperactivity disorder (ADHD), both in minors and adults. However, in a double-blind study of children, while aggression and hyperactivity as rated by the children's teachers were significantly improved in comparison to placebo, parents and clinicians could not distinguish between the effects of bupropion and placebo. The 2007 guideline on the ADHD treatment from American Academy of Child and Adolescent Psychiatry notes that the evidence for bupropion is "far weaker" than for the FDA-approved treatments. Its effect may also be "considerably less than of the approved agents ... Thus it may be prudent for the clinician to recommend a trial of behavior therapy at this point, before moving to these second-line agents." Similarly, the Texas Department of State Health Services guideline recommends considering bupropion or a tricyclic antidepressant as a fourth-line treatment after trying two different stimulants and atomoxetine.

Sexual dysfunction

Bupropion is one of few antidepressants that do not cause sexual dysfunction. A range of studies demonstrate that bupropion not only produces fewer sexual side effects than other antidepressants, but can actually help to alleviate sexual dysfunction. According to a survey of psychiatrists, it is the drug of choice for the treatment of SSRI-induced sexual dysfunction, although this is not an indication approved by the U.S. Food and Drug Administration. There have also been a few studies suggesting that bupropion can improve sexual function in women who are not depressed, if they have hypoactive sexual desire disorder (HSDD).

Obesity

Bupropion, when used for treating obesity over a period of 6 to 12 months, may result in weight loss of 2.7 kg over placebo. This is not much different from the weight loss produced by several other medications, such as sibutramine, orlistat and amfepramone.

It has been studied in combination with naltrexone. Concerns from bupropion include an increase in blood pressure and heart rate. In September 2014, a combination (bupropion/naltrexone) was approved by the USFDA for the treatment of obesity.

Other

There has been controversy about whether it is useful to add an antidepressant such as bupropion to a mood stabilizer in patients with bipolar depression, but recent reviews have concluded that bupropion in this situation does no significant harm and may sometimes give significant benefit.

Bupropion has shown no effectiveness in the treatment of cocaine dependence, but there is weak evidence that it may be useful in treating methamphetamine dependence.

Based on studies indicating that bupropion lowers the level of the inflammatory mediator TNF-alpha, there have been suggestions that it might be useful in treating inflammatory bowel disease or other autoimmune conditions, but very little clinical evidence is available.

Bupropion--like other antidepressants, with the exception of duloxetine (Cymbalta)--is not effective in treating chronic low back pain. It does, however, show some promise in the treatment of neuropathic pain.

Contraindications

GlaxoSmithKline advises that bupropion should not be prescribed to individuals with epilepsy or other conditions that lower the seizure threshold, such as anorexia nervosa, bulimia nervosa, active brain tumors, or concurrent alcohol and/or benzodiazepine use and/or withdrawal. It should be avoided in individuals who are also taking monoamine oxidase inhibitors (MAOIs). When switching from MAOIs to bupropion, it is important to include a washout period of about two weeks between the medications. The prescribing information approved by the FDA recommends that caution should be exercised when treating patients with liver damage, severe kidney disease, and severe hypertension, and in pediatric patients, adolescents and young adults due to the increased risk of suicidal ideation.

Side effects

Epileptic seizures are the most important adverse effect of bupropion. A high incidence of seizures was responsible for the temporary withdrawal of the drug from the market between 1986 and 1989. The risk of seizure is strongly dose-dependent, but also dependent on the preparation. The sustained-release preparation is associated with a seizure incidence of 0.1% at daily dosages of less than 300 mg of bupropion and 0.4% at 300-400 mg. The immediate release preparation is associated with a seizure incidence of 0.4% for dosages below 450 mg; the incidence climbs to 5% for dosages between 450-600 mg per day. For comparison, the incidence of unprovoked seizure in the general population is 0.07 to 0.09%, and the risk of seizure for a variety of other antidepressants is generally between 0 and 0.6% at recommended dosage levels. Given that clinical depression itself has been reported to increase the occurrence of seizures, it has been suggested that low to moderate doses of antidepressants may not actually increase seizure risk at all. However, this same study found that bupropion and clomipramine were unique among antidepressants in that they were associated with increased incidence of seizures.

The prescribing information notes that hypertension, sometimes severe, was observed in some patients, both with and without pre-existing hypertension. The frequency of this adverse effect was under 1% and not significantly higher than found with placebo. A review of the available data carried out in 2008 indicated that bupropion is safe to use in patients with a variety of serious cardiac conditions.

In the UK, more than 7,600 reports of suspected adverse reactions were collected in the first two years after bupropion's approval by the Medicines and Healthcare Products Regulatory Agency as part of the Yellow Card Scheme, which monitored side effects. Approximately 540,000 people were treated with bupropion for smoking cessation during that period. The MHRA received 60 reports of "suspected [emphasis MHRA's] adverse reactions to Zyban which had a fatal outcome". The agency concluded that "in the majority of cases the individual's underlying condition may provide an alternative explanation." This is consistent with a large, 9,300-patient safety study that showed that the mortality of smokers taking bupropion is not higher than the natural mortality of smokers of the same age.

Psychiatric

Suicidal thought and behavior are rare in clinical trials, and the FDA requires all antidepressants, including bupropion, to carry a boxed warning stating that antidepressants may increase the risk of suicide in persons younger than 25. This warning is based on a statistical analysis conducted by the FDA which found a 2-fold increase in suicidal thought and behavior in children and adolescents, and 1.5-fold increase in the 18-24 age group. For this analysis the FDA combined the results of 295 trials of 11 antidepressants in order to obtain statistically significant results. Considered in isolation, bupropion was not statistically different from placebo.

Suicidal behavior is less of a concern when bupropion is prescribed for smoking cessation. According to a 2007 Cochrane Database review, there have been four suicides per one million prescriptions and one case of suicidal ideation per ten thousand prescriptions of bupropion for smoking cessation in the UK. The review concludes, "Although some suicides and deaths while taking bupropion have been reported, thus far there is insufficient evidence to suggest they were caused by bupropion."

In 2009 the FDA issued a health advisory warning that the prescription of bupropion for smoking cessation has been associated with reports about unusual behavior changes, agitation and hostility. Some patients, according to the advisory, have become depressed or have had their depression worsen, have had thoughts about suicide or dying, or have attempted suicide. This advisory was based on a review of anti-smoking products that identified 75 reports of "suicidal adverse events" for bupropion over ten years.

Bupropion-induced psychosis may develop in select patient populations, or worsen a pre-existing psychotic syndrome. Symptoms may include delusions, hallucinations, paranoia, and confusion. In most cases these symptoms can be reduced or eliminated by reducing the dose, ceasing treatment or adding antipsychotic medication. However, adding a benzodiazepine to treat psychosis, instead of an antipsychotic, may become a valid alternative according to the model of amphetamine-induced psychosis. Psychotic symptoms are associated with factors such as higher doses of bupropion, a history of bipolar disorder or psychosis, concomitant medications, for example, lithium or benzodiazepines, old age, or substance abuse.

According to several case reports, the use of bupropion at therapeutic doses may induce a mild state of psychological dependence in some users; the associated psychological withdrawal symptoms which have been observed following the abrupt discontinuation of treatment include: dystonia, irritability, anxiety, mania, headache, aches and pains. The prescribing information recommends dose tapering after bupropion has been used for seasonal affective disorder; however it states that dose tapering is not required when discontinuing treatment for smoking cessation.

Overdose

Bupropion is considered moderately dangerous in overdose.

In the majority of childhood exploratory ingestions involving one or two tablets, children show no apparent symptoms. In teenagers and adults, seizures are more commonly observed, with the seizure rate increasing tenfold with doses of 600 mg daily.

Bupropion overdose rarely results in death, although some cases have been reported. Symptoms include hallucinations and delusions, vomiting, aggressive behavior, and seizures.

Interactions

Since bupropion is metabolized to hydroxybupropion by the CYP2B6 enzyme, drug interactions with CYP2B6 inhibitors are possible: this includes medications like paroxetine, sertraline, fluoxetine, diazepam, clopidogrel, and orphenadrine. The expected result is the increase of bupropion and decrease of hydroxybupropion blood concentration. The reverse effect (decrease of bupropion and increase of hydroxybupropion) can be expected with CYP2B6 inducers, such as carbamazepine, clotrimazole, rifampicin, ritonavir, St John's wort, phenobarbital, phenytoin and others. Conversely, because bupropion is itself an inhibitor of CYP2D6 (K_i=21 ?M), as is its active metabolite, hydroxybupropion (K_i=13.3 ?M), it can slow the clearance of other drugs metabolized by this enzyme.

Bupropion lowers the threshold for epileptic seizures, and therefore can potentially interact with other medications that also lower it, such as carbapenems, cholinergic agents, fluoroquinolones, interferons, chloroquine, mefloquine, lindane, theophylline, systemic corticosteroids (e.g., prednisone), and some tricyclic antidepressants (e.g., clomipramine). The prescribing information recommends minimizing the use of alcohol, since in rare cases bupropion reduces alcohol tolerance, and because the excessive use of alcohol may lower the seizure threshold. Also, bupropion should not be taken by individuals undergoing abrupt cessation of alcohol or benzodiazepine use.

Caution should be observed when combining bupropion with a monoamine oxidase inhibitor (MAOI).

Pharmacology

Pharmacodynamics

Based on animal and human proteins research, bupropion has been characterized as a weak norepinephrine-dopamine reuptake inhibitor (NDRI). It has also been found to act as a releasing agent of dopamine and norepinephrine (NDRA). However, in actual humans, bupropion is extensively converted in the body into several active metabolites with differing activity and influence on the effects of bupropion during first-pass metabolism. These metabolites are present in significantly higher levels in the body compared to bupropion itself. The most important example of this is bupropion's most major metabolite, hydroxybupropion, a selective norepinephrine reuptake inhibitor (and likely releasing agent) and nACh receptor antagonist that lacks significant dopaminergic actions, which, with oral bupropion treatment, can reach area under the curve (AUC) plasma concentrations that are as much as 16-20 times greater than those of bupropion itself. As such, it may be more accurate to describe bupropion as a prodrug in humans, and hence, its effects cannot be understood without reference to its metabolism.

The occupancy of dopamine transporter (DAT) sites by bupropion and its metabolites in the human brain as measured by positron emission tomography was 26% according to GlaxoSmithKline researchers and 14% in an independent study. Despite this weak DAT occupancy however, a subsequent study looked at the actual extracellular concentrations of dopamine in the human brain after an acute oral treatment of bupropion and failed to observe any increase, concluding that the weak DAT occupancy was not sufficient to increase dopamine levels. In contrast, the same study also looked at dopamine levels in the rat brain after administration of bupropion via intraperitoneal injection and did see an increase, which could have been related to species differences. However, an alternative explanation is that the difference had to do with the different routes of administration employed (i.e., oral vs. i.p.) and the associated differences in pharmacokinetics and metabolism, namely, the bypassing of first-past metabolism with the latter route, that resulted. Although oral bupropion at clinical doses does not appear to have a significant potential for abuse, there are many isolated case reports of bupropion abuse and "cocaine-like" effects in humans who ingested the drug via a non-oral route (e.g., injection, insufflation, etc.). Notably, awareness of the abuse potential of bupropion via non-conventional routes appears to be especially prominent in correctional facilities.

Bupropion is also known to act as a non-competitive antagonist of the ?₃?₂, ?₃?₄, ?₄?₂, and, very weakly, ?₇ nACh receptors, and these actions appear to be importantly involved in its beneficial properties not only in smoking cessation, but in depression as well. The metabolites of bupropion also act as non-competitive antagonists of these nACh receptors, and hydroxybupropion is even more potent in comparison.

Pharmacokinetics

Bupropion is metabolized in the liver by the cytochrome P450 isoenzyme CYP2B6. It has several active metabolites: R,R-hydroxybupropion, S,S-hydroxybupropion, threo-hydrobupropion and erythro-hydrobupropion, which are further metabolized to inactive metabolites and eliminated through excretion into the urine. Pharmacological data on bupropion and its metabolites are shown in the table. Bupropion is known to weakly inhibit the ?₁ adrenergic receptor, with a 14% potency of its dopamine uptake inhibition, and the H₁ receptor, with a 9% potency.

The biological activity of bupropion can be attributed to a significant degree to its active metabolites, in particular to S,S-hydroxybupropion. GlaxoSmithKline developed this metabolite as a separate drug called radafaxine, but discontinued development in 2006 due to "an unfavourable risk/benefit assessment".

Bupropion is metabolized to hydroxybupropion by CYP2B6, an isozyme of the cytochrome P450 system. Alcohol causes an increase of CYP2B6 in the liver, and persons with a history of alcohol use metabolize bupropion faster. Bupropion is metabolized to threo-hydrobupropion via cortisone reductase. The metabolic pathway responsible for the creation of erythro-hydrobupropion remains elusive.

The metabolism of bupropion is highly variable: the effective doses of bupropion received by persons who ingest the same amount of the drug may differ by as much as 5.5 times (and the half-life from 3 to 16 hours), and of hydroxybupropion by as much as 7.5 times (and the half-life from 12 to 38 hours). Based on this, some researchers have advocated monitoring of the blood level of bupropion and hydroxybupropion.

There are significant interspecies differences in the metabolism of bupropion, with the metabolism in humans being more similar to guinea pigs than to mice and rats.

Both bupropion and its primary metabolite hydroxybupropion act in the liver as potent inhibitors of the enzyme CYP2D6, which metabolizes not only bupropion itself but also a variety of other drugs and biologically active substances. This mechanism creates the potential for a variety of drug interactions.

There have been two reported cases of false-positive urine amphetamine tests in persons taking bupropion. More specific follow-up tests were negative.

Physical and chemical properties

Synthesis

Bupropion is a substituted cathinone. It is synthesized in two chemical steps starting from 3'-chloro-propiophenone. The alpha position adjacent to the ketone is first brominated followed by nucleophilic displacement of the resulting alpha-bromoketone with t-butylamine and treated with hydrochloric acid to give bupropion as the hydrochloride salt in 75-85% overall yield.

History

Bupropion was invented by Nariman Mehta of Burroughs Wellcome (now GlaxoSmithKline) in 1969, and the US patent for it was granted in 1974. It was approved by the United States Food and Drug Administration (FDA) as an antidepressant on 30 December 1985, and marketed under the name Wellbutrin. However, a significant incidence of epileptic seizures at the originally recommended dosage caused the withdrawal of the drug in 1986. Subsequently, the risk of seizures was found to be highly dose-dependent, and bupropion was re-introduced to the market in 1989 with a lower maximum recommended daily dose.

In 1996, the FDA approved a sustained-release formulation of bupropion called Wellbutrin SR, intended to be taken twice a day (as compared with three times a day for immediate-release Wellbutrin). In 2003, the FDA approved another sustained-release formulation called Wellbutrin XL, intended for once-daily dosing. Wellbutrin SR and XL are available in generic form in the United States and Canada. In Canada, generic XR bupropion is distributed by Mylan. In 1997, bupropion was approved by the FDA for use as a smoking cessation aid under the name Zyban. In 2006, Wellbutrin XL was similarly approved as a treatment for seasonal affective disorder.

In April 2008, the FDA approved a formulation of bupropion as a hydrobromide salt instead of a hydrochloride salt, to be sold under the name Aplenzin by Sanofi-Aventis.

Issue with generic bioequivalence

On 11 October 2007, two providers of consumer information on nutritional products and supplements, ConsumerLab.com and The People's Pharmacy, released the results of comparative tests of different brands of bupropion. The People's Pharmacy received multiple reports of increased side effects and decreased efficacy of generic bupropion, which prompted it to ask ConsumerLab.com to test the products in question. The tests showed that "one of a few generic versions of Wellbutrin XL 300 mg, sold as Budeprion XL 300 mg, didn't perform the same as the brand-name pill in the lab." The FDA investigated these complaints and concluded that Budeprion XL is equivalent to Wellbutrin XL in regard to bioavailability of bupropion and its main active metabolite hydroxybupropion. The FDA also said that coincidental natural mood variation is the most likely explanation for the apparent worsening of depression after the switch from Wellbutrin XL to Budeprion XL. On 3 October 2012, however, the FDA reversed this opinion, announcing that "Budeprion XL 300 mg fails to demonstrate therapeutic equivalence to Wellbutrin XL 300 mg." The FDA did not test the bioequivalence of any of the other generic versions of Wellbutrin XL 300 mg, but requested that the four manufacturers submit data on this question to the FDA by March 2013. As of October 2013 the FDA has made determinations on the formulations from some manufacturers not being bioequivalent.

In 2012, the U.S. Justice Department announced that GlaxoSmithKline had agreed to plead guilty and pay a $3-billion fine, in part for promoting the unapproved use of Wellbutrin for weight loss and sexual dysfunction.

In France, marketing authorization was granted for Zyban on 3 August 2001, with a maximum daily dose of 300 mg; only sustained-release bupropion is available, and only as a smoking cessation aid. Bupropion was granted a licence for use in adults with major depression in the Netherlands in early 2007, with GlaxoSmithKline expecting subsequent approval in other European countries.

Society and culture

Brand names

Bupropion is marketed under many brand names including Aplenzin, Budeprion, Elontril, Wellbutrin, Quomem, Prexaton, Voxra, and Zyban among others.

Recreational use

According to the US government classification of psychiatric medications, bupropion is "non-abusable". However, in animal studies, squirrel monkeys and rats could be induced to self-administer bupropion via the injection route, which is often taken as a sign of addiction potential. There have been a number of anecdotal and case-study reports of bupropion abuse, but the bulk of evidence indicates that the subjective effects of bupropion via the oral route are markedly different from those of addictive stimulants such as cocaine or amphetamine. That said, bupropion, via non-conventional routes of administration (e.g., injection, insufflation), is reported to be abused in the United States and Canada, notably in prisons.

References

External links

• Official Wellbutrin website
• List of international brand names for bupropion
• Bupropion at DMOZ
• Wellbutrin Pharmacology, Pharmacokinetics, Studies, Metabolism - Bupropion - RxList Monographs
• NAMI Wellbutrin
• Bupropion article from mentalhealth.com

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The drug combination fenfluramine/phentermine, usually called fen-phen, was an anti-obesity treatment that utilized two anorectics. Fenfluramine was marketed by American Home Products (later known as Wyeth) as Pondimin, but was shown to cause potentially fatal pulmonary hypertension and heart valve problems, which eventually led to its withdrawal and legal damages of over $13 billion. Phentermine was not shown to have harmful effects.

Fenfluramine acts as a serotonin releasing agent, phentermine as a norepinephrine, dopamine and serotonin releasing agent.

History

Fenfluramine as a single drug was first introduced in the 1970s, but was not popular because it only temporarily reduced weight. A 1984 study found a weight loss of 7.5 kg on average in 24 weeks, as compared to 4.4 kg under placebo. It sold modestly until the 1990s, when it was combined with phentermine and heavily marketed. A similar drug, aminorex, had caused severe lung damage and "provided reason to worry that similar drugs ... could increase the risk of a rare but often fatal lung disease, pulmonary hypertension." In 1994, Wyeth official Fred Wilson expressed concerns about fenfluramine's labeling containing only four cases of pulmonary hypertension when a total of 41 had been observed, but no action was taken until 1996. In 1995, Wyeth introduced dexfenfluramine (the dextro isomer, marketed as Redux), which it hoped would cause fewer adverse effects. However, the medical officer of the Food and Drug Administration (FDA), Leo Lutwak, insisted upon a black box warning of pulmonary hypertension risks. After Lutwak refused to approve the drug, the FDA management had someone else sign it and approved the drug with no black box warning for marketing in 1996. European regulators required a major warning of pulmonary hypertension risks.

In 1996, a paper in the New England Journal of Medicine (NEJM) from the Mayo Clinic discussed clinical findings in 24 patients who had taken fen-phen. The authors noted that their findings suggested a possible correlation between mitral valve dysfunction and the use of these anorectic agents. Later in 1996, a 30-year-old woman developed heart problems after a month of using it; when she died in February 1997, the Boston Herald devoted a front page article to her. The FDA alerted medical doctors that it had received nine additional reports of the same type, and requested all health care professionals to report any such cases to the agency's MedWatch program, or to their respective pharmaceutical manufacturers. The FDA subsequently received over a hundred additional reports of valvular heart disease in patients taking fen-phen, fenfluramine alone or dexfenfluramine alone. The FDA requested that the manufacturers of fenfluramine and dexfenfluramine stress the potential risk to the heart in the drugs' labeling and in patient package inserts. As of 1997, the FDA was continuing to receive reports of valvular heart disease in persons who had taken these drugs. This disease typically involves the aortic and mitral valves.

After reports of valvular heart disease and pulmonary hypertension, primarily in women who had been undergoing treatment with fen-phen or (dex)fenfluramine, the FDA requested its withdrawal from the market in September 1997.

The action was based on findings from doctors who had evaluated patients taking these two drugs with echocardiograms, a procedure that can test the functioning of heart valves. The findings indicated that approximately 30 percent of evaluated patients had abnormal echocardiograms, even though they had no symptoms. This percentage of abnormal test results was much higher than would be expected from a comparatively sized sample of the population who had not been exposed to either fenfluramine or dexfenfluramine.

Aftermath

Upon the release of the information regarding fen-phen's cardiac risks, the Association of Trial Lawyers of America formed a large trial lawyer group to seek damages from American Home Products, the distributor of fenfluramine and dexfenfluramine.

Fen-phen is no longer widely available. In April 2005, American Lawyer magazine ran a cover story on the wave of fen-phen litigation, reporting that more than 50,000 product liability lawsuits had been filed by alleged fen-phen victims. Estimates of total liability ran as high as $14 billion. As of February 2005, Wyeth was still in negotiations with injured parties, offering settlements of $5,000 to $200,000 to some of those who had sued, and stating they might offer more to those who were most seriously injured. One plaintiff's attorney claimed that "the payments [were] not going to be large enough to cover medical expenses." Thousands of injured persons rejected these offers. At the time, Wyeth announced it has set aside $21.1 billion (U.S.) to cover the cost of the lawsuits.

Possible uses

Obesity

In 1984, researchers at the University of Rochester Medical Center reported that they had performed a double-blind, controlled clinical trial comparing phentermine alone, fenfluramine alone, a combination of phentermine and fenfluramine, and placebo, for weight loss in humans. Weight loss in those receiving the fen-phen combination was significantly greater (8.4±1.1 kg) than in those receiving placebo (4.4±0.9 kg) and equivalent to that of those receiving fenfluramine (7.5±1.2 kg) or phentermine alone (10.0±1.2 kg). This amounts to an additional weight loss of 4±2 kg over the course of 24 weeks. Adverse effects were less frequent with the combination regimen than with the other active (non-placebo) treatments. The authors felt that combining fenfluramine and phentermine capitalized on their pharmacodynamic differences, resulting in equivalent weight loss, fewer adverse effects, and better appetite control.

Addiction

The term fen-phen was coined in 1994 when Pietr Hitzig and Richard B. Rothman reported that this combination could presumptively remit alcohol and cocaine craving. The authors suggested that other combined dopamine and serotonin agonists or precursors might share this therapeutic potential. Subsequent experiments in rats supported these preliminary reports. In 2006 it was confirmed that the combination of phentermine and the serotonin precursor 5-hydroxytryptophan (5-HTP), in place of fenfluramine, significantly decreased alcohol withdrawal seizures in rats.

Intramural National Institutes of Health (NIH) double-blind protocols to demonstrate the efficacy of fen-phen in alcohol and cocaine addiction were designed, but never performed.

Adverse effects

The findings on fen-phen, specifically fenfluramine, causing valvular heart disease and pulmonary hypertension prompted a renewed interest in the deleterious effects of systemic serotonin. It had already been known for decades that two of the major side-effects of the carcinoid syndrome, in which excessive serotonin is produced endogenously, are valvular disease and pulmonary hypertension. Several centers were able to note a relationship to an excessive activation of the serotonin receptor subtype 5-HT_2B.

In Popular Culture

Fen-phen is referenced in Season 2, Episode 14 of Arrested Development
Fen-phen is also referenced in Season 2, Episode 1 of Scrubs.

References

External links

• Frontline: Dangerous prescriptions - Interview with Leo Lutwak, in which he discusses the side effects of fenfluramine (Pondimin), its successor dexfenfluramine (Redux), and the fen-phen combination.
• U.S. FDA fen-phen information
• Tellier, P. (2001). "Fenfluramines, idiopathic pulmonary primary hypertension and cardiac valve disorders: Facts and artifacts". Annales de medecine interne 152 (7): 429-436. PMID 11965083. 

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Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, due to a mean loss of fluid, body fat or adipose tissue and/or lean mass, namely bone mineral deposits, muscle, tendon, and other connective tissue. Weight loss can either occur unintentionally due to malnourishment or an underlying disease or arise from a conscious effort to improve an actual or perceived overweight or obese state. "Unexplained" weight loss that is not caused by reduction in calorific intake or exercise is called cachexia and may be a symptom of a serious medical condition. Intentional weight loss is commonly referred to as slimming.

Unintentional

Characteristics

Unintentional weight loss may result from loss of body fats, loss of body fluids, muscle atrophy, or even a combination of these. It is generally regarded as a medical problem when at least 10% of a person's body weight has been lost in six months or 5% in the last month. Another criterion used for assessing weight that is too low is the body mass index (BMI). However, even lesser amounts of weight loss can be a cause for serious concern in a frail elderly person.

Unintentional weight loss can occur because of an inadequately nutritious diet relative to a person's energy needs (generally called malnutrition). Disease processes, changes in metabolism, hormonal changes, medications or other treatments, disease- or treatment-related dietary changes, or reduced appetite associated with a disease or treatment can also cause unintentional weight loss. Poor nutrient utilization can lead to weight loss, and can be caused by fistulae in the gastrointestinal tract, diarrhea, drug-nutrient interaction, enzyme depletion and muscle atrophy.

Continuing weight loss may deteriorate into wasting, a vaguely defined condition called cachexia. Cachexia differs from starvation in part because it involves a systemic inflammatory response. It is associated with poorer outcomes. In the advanced stages of progressive disease, metabolism can change so that they lose weight even when they are getting what is normally regarded as adequate nutrition and the body cannot compensate. This leads to a condition called anorexia cachexia syndrome (ACS) and additional nutrition or supplementation is unlikely to help. Symptoms of weight loss from ACS include severe weight loss from muscle rather than body fat, loss of appetite and feeling full after eating small amounts, nausea, anemia, weakness and fatigue.

Serious weight loss may reduce quality of life, impair treatment effectiveness or recovery, worsen disease processes and be a risk factor for high mortality rates. Malnutrition can affect every function of the human body, from the cells to the most complex body functions, including:

• immune response;
• wound healing;
• muscle strength (including respiratory muscles);
• renal capacity and depletion leading to water and electrolyte disturbances;
• thermoregulation; and
• menstruation.

In addition, malnutrition can lead to vitamin and other deficiencies and to inactivity, which in turn may pre-dispose to other problems, such as pressure sores.

Unintentional weight loss can be the characteristic leading to diagnosis of diseases such as cancer and type 1 diabetes.

In the UK, up to 5% of the general population is underweight, but more than 10% of those with lung or gastrointestinal diseases and who have recently had surgery. According to data in the UK using the Malnutrition Universal Screening Tool ('MUST'), which incorporates unintentional weight loss, more than 10% of the population over the age of 65 is at risk of malnutrition. A high proportion (10-60%) of hospital patients are also at risk, along with a similar proportion in care homes.

Causes

Disease-related

Disease-related malnutrition can be considered in four categories:

Weight loss issues related to specific diseases include:

• As chronic obstructive pulmonary disease (COPD) advances, about 35% of patients experience severe weight loss called pulmonary cachexia, including diminished muscle mass. Around 25% experience moderate to severe weight loss, and most others have some weight loss. Greater weight loss is associated with poorer prognosis. Theories about contributing factors include appetite loss related to reduced activity, additional energy required for breathing, and the difficulty of eating with dyspnea (labored breathing).
• Cancer, a very common and sometimes fatal cause of unexplained (idiopathic) weight loss. About one-third of unintentional weight loss cases are secondary to malignancy. Cancers to suspect in patients with unexplained weight loss include gastrointestinal, prostate, hepatobilary (hepatocellular carcinoma, pancreatic cancer), ovarian, hematologic or lung malignancies.
• People with HIV often experience weight loss, and it is associated with poorer outcomes. Wasting syndrome is an AIDS-defining condition.
• Gastrointestinal disorders are another common cause of unexplained weight loss - in fact they are the most common non-cancerous cause of idiopathic weight loss. Possible gastrointestinal etiologies of unexplained weight loss include: celiac disease, peptic ulcer disease, inflammatory bowel disease (crohn's disease and ulcerative colitis), pancreatitis, gastritis, diarrhea and many other GI conditions.
• Infection. Some infectious diseases can cause weight loss. Fungal illnesses, endocarditis, many parasitic diseases, AIDS, and some other subacute or occult infections may cause weight loss.
• Renal disease. Patients who have uremia often have poor or absent appetite, vomiting and nausea. This can cause weight loss.
• Cardiac disease. Cardiovascular disease, especially congestive heart failure, may cause unexplained weight loss.
• Connective tissue disease
• Neurologic disease, including dementia
• Oral, taste or dental problems (including infections) can reduce nutrient intake leading to weight loss.

Therapy-related

Medical treatment can directly or indirectly cause weight loss, impairing treatment effectiveness and recovery that can lead to further weight loss in a vicious cycle.

Many patients will be in pain and have a loss of appetite after surgery. Part of the body's response to surgery is to direct energy to wound healing, which increases the body's overall energy requirements. Surgery affects nutritional status indirectly, particularly during the recovery period, as it can interfere with wound healing and other aspects of recovery. Surgery directly affects nutritional status if a procedure permanently alters the digestive system. Enteral nutrition (tube feeding) is often needed. However a policy of 'nil by mouth' for all gastrointestinal surgery has not been shown to benefit, with some suggestion it might hinder recovery.

Early post-operative nutrition is a part of Enhanced Recovery After Surgery protocols. These protocols also include carbohydrate loading in the 24 hours before surgery, but earlier nutritional interventions have not been shown to have a significant impact.

Some medications can cause weight loss, while others can cause weight gain.

Social conditions

Social conditions such as poverty, social isolation and inability to get or prepare preferred foods can cause unintentional weight loss, and this may be particularly common in older people. Nutrient intake can also be affected by culture, family and belief systems. Ill-fitting dentures and other dental or oral health problems can also affect adequacy of nutrition.

Loss of hope, status or social contact and spiritual distress can cause depression, which may be associated with reduced nutrition, as can fatigue.

Intentional

Intentional weight loss is the loss of total body mass as a result of efforts to improve fitness and health, or to change appearance through slimming.

Weight loss in individuals who are overweight or obese can reduce health risks, increase fitness, and may delay the onset of diabetes. It could reduce pain and increase movement in people with osteoarthritis of the knee. Weight loss can lead to a reduction in hypertension (high blood pressure), however whether this reduces hypertension-related harm is unclear.

Weight loss occurs when the body is expending more energy in work and metabolism than it is absorbing from food or other nutrients. It will then use stored reserves from fat or muscle, gradually leading to weight loss.

It is not uncommon for some people who are at their ideal body weight to seek additional weight loss in order to improve athletic performance or meet required weight classification for participation in a sport. Others may be driven to lose weight to achieve an appearance they consider more attractive. Being underweight is associated with health risks such as difficulty fighting off infection, osteoporosis, decreased muscle strength, trouble regulating body temperature and even increased risk of death.

According to the U.S. Food and Drug Administration (FDA), healthy individuals seeking to maintain their weight should consume 2,000 calories (8.4 MJ) per day.

According to the Dietary Guidelines for Americans those who achieve and manage a healthy weight do so most successfully by being careful to consume just enough calories to meet their needs, and being physically active.

Low-calorie regimen diets are also referred to as balanced percentage diets. Due to their minimal detrimental effects, these types of diets are most commonly recommended by nutritionists. In addition to restricting calorie intake, a balanced diet also regulates macronutrient consumption. From the total number of allotted daily calories, it is recommended that 55% should come from carbohydrates, 15% from protein, and 30% from fats with no more than 10% of total fat coming from saturated forms. For instance, a recommended 1,200 calorie diet would supply about 660 calories from carbohydrates, 180 from protein, and 360 from fat. Some studies suggest that increased consumption of protein can help ease hunger pangs associated with reduced caloric intake by increasing the feeling of satiety. Calorie restriction in this way has many long-term benefits. After reaching the desired body weight, the calories consumed per day may be increased gradually, without exceeding 2,000 net (i.e. derived by subtracting calories burned by physical activity from calories consumed). Combined with increased physical activity, low-calorie diets are thought to be most effective long-term, unlike crash diets, which can achieve short-term results, at best. Physical activity could greatly enhance the efficiency of a diet. The healthiest weight loss regimen, therefore, is one that consists of a balanced diet and moderate physical activity.

Weight gain has been associated with excessive consumption of fats, sugars, carbohydrates in general, and alcohol consumption. Depression, stress or boredom may also contribute to weight increase, and in these cases, individuals are advised to seek medical help. A 2010 study found that dieters who got a full night's sleep lost more than twice as much fat as sleep-deprived dieters.

The majority of dieters regain weight over the long term.

Therapeutic techniques

The least intrusive weight loss methods, and those most often recommended, are adjustments to eating patterns and increased physical activity, generally in the form of exercise. The World Health Organization recommended that people combine a reduction of processed foods high in saturated fats, sugar and salt and caloric content of the diet with an increase in physical activity.

An increase in fiber intake is also recommended for regulating bowel movements.

Other methods of weight loss include use of drugs and supplements that decrease appetite, block fat absorption, or reduce stomach volume.

Bariatric surgery may be indicated in cases of severe obesity. Two common bariatric surgical procedures are gastric bypass and gastric banding. Both can be effective at limiting the intake of food energy by reducing the size of the stomach, but as with any surgical procedure both come with their own risks that should be considered in consultation with a physician.

Dietary supplements, though widely used, are not considered a healthy option for weight loss. Many are available, but very few are effective in the long term.

Virtual gastric band uses hypnosis to make the brain think the stomach is smaller than it really is and hence lower the amount of food ingested. This brings as a consequence weight reduction. This method is complemented with psychological treatment for anxiety management and with hypnopedia. Research has been conducted into the use of hypnosis as a weight management alternative. In 1996 a study found that cognitive-behavioral therapy (CBT) was more effective for weight reduction if reinforced with hypnosis. Acceptance and Commitment Therapy ACT, a mindfulness approach to weight loss, has also in the last few years been demonstrating its usefulness.

Crash dieting

A crash diet is the willful restriction of nutritional intake (except water) for more than 12 waking hours. The desired result is for the body to burn fat for energy and thereby lose a significant amount of weight in a short time. Crash dieting can be dangerous to health and this method of weight loss is not recommended by physicians.

According to the Academy of Nutrition and Dietetics, "If the diet or product sounds too good to be true, it probably is. There are no foods or pills that magically burn fat. No super foods will alter your genetic code. No products will miraculously melt fat while you watch TV or sleep." Certain ingredients in supplements and herbal products can be dangerous and even deadly for some people.

Weight loss industry

There is a substantial market for products which promise to make weight loss easier, quicker, cheaper, more reliable, or less painful. These include books, DVDs, CDs, cremes, lotions, pills, rings and earrings, body wraps, body belts and other materials, fitness centers, personal coaches, weight loss groups, and food products and supplements.

In 2008 between US$33 billion and $55 billion was spent annually in the US on weight-loss products and services, including medical procedures and pharmaceuticals, with weight-loss centers taking between 6 and 12 percent of total annual expenditure. Over $1.6 billion a year was spent on weight-loss supplements. About 70 percent of Americans' dieting attempts are of a self-help nature.

In Western Europe, sales of weight-loss products, excluding prescription medications, topped £900 million ($1.4 billion) in 2009.

See also

References

External links

• Weight loss at DMOZ
• Health benefits of losing weight By IQWiG at PubMed Health
• Weight-control Information Network U.S. National Institutes of Health
• Nutrition in cancer care By NCI at PubMed Health
• Unintentional weight loss

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King's Daughters Medical Center (KDMC) is located in Ashland, Kentucky and is the city's largest employer at over 4,000 employees, generating more than $155 million in payroll a year. It is a locally controlled, not-for-profit 465-bed hospital that offers "cardiac, medical, surgical, pediatric, rehabilitative, psychiatric, cancer, neurological, pain care, wound care and home care" services.

History

Early history

King's Daughters' Hospital opened in 1897 as a three-room emergency hospital over the Poage, Elliott and Poage Drug Store on Winchester Avenue near 16th Street. In 1899, the hospital itself was founded by What-so-ever Circle and moved to a seven-room building at 18th Street and Greenup Avenue. Ten years later, the hospital moved again to a nine-room building between 20th and 21st Street along Winchester Avenue.

In 1915, the hospital purchased property at the northeast corner of 22nd Street and Lexington Avenue. Two years later in November, it opened a new 50-bed facility in a two-story brick structure. An expansion in 1930-31 added an east wing, which was expanded again in 1945 and 1953, all to the east.

In 1958, that building closed (which is now known as Vincent Apartments), and a new administration building was completed across Lexington Avenue and the remainder of the hospital.

Developing into a modern facility

In 1963, the hospital began to study plans for a specialized Coronary Care Unit. The hospital expanded in 1965 with a northern extension. In 1967, a 24-hour emergency room was established. One year later, the Coronary Care Unit opens with four private patient rooms and a ten-bed Intensive Care Unit.

In 1968, the hospital expanded upon the 1953 extension with a two-story structure; this was expanded upward with an additional two levels in 1984. With the extension, the hospital now stretched from 22nd Street to 23rd Street. One year after the hospital was expanded upon, the Ashland Medical Arts Building was completed in 1969 at the corner of Lexington Avenue and 23rd Street.

In 1972, a new emergency room was completed. Six years later, the Cardiac Step Down Unit and Cardiac Rehabilitation opened, followed by the Echocardiology Department in 1981 and the Diabetes Clinic in the following year.

The hospital expanded northward again in 1984 to Montgomery Avenue. In 1986, a new 16-bed Intensive Care Unit was completed, followed by the opening of the Cardiac Catheterization Lab one year later. The Cardiac Lab was expanded in 1993 and again in 1994 with the addition of a second laboratory.

In 1985, the Tri-State Regional Cancer Center opened adjacent to the Medical Arts Building. In 1988, a new facade and lobby with atrium was completed along Lexington Avenue; the new lobby was constructed within the 1953 addition. During this year, the original 1917 hospital structure was demolished in favor of the Tri-State Diagnostics center.

In 1990, a four level parking structure was completed along Lexington Avenue. A medical library and health education center was completed in the lower level of the parking garage in 1992. Three years later, a new 22-bed emergency room was completed along 23rd Street. Three years later, a third Cardiac Lab and a 24-bed Cardiac Surgery Unit was opened.

The $32 million Center for Advanced Care, also known as the Parkview Addition, was completed in November 2000. It features a 24-bed Intensive Care Unit, 3 Cardiac Cath Labs bringing the total to five, a Cardiac Cath Lab pre-op and recovery areas, three dedicated Cardiothoracic surgery operating suites, a nine-bed Cardiovascular Recovery Unit, and a rooftop helipad. The Vascular/endovascular program was initiated at this time, the Cardiac Alert Unit was installed in the former Intensive Care Unit and the emergency department expanded to 45 beds. Three years later, Cardiac Alert Unit became a 10-bed Chest Pain Unit, expanding to 18-beds in 2005.

Campus expansion

Medical Plaza A, opened in 1998, and was originally constructed as a three-story building providing room for physician offices, a Wendy's fast-food restaurant, a National City Bank branch and a cafe. It was expanded in 2002 to five stories, and in 2003 the Outpatient Surgery Center opened on the building's third floor.

In 2000, a new five-story structure was completed along 23rd Street that provided new patient rooms, surgery facilities and Intensive Care Unit. The Center for Advanced Care features the hospital's new main entrance and the Parkview Cafe.

The 526-space parking structure at the corner of 23rd Street and Bath Avenue was completed and opened on March 22, 2005. The $5.5 million five-story facility can be utilized by patients, visitors, physicians and employees.

In the summer of 2005, the $2.3 million 12,000 sq ft (1,100 m²). Hospitality House at King's Daughters opened at the corner of 22nd Street and Central Avenue. Providing 13 guest rooms, a kitchen, dining area, living space and a reception area for those that are from out-of-town. It is styled to resemble a contemporary house and is adjacent to the northeast corner of Central Park. It celebrated its 1,000th family on February 6, 2007.

On May 3, 2005, Medical Plaza B, a four-story, 77,000 sq ft (7,200 m²). facility that houses 14 physician offices, the Surgical Weight Loss Center and a pharmacy opened. It is connected via a sky bridge to the 23rd Street Parking Garage.

On May 8, 2006, a new $60 million 200,000 sq ft (19,000 m²)., five-story Heart and Vascular Center opened along 23rd Street. Envisioned as a three-story $43.5 million facility, a rising demand in services relating to cardiac and heart care necessitated the expansion of the hospital while it was under construction. It features a "cardiac rehabilitation unit, a therapy pool, administrative offices, admitting and pre-admission testing areas, a chest pain unit, patient rooms for stress testing, outpatient diagnostic testing and procedures, cardiac catheterization laboratories and vascular surgery suites and beds."

On June 5, 2006, a new $2.3 million two-story 18,000 sq ft (1,700 m²). Center for Advanced Imaging opened along Central Avenue adjacent to the Hospitality House at a cost of $13.3 million. Construction began in October 2005 and was designed to free up space in the existing hospital complex for inpatient and emergency radiology. The center is home to outpatient radiology, MRI, CT scans, mammograms, ultrasounds and X-rays; part of the second floor is dedicated to breast care. The completion of the Outpatient Imaging Center was the last component of a four-building, $70 million expansion that was announced in 2004.

The hospital also features an Outpatient Services Center on 23rd Street, where audiology services, physical, occupational and speech therapy is offered.

Union Representation

The Service and Maintenance employees at King's Daughters Medical Center have been represented by the Service Employees International Union/District 1199 WV/KY/OH since 1980. The union currently represents approximately 600 employees in various classifications including: Central Supply Aides, Laboratory Clerks, Home Health Clerks, Maintenance Department Employees, Medical Records Clerks, Dietary Employees, Environmental Services Employees, and Respiratory Aides. The current Collective Bargaining Agreement expires in November, 2013.

Today

The hospital ranks fourth in the state of Kentucky in admissions and with number of employees at 4,100, making it the largest employer between Lexington and Charleston, West Virginia. It has been named one of America's top employers from 2002 to 2006 and was a recipient of the Commonwealth of Kentucky Quality Award from 2000 to 2002. It was also named one of the nation's Top 100 Hospitals by Solucient from 2005 to 2008, and was also named as one of the "100 Best Companies for Working Mothers" by Working Mother Magazine from 2003 to 2005.

The Chest Pain Unit also received accreditation in 2004 from the Society of Chest Pain Centers, making it the third such facility in Kentucky and the 78th in the United States. It is also ranked number one in the state and among the top 5% in the nation for cardiac surgery and is the recipient of HealthGrades 2007 Cardiac Surgery Excellence Award.

King's Daughters Medical Center went live with the Epic electronic medical record system in November 2008.

References

External links

• King's Daughters Medical Center

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Anti-obesity medication or weight loss drugs are all pharmacological agents that reduce or control weight. These drugs alter one of the fundamental processes of the human body, weight regulation, by altering either appetite, or absorption of calories. The main treatment modalities for overweight and obese individuals remain dieting and physical exercise.

In the United States only one anti-obesity medication orlistat (Xenical) is currently approved by the FDA for long term use. It reduces intestinal fat absorption by inhibiting pancreatic lipase. Rimonabant (Acomplia), a second drug, works via a specific blockade of the endocannabinoid system. It has been developed from the knowledge that cannabis smokers often experience hunger, which is often referred to as "the munchies". It had been approved in Europe for the treatment of obesity but has not received approval in the United States or Canada due to safety concerns. The European Medicines Agency in October 2008 recommended the suspension of the sale of rimonabant as the risks seem to be greater than the benefits. Sibutramine (Meridia), which acts in the brain to inhibit deactivation of the neurotransmitters, thereby decreasing appetite was withdrawn from the United States and Canadian markets in October 2010 due to cardiovascular concerns.

Because of potential side effects, it is recommended that anti-obesity drugs only be prescribed for obesity where it is hoped that the benefits of the treatment outweigh its risks.

Mechanisms of action

Current and potential anti-obesity drugs may operate through one or more of the following mechanisms:

• Appetite suppression-Catecholamines and their derivatives (such as phentermine and other amphetamine-based drugs) are the main tools used for this, although other classes of drugs such as anti-depressants and mood stabilizers have been anecdotally used for appetite suppression (see: bupropion and topiramate). Drugs blocking the cannabinoid receptors may be a future strategy for appetite suppression.
• Increase of the body's metabolism.
• Interference with the body's ability to absorb specific nutrients in food. For example, Orlistat (also known as Xenical and Alli) blocks fat breakdown and thereby prevents fat absorption. The OTC fiber supplements glucomannan and guar gum have been used for the purpose of inhibiting digestion and lowering caloric absorption

Anorectics are primarily intended to suppress the appetite, but most of the drugs in this class also act as stimulants (e.g., dexedrine), and patients have abused drugs "off label" to suppress appetite (e.g. digoxin).

History

The first described attempts at producing weight loss are those of Soranus of Ephesus, a Greek physician, in the second century AD. He prescribed elixirs of laxatives and purgatives, as well as heat, massage, and exercise. This remained the mainstay of treatment for well over a thousand years. It was not until the 1920s and 1930s that new treatments began to appear. Based on its effectiveness for hypothyroidism, thyroid hormone became a popular treatment for obesity in euthyroid people. It had a modest effect but produced the symptoms of hyperthyroidism as a side effect, such as palpitations and difficulty sleeping. 2,4-Dinitrophenol (DNP) was introduced in 1933; this worked by uncoupling the biological process of oxidative phosphorylation in mitochondria, causing them to produce heat instead of ATP. The most significant side effect was a sensation of warmth, frequently with sweating. Overdose, although rare, lead to a rise in body temperature and, ultimately, fatal hyperthermia. By the end of 1938 DNP had fallen out of use because the FDA had become empowered to put pressure on manufacturers, who voluntarily withdrew it from the market.

Amphetamines (marketed as Benzedrine) became popular for weight loss during the late 1930s. They worked primarily by suppressing appetite, and had other beneficial effects such as increased alertness. Use of amphetamines increased over the subsequent decades, including Obetrol and culminating in the "rainbow pill" regime. This was a combination of multiple pills, all thought to help with weight loss, taken throughout the day. Typical regimens included stimulants, such as amphetamines, as well as thyroid hormone, diuretics, digitalis, laxatives, and often a barbiturate to suppress the side effects of the stimulants. In 1967/1968 a number of deaths attributed to diet pills triggered a Senate investigation and the gradual implementation of greater restrictions on the market. This culminating in 1979 with the FDA banning the use of amphetamines, then the most effective of the diet drugs, in diet pills.

Meanwhile, phentermine had been FDA approved in 1959 and fenfluramine in 1973. The two were no more popular than other drugs until in 1992 a researcher reported that when combined the two caused a 10% weight loss which was maintained for more than two years. Fen-phen was born and rapidly became the most commonly prescribed diet medication. Dexfenfluramine (Redux) was developed in the mid-1990s as an alternative to fenfluramine with less side-effects, and received regulatory approval in 1996. However, this coincided with mounting evidence that the combination could cause valvular heart disease in up to 30% of those who had taken it, leading to withdrawal of Fen-phen and dexfenfluramine from the market in September 1997.

Ephedra was removed from the US market in 2004 over concerns that it raises blood pressure and could lead to strokes and death.

Contemporary anti-obesity drugs

Some patients find that diet and exercise is not a viable option; for these patients, anti-obesity drugs can be a last resort. Some prescription weight loss drugs are stimulants, which are recommended only for short-term use, and thus are of limited usefulness for extremely obese patients, who may need to reduce weight over months or years.

Orlistat

Orlistat (Xenical) reduces intestinal fat absorption by inhibiting pancreatic lipase. Some side-effects of using Orlistat include frequent, oily bowel movements (steatorrhea). But if fat in the diet is reduced, symptoms often improve. Originally available only by prescription, it was approved by the FDA for over-the-counter sale in February 2007. On 26 May 2010, the U.S. Food and Drug Administration (FDA) has approved a revised label for Xenical to include new safety information about cases of severe liver injury that have been reported rarely with the use of this medication. Of the 40 million users of Orlistat worldwide, 13 cases of severe liver damage have been reported.

Lorcaserin

Lorcaserin (Belviq) was approved June 28, 2012 for obesity with other co-morbidities. The average weight loss by study participants was modest, but the most common side effects of the drug are considered benign.

An excerpt from the Bloom 1 Study conducted by Arena Pharmaceuticals and later submitted for FDA approval:

At the end of Year 1 of the BLOOM trial, using Intent-to-Treat with Last Observation Carried Forward analysis (ITT-LOCF), the proportion of patients achieving at least 5% body weight loss in the lorcaserin group (47.5%) was more than twice that achieved by the placebo group (20.3%). Nearly three times as many patients achieved at least 10% weight loss in the lorcaserin group (22.6%) than in the placebo group (7.7%). Lorcaserin patients who completed the first year of the trial according to the protocol lost an average of 8.2% of their baseline weight, or approximately 18 pounds, at the end of Year 1 as compared to approximately 7 pounds in the placebo group. In Year 2, patients who continued to take lorcaserin were significantly better able to maintain their Year 1 weight loss than those who were switched to placebo.

In Year 1, lorcaserin caused significant decreases in waist circumference, BMI, glycemic parameters, high-sensitivity C-reactive protein, and fibrinogen levels compared to placebo. Total cholesterol, LDL cholesterol and triglyceride levels at Year 1 were significantly lower in the lorcaserin group than in the placebo group. Lorcaserin did not increase heart rate or blood pressure; rather, heart rate, systolic blood pressure and diastolic blood pressure decreased slightly but significantly with lorcaserin treatment compared to placebo. Quality of life, measured by the Impact of Weight on Quality of Life-Lite questionnaire, improved in both treatment groups, with a greater improvement in the lorcaserin group than in the placebo group.

At the end of Year 1, 55.4% of patients in the lorcaserin group and 45.1% of patients in the placebo group remained enrolled in the study, and 7.1% and 6.7% of patients, respectively, discontinued the study due to an adverse event. Among the most frequent adverse events reported with lorcaserin were headache (18.0% vs. 11.0%, lorcaserin vs. placebo); dizziness (8.2% vs. 3.8%); and nausea (7.5% vs. 5.4%). The rates of serious adverse events were similar in both treatment groups. The rates of depression and the incidence of anxiety and suicidal thoughts were low in both treatment groups. Lorcaserin caused no significant increase compared to placebo in the incidence of new cardiac valvulopathy.

Sibutramine

Sibutramine (Reductil or Meridia) is an anorectic or appetite suppressant, reducing the desire to eat. Sibutramine may increase blood pressure and may cause dry mouth, constipation, headache, and insomnia.

In the past, it was noted by the US that Meridia was a harmless drug for fighting obesity. The US District Court of the Northern District of Ohio rejected 113 cases complaining about the negative effects of the drug, stating that the clients lacked supporting facts and that the representatives involved were not qualified enough.

Sibutramine has been withdrawn from the market in the United States, the UK, the EU, Australia, Canada, Hong Kong and Colombia. Its risks (non-life-threatening myocardial infarction and stroke) have been shown to outweigh the benefits.

Rimonabant

Rimonabant (Acomplia) is a recently developed anti-obesity medication. It is a cannabinoid (CB1) receptor antagonist that acts centrally on the brain thus decreasing appetite. It may also act peripherally by increasing thermogenesis and therefore increasing energy expenditure.

Weight loss with Rimonabant however has not been shown to be greater than other available weight-loss medication. Due to safety concerns, primarily psychiatric in nature, the drug has not received approval in the United States or Canada, either as an anti-obesity treatment or as a smoking-cessation drug.

Sanofi-Aventis has received approval to market Rimonabant as a prescription anti-obesity drug in the European Union, subject to some restrictions. However, in October 2008, the European Medicines Agency (EMEA) recommended that Acomplia no longer be available in UK. One month later, Sanofi-Aventis decided it would no longer study rimonabant for any indication.

Metformin

In people with Diabetes mellitus type 2, the drug metformin (Glucophage) can reduce weight. Metformin limits the amount of glucose that is produced by the liver as well as increases muscle consumption of glucose. It also helps in increasing our body's response to insulin.

Exenatide

Exenatide (Byetta) is a long-acting analogue of the hormone GLP-1, which the intestines secrete in response to the presence of food. Among other effects, GLP-1 delays gastric emptying and promotes a feeling of satiety. Some obese people are deficient in GLP-1, and dieting reduces GLP-1 further. Byetta is currently available as a treatment for Diabetes mellitus type 2. Some, but not all, patients find that they lose substantial weight when taking Byetta. Drawbacks of Byetta include that it must be injected subcutaneously twice daily, and that it causes severe nausea in some patients, especially when therapy is initiated. Byetta is recommended only for patients with Type 2 Diabetes. A somewhat similar drug, Symlin, is currently available for treating diabetes and is in testing for treating obesity in non-diabetics.

Pramlintide

Pramlintide (Symlin) is a synthetic analogue of the hormone Amylin, which in normal people is secreted by the pancreas in response to eating. Among other effects, Amylin delays gastric emptying and promotes a feeling of satiety. Many diabetics are deficient in Amylin. Currently, Symlin is only approved to be used along with insulin by Type 1 and Type 2 diabetics. However, Symlin is currently being tested in non-diabetics as a treatment for obesity. A drawback is that Symlin must be injected at mealtimes.

Other drugs

Other weight loss drugs have also been associated with medical complications, such as fatal pulmonary hypertension and heart valve damage due to Redux and Fen-phen, and hemorrhagic stroke due phenylpropanolamine. Many of these substances are related to amphetamine.

Unresearched nonprescription products or programs for weight loss are heavily promoted by mail and print advertising and on the internet. The US Food and Drug Administration recommends caution with use of these products, since many of the claims of safety and effectiveness are unsubstantiated. Individuals with anorexia nervosa and some athletes try to control body weight with laxatives, diet pills or diuretic drugs, although these generally have no impact on body fat. Products that work as a laxative can cause the blood's potassium level to drop, which may cause heart and/or muscle problems. Pyruvate is a popular product that may result in a small amount of weight loss. However, pyruvate, which is found in red apples, cheese, and red wine, has not been thoroughly studied and its weight loss potential has not been scientifically established.

Phentermine/topiramate

The combination of phentermine and topiramate, brand name Qsymia (formerly Qnexa) was approved by the U.S. FDA on July 17, 2012, as an obestity treatment complementary to a diet and exercise regimen.

Alternative medicine

Some supplements and alternative medicine have insufficient evidence to support or oppose their use.

Side effects

Some anti-obesity drugs can have severe, even, lethal side effects, fen-phen being a famous example. Fen-phen was reported through the FDA to cause abnormal echocardiograms, heart valve problems, and rare valvular diseases. One of, if not the first, to sound alarms was Sir Arthur MacNalty, Chief Medical Officer (United Kingdom). As early as the 1930s, he warned against the use of dinitrophenol as an anti-obesity medication and the injudicious and/or medically unsupervised use of thyroid hormone to achieve weight reduction. The side effects are often associated with the medication's mechanism of action. In general, stimulants carry a risk of high blood pressure, faster heart rate, palpitations, closed-angle glaucoma, drug addiction, restlessness, agitation, and insomnia.

Another drug, orlistat, blocks absorption of dietary fats, and as a result may cause oily spotting bowel movements (steatorrhea), oily stools, stomach pain, and flatulence. A similar medication designed for patients with Type 2 diabetes is Acarbose; which partially blocks absorption of carbohydrates in the small intestine, and produces similar side effects including stomach pain and flatulence.

Limitations of current knowledge

The limitation of drugs for obesity is that we do not fully understand the neural basis of appetite and how to modulate it. Appetite is clearly a very important instinct to promote survival. Arguably any drug that would abolish appetite may carry a high mortality risk and may be unsuitable for clinical use.

Because the human body uses various chemicals and hormones to protect its stores of fat (a reaction probably useful to our ancestors when food was scarce in the past,) there has not yet been found a 'silver bullet', or a way to completely circumvent this natural habit of protecting excess food stores. Because of this, anti-obesity drugs are not presently a practical long-term solution for people who are overweight.

In order to circumvent the number of feedback mechanisms that prevent most monotherapies from producing sustained large amounts of weight loss, it has been hypothesized that combinations of drugs may be more effective by targeting multiple pathways and possibly inhibiting feedback pathways that work to cause a plateau in weight loss. This was evidenced by the success of the combination of phentermine and fenfluramine or dexfenfluramine, popularly referred to phen-fen, in producing significant weight loss but fenfluramine and dexfenfluramine were pulled from the market due to safety fears regarding a potential link to heart valve damage. The damage was found to be a result of activity of fenfluramine and dexfenfluramine at the 5-HT2B serotonin receptor in heart valves. Newer combinations of SSRIs and phentermine, known as phenpro, have been used with equal efficiency as fenphen with no known heart valve damage due to lack of activity at this particular serotonin receptor due to SSRIs. There has been a recent resurgence in combination therapy clinical development with the development of 3 combinations: Qsymia (topiramate + phentermine), Empatic (bupropion + zonisamide) and Contrave (bupropion + naltrexone).

Future developments

Other classes of drugs in development include lipase inhibitors, similar to orlistat. Another lipase inhibitor, called GT 389-255, was being developed by Peptimmune (licensed from Genzyme). This was a novel combination of an inhibitor and a polymer designed to bind the undigested triglycerides therefore allowing increased fat expulsion without side effects such as oily stools that occur with orlistat. The development stalled as Phase 1 trials were conducted in 2004 and there was no further human clinical development afterward. In 2011, Peptimmune filed for Chapter 7 Liquidation.

Another potential long-term approach to anti-obesity medication is through the development of ribonucleic acid interference (RNAi). Animal studies have illustrated that the deletion of the RIP140 gene in mice by genetic knockdown results in the lack of fat accumulation, even when mice are fed a high fat diet. Similarly, another nuclear hormone receptor co-repressor, SMRT, has demonstrated an opposing effect in genetically engineered mice. Dr. Russell Nofsinger and Dr. Ronald Evans of the Salk Institute showed that disruption of the molecular interaction between SMRT and their nuclear hormone receptor partners leads to increased adiposity and a decreased metabolic rate. These studies suggest that new drugs targeting the molecular interaction between nuclear hormone receptors and their regulatory cofactors could provide a useful new category of therapeutic targets to be developed in an effort to control obesity.

Another approach is to induce a sense of satiety by occupying space in the gastric and intestinal cavities. One clinical trial involves a hydrogel (Gelesis) made of indigestible, food-grade materials. Another pilot study uses pseudobezoars.

Other drugs in clinical trials as of October 2009 include Cetilistat and TM38837.

See also

• Weight loss effects of water

References

Further reading

Boss, Olivier; Karl G. Hofbauer (2004). Pharmacotherapy of obesity: options and alternatives. Boca Raton: CRC Press. ISBN 0-415-30321-4. 

External links

• Prescription Medications for the Treatment of Obesity

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