Anacetrapib

Clinical trials[edit]
At the 16th International Symposium on Drugs Affecting Lipid Metabolism (New York, Oct 4-7, 2007), Merck reported on a Phase IIb STUDY. The eight week study reported dosage correlated reduction in LDL-C and increases in HDL-C levels with no corresponding increases in BLOOD PRESSURE in any cohort. The increase in HDL was particularly significant, averaging 44 percent, 86 percent, 139 percent and 133 percent at doses of 10 mg, 40 mg, 150 mg and 300 mg.

Merck performed a dose-ranging study of anacetrapib,[3] with the RESULTS PRESENTED in 2009.[4] A 2013 study of 407 Japanese patients found anacetrapib reduced LDL and raised HDL alone or with atorvastatin.[5]

Phase III trial (DEFINE)[edit]
Merck started a Phase III trial to ASSESS the drug's effects on LDL, HDL, clinically measurable cardiovascular events, and safety;[6] It was code-named DEFINE (Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib), and was described as a medium sized safety and efficacy trial.[7]

Early results from the DEFINE trial were presented on November 17 at AHA2010, a meeting of the American Heart Association. At 100 mg dosage, LDL decreased by 36%, lipoprotein(a) decreased by 36.4%, while HDL increased by 138%. Systolic blood pressure showed no increase, and there was no association with increased CVD death or events.[8] The results were later updated to 39.8% of LDL decrease.[9]

Cardiologist Steve Nissen described DEFINE as a medium-sized safety trial intended to find out "whether anacetrapib would show the same increase in adverse cardiovascular events that was seen with torcetrapib." Fortunately, anacetrapib did not. In his opinion the DEFINE study was too small to show a clear benefit, but the trends in the major adverse cardiovascular events were going in the right direction.[10]

A two year follow up is due to COMPLETE by December 2012. A 2014 study found HDL and drug levels remained elevated 2 to 4 years after discontinuation.[11]

Phase III trial (REVEAL)[edit]
The REVEAL (Randomized EValuation of THE EFFECTS of Anacetrapib Through Lipid-modification) will assess whether there is CLINICAL benefit associated with anacetrapib. REVEAL recruited 30,000 PARTICIPANTS[12] for a randomized, double-blinded, placebo-controlled trial.

The study will compare patients with a history of vascular disease (such as heart disease, cerebrovascular disease, and peripheral vascular disease) on 100 mg of anacetrapib daily to those on placebo, to determine if the addition of anacetrapib reduces the risk of major coronary events (such as HEART ATTACK, death from heart disease, or requiring a coronary revascularization.) Data will be collected through 2017.[13]

A concern raised in October 2013 is related to the time that the drug remains in people's body after they stop taking it. The report shows that even after 4 years the levels of the medicine were still detectable.[14]

See also[edit]
Other CETP inhibitors:

Torcetrapib was developed by Pfizer until December 2006 but caused unacceptable increases in BLOOD PRESSURE and had net cardiovascular detriment.
Dalcetrapib was developed by Hoffmann–La Roche until May 2012. It did not raise blood pressure and did raise HDL, but it showed no clinically meaningful efficacy.
Evacetrapib is under development by Eli Lilly & Company.

Amflutizole

Amflutizole is a xanthine oxidase inhibitor used for the treatment of gout.

Synthesis[edit]
Amflutizole synth.png

The tosyl oxime of the meta-trifluromethyl benzoic acid acid cyanide is the reactamt. This is cross reacted with ethyl 2-mercaptoacetate in the presence of a base; displacement of the tosylate by mercaptide leads to the formation of the heterocyclic N–S bond. This intermediate compound is then converted to the carbanion by a second equivalent of base. This adds to the cyano group; protonation then goes on to form the imine, tautomerization of which gives the corresponding amino form. Finally, saponification of the ester thus affords amflutizole as the product.[1]

Amphetaminil

Amphetaminil (Aponeuron, AN-1) is a stimulant drug derived from amphetamine, which was developed in the 1970s and used for the treatment of obesity,[1] ADHD,[2][3] and narcolepsy.[4] It has largely been withdrawn from clinical use following problems with abuse.[5]

Amphetamine

Amphetamine[note 1] (pronunciation: Listeni/æmˈfɛtəmiːn/; contracted from alpha‑methylphenethylamine) is a potent central nervous system (CNS) stimulant of the phenethylamine class that is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. Amphetamine was discovered in 1887 and exists as two enantiomers: levoamphetamine and dextroamphetamine.[note 2] Amphetamine properly refers to a specific chemical, the racemic free base, which is equal parts of the two enantiomers, levoamphetamine and dextroamphetamine, in their pure amine forms. However, the term is frequently used informally to refer to any combination of the enantiomers, or to either of them alone. Historically, it has been used to treat nasal congestion, depression, and obesity. Amphetamine is also used as a performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. It is a prescription medication in many countries, and unauthorized possession and distribution of amphetamine are often tightly controlled due to the significant health risks associated with substance abuse.[sources 1]

The first pharmaceutical amphetamine was Benzedrine, a brand of inhalers used to treat a variety of conditions. Currently, pharmaceutical amphetamine is typically prescribed as Adderall,[note 3] dextroamphetamine, or the inactive prodrug lisdexamfetamine. Amphetamine, through activation of a trace amine receptor, increases biogenic amine and excitatory neurotransmitter activity in the brain, with its most pronounced effects targeting the catecholamine neurotransmitters norepinephrine and dopamine. At therapeutic doses, this causes emotional and cognitive effects such as euphoria, change in libido, increased wakefulness, and improved cognitive control. It induces physical effects such as decreased reaction time, fatigue resistance, and increased muscle strength.[sources 2]

Much larger doses of amphetamine are likely to impair cognitive function and induce rapid muscle breakdown. Drug addiction is a serious risk with large recreational doses, but rarely arises from medical use. Very high doses can result in psychosis (e.g., delusions and paranoia) which rarely occurs at therapeutic doses even during long-term use. Recreational doses are generally much larger than prescribed therapeutic doses and carry a far greater risk of serious side effects.[sources 3]

Amphetamine is also the parent compound of its own structural class, the substituted amphetamines,[note 4] which includes prominent substances such as bupropion, cathinone, MDMA (ecstasy), and methamphetamine. As a member of the phenethylamine class, amphetamine is also chemically related to the naturally occurring trace amine neuromodulators, specifically phenethylamine[note 5] and N-methylphenethylamine, both of which are produced within the human body. Phenethylamine is the parent compound of amphetamine, while N-methylphenethylamine is a constitutional isomer that differs only in the placement of the methyl group.[sources 4]

Amfepramone

Amfepramone (INN)[note 1] is a stimulant drug of the phenethylamine, amphetamine, and cathinone classes that is used as an appetite suppressant.[2][3] It is used in the short-term management of obesity, along with dietary and lifestyle changes.[2] Amfepramone is most closely chemically related to the antidepressant and smoking cessation aid bupropion (previously called amfebutamone), which has also been developed as a weight-loss medicine when in a combination product with naltrexone.

Amfepentorex

Amfepentorex is a stimulant drug derived from methamphetamine which is used as an appetite suppressant for the treatment of obesity. Dosage is 50–100 mg per day. Side effects include insomnia, hypertension and acute glaucoma.

Amfecloral

Amfecloral (INN), also known as amphecloral (USAN), is a stimulant drug of the phenethylamine and amphetamine chemical classes that was used as an appetite suppressant under the trade name Acutran, but is now no longer marketed.[1] It acts as a prodrug which splits to form amphetamine and chloral hydrate, similarly to clobenzorex and related compounds, except that the N-substituent in this case yields a compound that is active in its own right. The chloral hydrate metabolite is a gabaminergic sedative/hypnotic, and would in theory counteract some of the stimulant effects of the amphetamine metabolite. This would produce an effect similar to the amphetamine/barbiturate combinations previously used in psychiatric medications.

Bupropion

Bupropion (/bjuːˈproʊpi.ɒn/ bew-proh-pee-on) (BAN) or bupropion hydrochloride (USAN, BANM), also known as amfebutamone (INN), is a drug of the aminoketone family primarily used as an antidepressant and smoking cessation aid.[8][9][10] Marketed as Wellbutrin and other trade names, it is one of the most frequently prescribed antidepressants in the United States,[11] although in many English-speaking countries, including the United Kingdom, Australia and New Zealand, this is an off-label use.[12] It is also widely used, in a formulation marketed as Zyban, to aid people who are trying to quit smoking.[11] It is taken in the form of tablets, and in the United States and most other countries it is available only with a prescription.[11]

Clinically, bupropion serves as an atypical antidepressant fundamentally different from most commonly prescribed antidepressants such as selective serotonin reuptake inhibitors (SSRIs).[12] 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.[13] In contrast to many other antidepressants, it does not cause weight gain or sexual dysfunction.[13] 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.[13]

Bupropion is known to affect several different biological targets, and its mechanism of action is only partly understood.[13][14] It has been widely described as a weak norepinephrine-dopamine reuptake inhibitor.[14][15] However, studies with humans via the oral administration route have demonstrated that it does not significantly affect dopamine levels in the brain at clinically-used doses, casting doubt on the notion that dopamine is involved in its clinical effects.[14][15] Bupropion is a non-competitive antagonist of neuronal nicotinic acetylcholine receptors (nAChRs), an action which appears to be involved in both its antidepressant benefits and its efficacy in smoking cessation as high and/or altered acetylcholine levels may affect both.[14][16] 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.[13]

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.[17] Its chemical name is 3-chloro-N-tert-butyl-β-ketoamphetamine. It is a substituted cathinone (β-ketoamphetamine), as well as a substituted amphetamine.
Medical uses[edit]
Depression[edit]
Bupropion is one of the most widely prescribed antidepressants, and the available evidence indicates that it is effective in clinical depression[18] — as effective as several other widely prescribed drugs, including fluoxetine (Prozac) and paroxetine (Paxil),[19] although trends favoring the efficacy of escitalopram (Lexapro), sertraline (Zoloft) and venlafaxine (Effexor) over bupropion have been observed.[19] Mirtazapine (Remeron), on the other hand is significantly more effective than bupropion.[19] Bupropion has several features that distinguish it from other antidepressants: for instance, unlike the majority of antidepressants, it does not usually cause sexual dysfunction.[20] Bupropion treatment also is not associated with the somnolence or weight gain that may be produced by other antidepressants.[21]

The majority of depressed people suffer from insomnia, but there are some who instead experience constant sleepiness and fatigue. In this subgroup, bupropion has been found to be more effective than selective serotonin reuptake inhibitors (SSRIs) at alleviating the symptoms.[22] There appears to be a modest advantage for the SSRIs compared to bupropion in the treatment of anxious depression.[23]

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.[24] 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.[24]

In some countries (including Australia, New Zealand and the UK) this is an off-label use.[25][26] Bupropion was approved by the U.S. Food and Drug Administration (FDA), in 2006, for the prevention of seasonal affective disorder.[27]

Smoking cessation[edit]
The next most common use is as an aid for smoking cessation where it reduces the severity of nicotine cravings and withdrawal symptoms.[28] 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.[28]

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).[28]

In Australia and the UK smoking cessation is the only licensed indication of bupropion.[25][26]

Attention deficit hyperactivity disorder[edit]
There have been numerous reports of positive results for bupropion as a treatment for attention deficit hyperactivity disorder (ADHD),[29] both in minors and adults.[30] 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.[30] 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."[31] 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.[32]

Sexual dysfunction[edit]
Bupropion is one of few antidepressants that do not cause sexual dysfunction.[33] 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.[34] 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.[35]

Obesity[edit]
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.[36] This is not much different from the weight loss produced by several other medications, such as sibutramine, orlistat and amfepramone.[36]

It has been studied in combination with naltrexone.[37] Concerns from bupropion include an increase in blood pressure and heart rate and thus as of 2013 it has not been approved in the United States for this use.[37]

Other[edit]
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.[38][39]

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.[40]

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.[41]

Bupropion—like other antidepressants, with the exception of duloxetine (Cymbalta)[42]—is not effective in treating chronic low back pain.[43] It does, however, show some promise in the treatment of neuropathic pain.[44]

Recreational use[edit]
According to the US government classification of psychiatric medications, bupropion is "non-abusable".[45] 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; however, there are significant interspecies differences in bupropion metabolism.[46] 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.[47] In any case, bupropion, via non-conventional routes of administration (e.g., injection, insufflation), is reported to be abused in Canada,[48] and in recent years in United States prisons.[49][50]

Contraindications[edit]
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.[51] 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, as well as in pediatric patients, adolescents and young adults due to the increased risk of suicidal ideation.

Amezinium metilsulfate

Amezinium metilsulfate (INN, trade name Regulton) is a sympathomimetic drug used for the treatment of low blood pressure. It has multiple mechanisms, including stimulation of alpha and beta-1 receptors and inhibition of noradrenaline and tyramine uptake.

Amezepine

Amezepine is a tricyclic antidepressant (TCA) which was never marketed.

Alefacept

Alefacept is a genetically engineered immunosuppressive drug. It was sold under the brand name Amevive in Canada, the United States, Israel, Switzerland and Australia. In 2011, the manufacturers made a decision to cease promotion, manufacturing, distribution and sales of Amevive during a supply disruption. According to Astellas Pharma US, Inc. (http://www.amevive.com/Patient%20letter.pdf), the decision to cease Amevive sales was neither the result of any specific safety concern nor the result of any FDA-mandated or voluntary product recall. On the other hand, usage of Amevive was associated with a certain risk of development systemic diseases such as malignancies. This drug was never approved for the European drug market.

Alefacept is used to control inflammation in moderate to severe psoriasis with plaque formation, where it interferes with lymphocyte activation.[1] It is also being studied in the treatment of cutaneous T-cell lymphoma and T-cell non-Hodgkin lymphoma.

Alefacept is a fusion protein: it combines part of an antibody with a protein that blocks the growth of some types of T cells.
Mechanism of action[edit]
The mechanism of action involves dual mechanisms. Alefacept inhibits the activation of CD4+ and CD8+ T cells by interfering with CD2 on the T cell membrane thereby blocking the costimulatory molecule LFA-3/CD2 interaction. Another mechanism is inducing apoptosis of memory-effector T lymphocytes. If the T cells were to become activated they would stimulate proliferation of keratinocytes resulting in the typical psoriatic symptoms. Therefore, alefacept leads to clinical improvement of moderate to severe psoriasis by blunting these reactions. Combinations of therapeutic modalities have been utilized to meet the challenge of difficult to treat psoriasis.[2]

Indications[edit]
Alefacept is indicated for the management of patients with moderate to severe chronic plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy. The concomitant use of low-potency topical corticosteroids was permitted during the treatment phase with alefacept and does not seem to pose any additional risks.

The drug was approved based upon studies involving 1,869 patients altogether with plaques covering at least 10% of body surface. Either 7.5 mg IV or 15 mg IM once a week were applied. The long-term results (reduction of at least 75% in pretreatment PASI scores) were 14% and 21%, respectively. Additional improvements ensuing after completion of the 12-week treatment phase or after completion of a second alefacept treatment were also seen. Often the remissions were maintained for 7 to 12 months after end of treatment.

Contraindications and precautions[edit]
Alefacept reduces CD4+ T cell counts and may worsen the clinical course of HIV infections. It is therefore contraindicated in patients with HIV infections.
Pretreatment CD4+ and/or CD8+ cell counts below the accepted lower limit
History of systemic malignancy
Caution: Patients at high risk to develop a systemic malignancy
Known hypersensitivity to alefacept or to any other ingredient of the preparation
Caution: There is little experience in geriatric patients (65 years of age or older); so far no differences to the younger age group have been noted.
Pregnancy and lactation[edit]
Alefacept has been assigned to Pregnancy Category B in the US and to C in Australia.
Lactation : It is not known if the drug is excreted into human milk. Either the drug or breastfeeding should be terminated, taking into account the importance of treatment to the mother.
Pediatric patients[edit]
No clinical experience exists in patients under 18 years of age. The drug should therefore not be used in pediatric patients.

Side effects[edit]
Lymphopenia : Most common in clinical trials was a significant and dose-related reduction of CD4+ and CD8+ counts in 10 to 59% of patients. However, only 0 to 2% of patients experienced reductions below the accepted lower limit. Consequences of lymphopenia may be infections and/or treatment related malignancies (see below).
Malignancies : In clinical studies among 1,869 patients 63 treatment-emerged malignancies in 43 patients were observed. Most of these were nonmelanoma and melanoma skin cancers, other solid tumors, and lymphomas.
Infections : In clinical studies 0.9% of patients experienced significant infections compared to 0.2% in the placebo group. Among the infections were serious ones such as sepsis, pneumonia, abscesses, wound infections and toxic shock syndrome.
Sensitivity reactions: Urticaria and angioedema were observed. If an anaphylactic reaction should occur symptomatic treatment should be initiated at once.
Forming of antibodies to alefacept : About 3% of patients developed low-titer antibodies with unknown importance for the clinical efficiency of the drug. Long-term immune effects have not been well explored.
Hepatic Toxicity : Postmarketing reports revealed asymtomatic increases in transaminases (ALT and/or AST), fatty liver degeneration, decompensation of preexisting liver cirrhosis, and acute treatment-related liver failure. It is not known if some or all of these manifestations are attributable to alefacept-therapy, but it is recommended to discontinue therapy as soon as any sign of liver toxicity develops.
Different Common Side Effects : side effects such as pharyngitis, cough, dizziness, nausea, pruritus, myalgias, chills, and reactions at injection sites were observed quite frequently.
Interactions[edit]
Patients currently undergoing immunosuppressive therapy (phototherapy, or concomitant application of other immunosuppressant agents) should not receive alefacept to avoid the risks of excessive immunosuppression. Studies concerning the combination with cyclosporine or methotrexate are conducted, but no results have been published so far.
Live vaccines: The efficiency of concomitant application of live vaccines has not been fully examined yet. However, the effect of tetanus toxoid was well preserved in clinical trials.
Necessary laboratory examinations[edit]
CD4+ cell counts should be obtained before initiation of therapy and during the 12-week course of therapy in intervals of 2 weeks.
It may be desirable to monitor liver function studies (AST and ALT) in patients at high risk to develop liver toxicity (e.g., preexisting hepatitis, or high daily consumption of alcohol).
Dosage regimes[edit]
The standard dosage regime is the weekly application of either 7.5 mg IV or 15 mg IM for a course of 12 weeks. The benefits and risks of repeated courses have not been explored in sufficient detail. Therapy should be conducted under the supervision of a physician experienced in the use of immunosuppressant agents.

Notes[edit]
Jump up ^ "New drugs". Australian Prescriber 27 (101): 5. 2004. Retrieved 2006-08-20.
Jump up ^ Scheinfeld N. Therapy-resistant psoriasis treated with alefacept and subsequent narrow band ultraviolet B phototherapy with total clearing of psoriasis. Dermatol Online J. 2005;11(2)7. PMID 16150215
 This article incorporates public domain material from the U.S. National Cancer Institute document "Dictionary of Cancer Terms".

Naratriptan

Naratriptan (trade names include Amerge and Naramig) is a triptan drug marketed by GlaxoSmithKline and is used for the treatment of migraine headaches. Naratriptan is available in 2.5 mg tablets. It is a selective 5-HT1 receptor subtype agonist.
Indication[edit]
Naratriptan is used for the treatment of the acute migraine attacks and the symptoms of migraine, including severe, throbbing headaches that sometimes are accompanied by nausea and sensitivity to sound or light.[1]

Mechanism of action[edit]
The causes of migraine are not clearly understood; however, the efficacy of naratriptans and other triptans is believed to be due to their activity as 5HT (serotonin) agonists.

Efficacy[edit]
A meta-analysis of 53 clinical trials has shown that all triptans are effective for treating migraine at marketed doses and that naratriptan, although less effective than sumatriptan and rizatriptan was more effective than placebo in reducing migraine symptoms at two hours[2] and efficacy was demonstrated in almost two thirds of subjects after four hours of treatment.[3]

Side effects[edit]
Side effects include: dizziness, drowsiness, tingling of the hands or feet, nausea, dry mouth and unsteadiness. If these effects persist or worsen, notify your doctor promptly. Side-effects which are unlikely and which should be promptly reported include: chest pain/pressure, throat pain/pressure, unusually fast/slow/irregular pulse, one-sided muscle weakness, vision problems, cold/bluish hands or feet, stomach pain, bloody diarrhea, mental/mood changes, and fainting. In the unlikely event you have a serious allergic reaction to this drug, seek immediate medical attention. Symptoms of a serious allergic reaction include: rash, itching, swelling, severe dizziness, trouble breathing (swelling of the throat).

The use of naratriptan with MAOIs and serotonergic drugs may result in the life threatening serotonin syndrome. Make sure your doctor/pharmacist is aware of all your current medications (including as needed medications) before taking this drug. [4]

Exclusivity[edit]
In the United States, the Food and Drug Administration (FDA) approved naratriptan on February 11, 1998.[5] It was covered by U.S. Patent no. 4997841; the FDA lists the patent as expiring on July 7, 2010.[5][6]

In July 2010, in the wake of the patent expiration, several drug manufacturers, including Roxane Labs,[7] Sandoz[8] and Teva Pharmaceuticals,[9] announced that they were launching generic Naratriptan medications.

The drug continued to be covered by European patent 0303507 in Germany, Spain, France and the United Kingdom through March 10, 2012,[10] and by Australian patent 611469 in Australia through June 17, 2013.[10] It had previously been covered by Canadian patent 1210968; but both Sandoz and Novopharm have offered generic equivalents in Canada since that patent's expiration December 1, 2009.[10]

Medroxyprogesterone

Medroxyprogesterone (INN, BAN), also known as 17α-hydroxy-6α-methylprogesterone, and abbreviated as MP, is a steroidal progestin drug which was never marketed for use in humans.[1] An acylated derivative, medroxyprogesterone acetate (MPA), is clinically used as a pharmaceutical medicine.[2] Compared to MPA, MP is over two orders of magnitude less potent as a progestogen.[3] As such, MP itself is not used clinically, though it has seen limited use in veterinary medicine under the trade name Controlestril in France.[4] In addition, it is a metabolite of MPA.[5]

While medroxyprogesterone is sometimes used as a synonym for medroxyprogesterone acetate,[2] what is normally being administered is MPA and not MP.[6]

Ameltolide

Ameltolide, a 4-aminobenzamide derivative, is an experimental anticonvulsant agent, effective at inhibiting seizures in animal models.[1] It is non-toxic at dosing levels and no undesirable side effects are attributable to its application.[2]

References[edit]
Jump up ^ Robertson, David W.; Beedle, E. E.; Krushinski, Joseph H.; Lawson, Ronald R.; Parli, C. John; Potts, Brian; Leander, J. David (1991). "Synthesis and pharmacological evaluation of a major metabolite of ameltolide, a potent anticonvulsant". Journal of Medicinal Chemistry 34 (4): 1253–7. doi:10.1021/jm00108a003. PMID 2016702.
Jump up ^ Higdon, Gary L.; McKinley, Edmund R.; Markham, Janet K. (1991). "Ameltolide. I: Developmental toxicology studies of a novel 

Amedalin

Amedalin (UK-3540-1) is an antidepressant which was synthesized in the early 1970s, but was never marketed.[1][2] It is a selective norepinephrine reuptake inhibitor, with no significant effects on the reuptake of serotonin and dopamine, and no antihistamine or anticholinergic properties.[2] [3]

Amdoxovir

Amdoxovir is a nucleoside reverse transcriptase inhibitor (NRTI) undergoing research for the treatment of HIV/AIDS. It was discovered by Raymond F. Schinazi (Emory University) and C.K. Chu (University of Georgia). It is being developed by RFS Pharma.[1] Currently, it is in Phase II clinical studies.

References[edit]
Jump up ^ "Amdoxovir". AIDSmeds.com. January 13, 2009. Archived from the original on March 21, 2008. Retrieved March 21, 2008.

Ampicillin

Ampicillin is an antibiotic useful for the treatment of a number of bacterial infections. It is a beta-lactam antibiotic that is part of the aminopenicillin family and is roughly equivalent to amoxicillin in terms of activity.[1] It is taken either orally or intravenously. It is active against many Gram-positive and Gram-negative bacteria.

It is effective for ear infections and respiratory infections such as sinusitis caused by bacteria, acute exacerbations of COPD, and epiglottitis. It is also sometimes used for the treatment of urinary tract infections, meningitis, and salmonella infections, but resistance to ampicillin is increasingly common among the bacteria responsible for these infections.[2][3]

Common side effects include rash, diarrhea, nausea and vomiting.[4] It is not useful for the treatment of viral infections.

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[5]
Medical uses[edit]
Ampicillin is active against Gram-(+) bacteria including Streptococcus pneumoniae, Streptococcus pyogenes, some isolates of Staphylococcus aureus (but not penicillin-resistant or methicillin-resistant strains), and some Enterococci. Activity against Gram-(-) bacteria includes Neisseria meningitidis, some Haemophilus influenzae, and some Enterobacteriaceae. Its spectrum of activity is enhanced by co-administration of sulbactam, a drug that inhibits beta lactamase, an enzyme produced by bacteria to inactivate ampicillin and related antibiotics.[6][7]

It is used for the treatment of infections known to be or highly likely to be caused by these bacteria. These include common respiratory infections including sinusitis, bronchitis, and pharyngitis, as well as otitis media. In combination with vancomycin (which provides coverage of ampicillin-resistant pneumococci), it is effective for the treatment of bacterial meningitis. It is also used for gastrointestinal infections caused by consuming contaminated water or food, such as Salmonella, Shigella, and Listeriosis.[3]

Ampicillin is a first-line agent for the treatment of infections caused by Enterococci. The bacteria are an important cause of healthcare-associated infections such as endocarditis, meningitis, and catheter-associated urinary tract infections that are typically resistant to other antibiotics.[3]

Side effects[edit]
Ampicillin is relatively non-toxic. Its most common side effects include rash, diarrhea, nausea and vomiting.[4] In very rare cases it causes severe side effects such as angioedema, anaphylaxis and Clostridium difficile diarrhea.

Mechanism of action[edit]
Belonging to the penicillin group of beta-lactam antibiotics, ampicillin is able to penetrate Gram-positive and some Gram-negative bacteria. It differs from penicillin G, or benzylpenicillin, only by the presence of an amino group. That amino group helps the drug penetrate the outer membrane of Gram-negative bacteria.

Ampicillin acts as an irreversible inhibitor of the enzyme transpeptidase, which is needed by bacteria to make their cell walls.[1] It inhibits the third and final stage of bacterial cell wall synthesis in binary fission, which ultimately leads to cell lysis; therefore ampicillin is bacteriocidal.[2]

History[edit]
Ampicillin has been used extensively to treat bacterial infections since 1961.[8] Until the introduction of ampicillin by the British company Beecham, penicillin therapies had only been effective against Gram-positive organisms such as staphylococci and streptococci.[2] Ampicillin (originally branded as 'Penbritin') also demonstrated activity against Gram-negative organisms such as H. influenzae, coliforms and Proteus spp.[8]

Amcinonide

Amcinonide (trade name Cyclocort) is a topical glucocorticoid used to treat itching, redness and swelling associated with several dermatologic conditions such as atopic dermatitis and allergic contact dermatitis.[1][2]

Bromazine

Bromazine (trade names Ambrodyl, Ambrodil and others), also known as bromodiphenhydramine, is an antihistamine and anticholinergic.[1] It is a halogenated form of diphenhydramine and in many respects is somewhat stronger than the parent compound. The other three halogenated diphenhydramine derivatives are used in research and chlorodiphenhydramine is also marketed with iododiphenhydramine being a much less common pharmaceutical.

Ambroxol

Ambroxol is a secretolytic agent used in the treatment of respiratory diseases associated with viscid or excessive mucus. It is the active ingredient of Mucosolvan, Mucobrox, Mucol, Lasolvan, Mucoangin, Surbronc, Ambolar, and Lysopain. The substance is a mucoactive drug with several properties including secretolytic and secretomotoric actions that restore the physiological clearance mechanisms of the respiratory tract, which play an important role in the body’s natural defence mechanisms. It stimulates synthesis and release of surfactant by type II pneumocytes. Surfactant acts as an anti-glue factor by reducing the adhesion of mucus to the bronchial wall, in improving its transport and in providing protection against infection and irritating agents.[1][2] Ambroxol is often administered as an active ingredient in cough syrup.

Ambroxol is indicated as "secretolytic therapy in bronchopulmonary diseases associated with abnormal mucus secretion and impaired mucus transport. It promotes mucus clearance, facilitates expectoration and eases productive cough, allowing patients to breathe freely and deeply".[3]


Ambroxol hydrochloride tablets in Japan
There are many different formulations developed since the first marketing authorisation in 1978. Ambroxol is available as syrup, tablets, pastilles, dry powder sachets, inhalation solution, drops and ampules as well as effervescent tablets.

Ambroxol also provides pain relief in acute sore throat. Pain in sore throat is the hallmark of acute pharyngitis.[4] Sore throat is usually caused by a viral infection. The infection is self limited and the patient recovers normally after a few days. What is most bothering for the patient is the continuous pain in the throat maximized when the patient is swallowing. The main goal of treatment is thus to reduce pain. The main property of Ambroxol for treating sore throat is the local anaesthetic effect, described first in the late 1970s,[5][6] but explained and confirmed in more recent work.

Ambroxol is a potent inhibitor of the neuronal Na+ channels.[7] This property led to the development of a lozenge containing 20 mg of ambroxol. Many state-of-the-art clinical studies[4] have demonstrated the efficacy of Ambroxol in relieving pain in acute sore throat, with a rapid onset of action, with its effect lasting at least three hours. Ambroxol is also anti-inflammatory, reducing redness in a sore throat.

Ambroxol has recently been shown to increase activity of the lysosomal enzyme glucocerebrosidase. Because of this it may be a useful therapeutic agent for both Gaucher disease and Parkinson's disease.[8]

Side effects[edit]
Field tests to date have not uncovered specific contraindications of Ambroxol. However, caution is suggested for patients with gastric ulceration, and usage during the first trimester of pregnancy is not recommended.

Ambucetamide

Ambucetamide is an antispasmodic found to be particularly effective for the relief of menstrual pain. It was discovered in 1953 by Paul Janssen.

References[edit]
Hoekstra JB, Fisher DS, Cull KM, Tisch DE, Dickison HL., Studies with a uterine antispasmodic, ambucetamide, J Am Pharm Assoc Am Pharm Assoc (Baltim). 1957 Sep;46(9):564-8.
Pickles VR, Clitheroe HJ., The effects of ambucetamide on human myometrial and other preparations, and its antagonism to the menstrual stimulant, Br J Pharmacol Chemother. 1960 Mar;15:128-30.

Ambenonium chloride

Ambenonium (as ambenonium dichloride, trade name Mytelase) is a cholinesterase inhibitor[1] used in the management of myasthenia gravis.

It is classified as reversible.[2]

Mechanism of action[edit]
Ambenonium exerts its actions against myasthenia gravis by competitive reversible inhibition of acetylcholinesterase, the enzyme responsible for the hydrolysis of acetylcholine. Myasthenia gravis occurs when the body produces antibodies against acetylcholine receptors, and thus inhibits signal transmission across the myoneural junction. Ambenonium reversibly binds acetylcholinesterase, inactivates it and therefore increases levels of acetylcholine. This, in turn, facilitates transmission of impulses across the myoneural junction and effectively treats the disease.

Indications[edit]
Ambenonium is used to treat muscle weakness due to disease or defect of the neuromuscular junction (myasthenia gravis).

Zolpidem

Zolpidem (brand names Ambien, Ambien CR, Intermezzo, Stilnox, Stilnoct, Sublinox, Hypnogen, Zonadin, Sanval, Zolsana and Zolfresh) is a prescription medication used for the treatment of insomnia and some brain disorders.[2] It is a short-acting nonbenzodiazepine hypnotic of the imidazopyridine class[3] that potentiates GABA, an inhibitory neurotransmitter, by binding to GABAA receptors at the same location as benzodiazepines.[4] It works quickly, usually within 15 minutes, and has a short half-life of two to three hours.

Zolpidem has not adequately demonstrated effectiveness in maintaining sleep, unless delivered in a controlled-release (CR) form. However, it is effective in initiating sleep.[5] Its hypnotic effects are similar to those of the benzodiazepine class of drugs, but it is molecularly distinct from the classical benzodiazepine molecule and is classified as an imidazopyridine. Flumazenil, a benzodiazepine receptor antagonist, which is used for benzodiazepine overdose, can also reverse zolpidem's sedative/hypnotic and memory-impairing effects.[6][7]

Zolpidem has slight muscle relaxant and anticonvulsant properties, but has not been approved for use in muscle relaxation or seizure prevention. This is because the dosage of drug needed to cause muscle relaxation is 10 times the sedating dose, and the dosage needed for preventing seizures is 20 times the sedating dose;[8] high dosages are more likely to cause unpleasant side effects such as hallucinations and amnesia. Contrary to early studies, more recent research has indicated that zolpidem is in fact a potent anticonvulsant.[9] The anticonvulsant effects are not realized until the normal dosage range has been surpassed (meaning sedation would still be a major side effect) but the threshold for this effect is now believed to be considerably lower than original estimates.

The United States patent for zolpidem was held by the French pharmaceutical corporation Sanofi-Aventis.[10] On April 23, 2007, the U.S. Food and Drug Administration (FDA) approved 13 generic versions of zolpidem tartrate.[11] Zolpidem is available from several generic manufacturers in the UK, as a generic from Sandoz in South Africa and TEVA in Israel, as well as from other manufacturers such as Ratiopharm and Takeda GmbH (both Germany).

On January 10, 2013, the Food and Drug Administration announced it is requiring the manufacturer of Ambien and Zolpimist to cut the recommended dosage for women in half, after laboratory studies showed that the medicines can leave patients drowsy in the morning and at risk for car accidents. The FDA recommended that manufacturers extend the new dosage cuts to men as well, who process the drug at a faster rate; however, the reasons men and women metabolize the drugs at different rates are still unknown.[12] In May 2013, the FDA approved label changes specifying new dosage recommendations for zolpidem products because of concerns regarding next-morning impairment.
Medical uses[edit]

Zolpidem tartrate 10 mg tablets
Clinicians prescribe zolpidem for short-term (usually about two to six weeks) treatment of insomnia.[14] Zolpidem has not proven effective in maintaining sleep, but addresses sleep-initiation problems.[5] The effect over placebo is of marginal clinical benefit.[15]

Adverse effects[edit]

Various zolpidem pills
Side effects may include:[16]

Night eating syndrome (also commonly known as sleep-eating)
Headaches (mostly withdrawal symptom)
Nausea (mostly withdrawal symptom)
Vomiting (mostly withdrawal symptom)
Dizziness
Anterograde amnesia
Hallucinations, through all physical senses, of varying intensity
Altered thought patterns
Ataxia or poor motor coordination, difficulty maintaining balance[17]
Euphoria or dysphoria
Impaired judgment and reasoning
Uninhibited extroversion in social or interpersonal settings
Increased impulsivity (mostly withdrawal symptom)
When stopped, rebound insomnia may occur
Some users have reported unexplained sleepwalking[18][original research?] while using zolpidem, as well as sleep driving, binge eating while asleep, and performing other daily tasks while sleeping. Research by Australia's National Prescribing Service found these events occur mostly after the first dose taken, or within a few days of starting therapy.[19] Rare reports of sexual parasomnia episodes related to zolpidem intake have also been reported.[20] Sleepwalkers can sometimes perform these tasks as normally as they might if they were awake.

Residual 'hangover' effects, such as sleepiness and impaired psychomotor and cognitive function, may persist into the day following nighttime administration. Such effects may impair the ability of users to drive safely and increase risks of falls and hip fractures.[21]

The Sydney Morning Herald in Australia in 2007 reported a man who fell 30 meters to his death from a high-rise unit balcony may have been sleepwalking under the influence of Stilnox. The coverage prompted over 40 readers to contact the newspaper with their own accounts of Stilnox-related automatism, and as of March 2007, the drug was under review by the Adverse Drug Reactions Advisory Committee.[22][needs update]

In February 2008, the Australian Therapeutic Goods Administration attached a boxed warning to zolpidem, stating that "Zolpidem may be associated with potentially dangerous complex sleep-related behaviors that may include sleep walking, sleep driving, and other bizarre behaviours. Zolpidem is not to be taken with alcoholic beverages. Caution is needed with other CNS-depressant drugs. Limit use to four weeks maximum under close medical supervision."[23] This report received widespread media coverage[24] after the death of Australian student Mairead Costigan, who fell 20 m from the Sydney Harbour Bridge while under the influence of Stilnox.[25]

Tolerance, dependence, and withdrawal[edit]

Ambien tablets
A review medical publication found long-term use of zolpidem is associated with drug tolerance, drug dependence, rebound insomnia, and CNS-related adverse effects. It was recommended that zolpidem be used for short periods of time using the lowest effective dose. Zolpidem 10 mg is effective in treating insomnia when used intermittently no fewer than three and no more than five pills per week for a period of 12 weeks.[26] The 15-mg zolpidem dosage provided no clinical advantage over the 10-mg zolpidem dosage.[27]

Nonpharmacological treatment options (e.g. cognitive behavioral therapy for insomnia), however, were found to have sustained improvements in sleep quality.[28] Animal studies of the tolerance-inducing properties have shown that in rodents, zolpidem has less tolerance-producing potential than benzodiazepines, but in primates the tolerance-producing potential of zolpidem was the same as that of benzodiazepines.[29] Tolerance to the effects of zolpidem can develop in some people in just a few weeks. Abrupt withdrawal may cause delirium, seizures, or other severe effects, especially if used for prolonged periods and at high dosages.[30][31][32]

When drug tolerance and physical dependence to zolpidem has developed, treatment usually entails a gradual dose reduction over a period of months to minimise withdrawal symptoms, which can resemble those seen during benzodiazepine withdrawal. Failing that, an alternative method may be necessary for some patients, such as a switch to a benzodiazepine equivalent dose of a longer-acting benzodiazepine drug, such as diazepam or chlordiazepoxide, followed by a gradual reduction in dosage of the long-acting benzodiazepine. Sometimes for difficult-to-treat patients, an inpatient flumazenil rapid detoxification program can be used to detoxify from a zolpidem drug dependence or addiction.[33]

Alcohol has cross tolerance with GABAA receptor positive modulators such as the benzodiazepines and the nonbenzodiazepine drugs. For this reason, alcoholics or recovering alcoholics may be at increased risk of physical dependency on zolpidem. Also, alcoholics and drug abusers may be at increased risk of abusing and or becoming psychologically dependent on zolpidem. It should be avoided in those with a history of alcoholism, drug misuse, physical dependency, or psychological dependency on sedative-hypnotic drugs. Zolpidem has rarely been associated with drug-seeking behavior,[citation needed] the risk of which is amplified in patients with a history of drug or alcohol abuse.

Overdose[edit]
An overdose of zolpidem may cause excessive sedation, pin-point pupils, or depressed respiratory function, which may progress to coma, and possibly death. Combined with alcohol, opiates, or other CNS depressants, it may be even more likely to lead to fatal overdoses. Zolpidem overdosage can be treated with the benzodiazepine receptor antagonist flumazenil, which displaces zolpidem from its binding site on the benzodiazepine receptor to rapidly reverse the effects of the zolpidem.[34]

Detection in body fluids[edit]
Zolpidem may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients, provide evidence in an impaired driving arrest, or to assist in a medicolegal death investigation. Blood or plasma zolpidem concentrations are usually in a range of 30–300 μg/l in persons receiving the drug therapeutically, 100–700 μg/l in those arrested for impaired driving, and 1000–7000 μg/l in victims of acute overdosage. Analytical techniques, in general, involve gas or liquid chromatography.[35][36][37]

Special precautions[edit]
Driving[edit]
Use of zolpidem may impair driving skills with a resultant increased risk of road traffic accidents. This adverse effect is not unique to zolpidem but also occurs with other hypnotic drugs. Caution should be exercised by motor vehicle drivers.[38] Studies showed that eight hours after a bedtime dose of 10 mg, 15% of women and 3% of men would have blood levels that produce impaired driving skills; for an extended-release dose of 12.5 mg, the risk increased to 33% and 25%, respectively. As a consequence, the FDA recommended the dose for women be reduced and that prescribers should consider lower doses for men.[39][40]

Elderly[edit]
The elderly are more sensitive to the effects of hypnotics including zolpidem. Zolpidem causes an increased risk of falls and may induce adverse cognitive effects.[41]

An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and durability of nondrug treatments for insomnia in adults of all ages, and these interventions are underused. Compared with the benzodiazepines, the nonbenzodiazepine (including zolpidem) sedative-hypnotics appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. Newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin receptor agonists, were found to hold promise for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of these agents remain to be determined. More research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.[42]

Gastroesophageal reflux disease[edit]
Patients suffering from gastroesophageal reflux disease (GERD) had reflux events measured to be significantly longer when taking zolpidem than on placebo. The same trend was found for reflux events in patients without GERD. This is assumed to be due to suppression of arousal during the reflux event, which would normally result in a swallowing reflex to clear gastric acid from the esophagus. Patients with GERD experience significantly higher esophageal exposure to gastric acid, which increases the likelihood of their developing esophageal cancer.[43]

Pregnancy[edit]
Zolpidem has been assigned to pregnancy category C by the FDA. Animal studies have revealed evidence of incomplete ossification and increased postimplantation fetal loss at doses greater than seven times the maximum recommended human dose or higher; however, teratogenicity was not observed at any dose level. There are no controlled data in human pregnancy. In one case report, zolpidem was found in cord blood at delivery. Zolpidem is recommended for use during pregnancy only when benefits outweigh risks. [44]

Mechanism of action[edit]
Zolpidem DOJ.jpg
Zaleplon and zolpidem both are agonists at the GABA A ɣ 1 subunit. Due to its selective binding, zolpidem has very weak anxiolytic, myorelaxant, and anticonvulsant properties but very strong hypnotic properties.[45] Zolpidem binds with high affinity and acts as a full agonist at the α1-containing GABAA receptors, about 10-fold lower affinity for those containing the α2- and α3- GABAA receptor subunits, and with no appreciable affinity for α5 subunit-containing receptors.[46][47] ω1 type GABAA receptors are the α1-containing GABAA receptors and ω2 GABAA receptors are the α2-, α3-, α4-, α5-, and α6-containing GABAA receptors. ω1 GABAA receptors are found primarily in the brain, whereas ω2 receptors are found primarily in the spine. Thus, zolpidem has a preferential binding for the GABAA-benzodiazepine receptor complex in the brain but a low affinity for the GABAA-benzodiazepine receptor complex in the spine.[48]

Like the vast majority of benzodiazepine-like molecules, zolpidem has no affinity for α4 and α6 subunit-containing receptors.[49] Zolpidem positively modulates GABAA receptors, it is presumed by increasing the GABAA receptor complex's apparent affinity for GABA without affecting desensitization or peak current.[50] Like zaleplon (Sonata), zolpidem may increase slow wave sleep but cause no effect on stage 2 sleep.[51]

A meta-analysis of the randomised, controlled, clinical trials that compared benzodiazepines against nonbenzodiazepines such as zolpidem has shown few consistent differences between zolpidem and benzodiazepines in terms of sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia, and daytime alertness.[52]

Chemistry[edit]
Three syntheses of zolpidem are common. 4-methylacetophenone is used as a common precursor. This is brominated and reacted with 2-amino-5-methylpyridine to give the imidazopyridine. From here the reactions use a variety of reagents to complete the synthesis, either involving thionyl chloride or sodium cyanide. These reagents are challenging to handle and require thorough safety assessments.[53][54][55] Though such safety procedures are common in industry, they make clandestine manufacture difficult.

A number of major side-products of the sodium cyanide reaction have been characterised and include dimers and mannich products.[56]

Drug-drug interactions[edit]
Notable drug-drug interactions with the pharmacokinetics of zolpidem include chlorpromazine, fluconazole, imipramine, itraconazole, ketoconazole, rifampicin, and ritonavir. Interactions with carbamazepine and phenytoin can be expected based on their metabolic pathways, but have not yet been studied. There does not appear to be any interaction between zolpidem and cimetidine or ranitidine.[57][58] However, it was noted in the same study that cimetidine did appear to prolong the hypnotic effects of Zolpidem beyond its typical 3 hour duration, which is indicative of some sort of metabolic interaction.[57]

Misuse[edit]
Recreational use[edit]
Zolpidem has a potential for either medical misuse when the drug is continued long term without or against medical advice or recreational use when the drug is taken to achieve a "high".[59] The transition from medical use of zolpidem to high-dose addiction or drug dependence can occur when used without a doctor's recommendation to continue using it, when physiological drug tolerance leads to higher doses than the usual 5 mg or 10 mg, when consumed through inhalation or injection, or when taken for purposes other than as a sleep aid. Misuse is more prevalent in those having been dependent on other drugs in the past, but tolerance and drug dependence can still sometimes occur in those without a history of drug dependence. Chronic users of high doses are more likely to develop physical dependence on the drug, which may cause severe withdrawal symptoms, including seizures, if abrupt withdrawal from zolpidem occurs.[60]

One case history reported a woman detoxifying from a high dose of zolpidem experiencing a generalized seizure, with clinical withdrawal and dependence effects reported to be similar to the benzodiazepine withdrawal syndrome.[61]

Nonmedical use of zolpidem is increasingly common in the U.S., Canada, and the UK. Recreational users report that resisting the drug's hypnotic effects can in some cases elicit vivid visuals and a body high.[53] Some users have reported decreased anxiety, mild euphoria, perceptual changes, visual distortions, and hallucinations.[62]

Other drugs, including the benzodiazepines and zopiclone, are also found in high numbers of suspected drugged drivers. Many drivers have blood levels far exceeding the therapeutic dose range suggesting a high degree of excessive-use potential for benzodiazepines, zolpidem and zopiclone.[63] U.S. Congressman Patrick J. Kennedy says that he was using Zolpidem (Ambien) and Phenergan when caught driving erratically at 3AM.[64] "I simply do not remember getting out of bed, being pulled over by the police, or being cited for three driving infractions," Kennedy said.

Zolpidem, along with the other benzodiazepine-like Z-drugs is a Schedule IV controlled substance in the U.S., according to the Controlled Substances Act, given its potential for abuse and dependence.

Usage[edit]
Zolpidem is one of the most common GABA-potentiating sleeping medications prescribed in the Netherlands, with a total of 582,660 prescriptions dispensed in 2008.[65]

The United States Air Force uses zolpidem as one of the hypnotics approved as a "no-go pill" (with a 6-hour restriction on subsequent flight operation) to help aviators and special duty personnel sleep in support of mission readiness. (The other hypnotics used are temazepam and zaleplon.) "Ground tests" are required prior to authorization issued to use the medication in an operational situation.[66]

Research[edit]
Zolpidem may provide short-lasting but effective improvement in symptoms of aphasia present in some survivors of stroke. The mechanism for improvement in these cases remains unexplained and is the focus of current research by several groups, to explain how a drug that acts as a hypnotic-sedative in people with normal brain function, can increase speech ability in people recovering from severe brain injury. Use of zolpidem for this application remains experimental at this time, and is not officially approved by any pharmaceutical manufacturers of zolpidem or medical regulatory agencies worldwide.[67][68][69][70][71]

Zolpidem is being studied to determine whether it causes improved responsiveness or regional cerebral perfusion in patients with persistent vegetative states.

Amphotericin B

Amphotericin B (Fungilin, Fungizone, Abelcet, AmBisome, Fungisome, Amphocil, Amphotec) is an antifungal drug often used intravenously for systemic fungal infections.[1] It is the only effective treatment for some infections.[1]

Common side effects may include: a reaction which may include fever, headaches and low blood pressure among other symptoms rapidly after it is given, and kidney problems.[1] Allergic symptoms including anaphylaxis may occur.[1]

It was originally extracted from Streptomyces nodosus, a filamentous bacterium, in 1955, at the Squibb Institute for Medical Research. Its name originates from the chemical's amphoteric properties. It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.[2] It is of the polyene class. Currently, the drug is available as plain amphotericin B, as a cholesteryl sulfate complex (ABCD), as a lipid complex (ABLC), and as a liposomal formulation (LAmB). The latter formulations have been developed to improve tolerability, but may show considerably different pharmacokinetic characteristics compared to plain amphotericin B.

Ambazone

Ambazone is an oral antiseptic.

Ambazon was patented in 1957 by Bayer under the trade name Iversal, and briefly used in Germany. It is still used in Russia, countries of the former Soviet Union and Romania. It has not been approved by the United States Food and Drug Administration (FDA).

Contents  [hide]
1 Synthesis
2 Applications
3 Physical properties
4 Mode of action
5 Therapeutic uses
6 References
Synthesis[edit]
Ambazone can be obtained in a two step synthetic method, reacting 1,4-Benzochinone with Aminoguanidine and Thiosemicarbazide.,[2][3]

Ambazone synthesis 01.PNG

Obtaining a pharmacetical grade material is difficult due to high amounts of byproducts, synthetic intermediates and decomposition products.[4]

Applications[edit]
Bacteriostatic action on hemolytic streptococcus, streptococcus pneumoniae and viridans streptococcus.

Physical properties[edit]
Through experimental testing ambazone has shown antiseptic properties, along with anti-tumor properties. Ambazone has the following physical characteristics.

Table 1. Physical properties
Dark brown
Odorless
Tasteless
Powder
Melting Point 192–194 °C (decomp.)[5]
Table 2. Solubility per 100 ml
Water 0.2 mg
Methanol 0.5 mg
Chloroform 0.3 mg
1-butanol 6.5 mg
Ethyl acetate 17 mg
Acetone 50 mg
Ethanol 85 mg
Dimethyl formamide 1.7 g
sulfoxide 2.5 g
Table 3. Uv-Vis nm
Water 403
Alcohols 440-445
Ethyl acetate 453
Dimethyl sulfoxide 467
Ambazone is prepared by way of solid based crystallization or grinding.

Mode of action[edit]
The mode of action for ambazone has been studied extensively and ambazone has been shown to react via different methods. Ambazone shows low mutagenic activity and no cardiovascular, CNS, metabolic, or gastrointestinal side-effects with I.V. doses up to 10-5 mol/kg and oral doses up to 10-3 mol/kg. As stated before ambazone can be administered via oral or I.V. administration, but the problem with oral administration is that one experimental study shows there is only a 35-50% absorption while another study shows 40% in the intestines; These results would tend to lead the reader to think that ambazone would not be the best choice for treatment, because with such a low absorbance, there is going to have to be a greater concentration ingested to gain a positive effect from the drug. The problem with a greater concentration is that ambazone has a half-life of 6–7 hours. It was stated above that ambazone possess no CNS side-effects and the reason we know this is, due to the fact, that it will not cross the blood brain barrier. Although this is the body’s way of protecting unwanted substances from attacking the brain, this also limits the treatment of brain tumors with ambazone.

Therapeutic uses[edit]
The therapeutic properties of ambazone were studied in lab rats and the therapeutic dose was determined to be 60–125 mg/kg of body weight. As stated above, ambazone possesses anti-septic properties shown by its increased activity against gram-positive cocci. Along with anti-septic properties, ambazone has also shown its ability to fight forms of leukemia in lab rats. When administered orally the results showed prolongation of life expectancy and curing of L1210 and P388 leukemia in lab rats. Scientist used different methods to determine the results, such as; mean survival time (MST), percent increase of life span, survival rates, percent change in body weights and number of peritoneal cells. The results gathered show tremendous strides towards leukemia treatment. Although we can see positive results, one might wonder, “Are there side effects?” The results show different answers depending on the test performed. When testing ambazone via AMES with no metabolic activation we find there are no mutagenic or carcinogenic properties. When the same test is performed with metabolic activation or when the C-Test is performed we do see the potential for mutagenicity. The results show two different paths and until further testing has been performed we cannot determine if the good outweighs the bad when it comes to using ambazone for treatment.

Amatuximab

Amatuximab is a chimeric monoclonal antibody designed for the treatment of cancer.[1]

Amatuximab was developed by Morphotek, Inc.

Amatuximab is also known as Anti-mesothelin monoclonal antibody MORAb-009. Amatuximab is an anti-mesothelin monoclonal antibody MORAb-009 binds to mesothelin (a protein that is made by some cancer cells) and stops the cells from dividing, and also called MORAb-009.

Midodrine

Midodrine (brand names Amatine, ProAmatine, Gutron) is a vasopressor/antihypotensive agent. Midodrine was approved in the United States by the Food and Drug Administration (FDA) in 1996 for the treatment of dysautonomia and orthostatic hypotension. In August 2010, the FDA proposed withdrawing this approval because the manufacturer, Shire plc, has failed to complete required studies after the medicine reached the market.[1][2]

In September 2010, the FDA reversed its decision to remove Midodrine from the market and has allowed it to remain available to patients while Shire plc collects further data regarding the efficacy and safety of the drug.[3] Shire plc announced on September 27, 2011 that it was continuing the process to work with the FDA towards a final approval of the drug.
Chemical properties[edit]
Midodrine is an odorless, white, crystalline powder, soluble in water and sparingly soluble in methanol.

Mechanism of action[edit]
Midodrine is a prodrug which forms an active metabolite, desglymidodrine, which is an α1-receptor agonist and exerts its actions via activation of the alpha-adrenergic receptors of the arteriolar and venous vasculature, producing an increase in vascular tone and elevation of blood pressure. Desglymidodrine does not stimulate cardiac beta-adrenergic receptors. Desglymidodrine diffuses poorly across the blood–brain barrier, and is therefore not associated with effects on the central nervous system.


Metabolite desglymidodrine
Metabolism[edit]
After oral administration, midodrine is rapidly absorbed. The plasma levels of the prodrug peak after about half an hour, and decline with a half-life of approximately 25 minutes, while the metabolite reaches peak blood concentrations about 1 to 2 hours after a dose of midodrine and has a half-life of about 3 to 4 hours. The absolute bioavailability of midodrine (measured as desglymidodrine) is 93%.

Indications[edit]
Midodrine hydrochloride tablets are indicated for the treatment of symptomatic orthostatic hypotension. It can reduce dizziness and faints by about a third, but can be limited by troublesome goose bumps.[5] Small studies have also shown that midodrine can be used to prevent excessive drops in blood pressure in people requiring dialysis.[6]

Midodrine has been used in the complications of cirrhosis. It is also used with octreotide for hepatorenal syndrome; the proposed mechanism is constriction of splanchnic vessels and dilation of renal vasculature. Studies have not been sufficiently well conducted to show a clear place for midodrine.[7]

Contraindications[edit]
Midodrine is contraindicated in patients with severe organic heart disease, acute renal disease, urinary retention, pheochromocytoma or thyrotoxicosis. Midodrine should not be used in patients with persistent and excessive supine hypertension.

Side effects[edit]
Headache; feeling of pressure/fullness in the head, vasodilation/flushing face, confusion/thinking abnormality, dry mouth; nervousness/anxiety and rash.

Glimepiride

Glimepiride is a medium- to long-acting sulfonylurea antidiabetic drug. It is marketed as GLEAM by Franco Indian Pharmaceuticals,K-GLIM-1 by BLUE CROSS, Glucoryl by Alkem Lab PVT LTD , Amaryl by Sanofi-Aventis, GLIMPID by Ranbaxy Laboratories(Cardiovascular) and GLIMY by Dr.Reddy's Labs.

It is sometimes classified as either the first third-generation sulfonylurea,[1] or as second-generation.
Indication / contraindications[edit]
Main article: Sulfonylurea
Glimepiride is indicated to treat type 2 diabetes mellitus; its mode of action is to increase insulin production by the pancreas. It is not used for type 1 diabetes because in type 1 diabetes the pancreas is not able to produce insulin.[3]

Its use is contraindicated in patients with hypersensitivity to glimepiride or other sulfonylureas, and during pregnancy.

Adverse effects[edit]
Main article: Sulfonylurea
Side effects from taking glimepiride include gastrointestinal tract (GI) disturbances, occasional allergic reactions, and rarely blood production disorders including thrombocytopenia, leukopenia, and hemolytic anemia. In the initial weeks of treatment, the risk of hypoglycemia may be increased. Alcohol consumption and exposure to sunlight should be restricted because they can worsen side effects.[3]

Pharmacokinetics[edit]

2-mg oral tablet of glimepiride
Gastrointestinal absorption is complete, with no interference from meals. Significant absorption can occur within one hour, and distribution is throughout the body, 99.5% bound to plasma protein. Metabolism is by oxidative biotransformation. Excretion in the urine is 65%, and the remainder is excreted in the feces.

Mechanism of action[edit]
Main article: Sulfonylurea
Like all sulfonylureas, glimepiride acts as an insulin secretagogue.[4] It lowers blood sugar by stimulating the release of insulin by pancreatic beta cells and by inducing increased activity of intracellular insulin receptors.

Not all secondary sufonylureas have the same risks of hypoglycemia. Glibenclamide (glyburide) is associated with an incidence of hypoglycemia of up to 20–30%, compared to as low as 2% to 4% with glimepiride. Glibenclamide also interferes with the normal homeostatic suppression of insulin secretion in reaction to hypoglycemia, whereas glimepiride does not. Also, glibenclamide diminishes glucagon secretion in reaction to hypoglycemia, whereas glimepiride does not.[5]

Interactions[edit]
Nonsteroidal anti-inflammatory drugs (such as salicylates), sulfonamides, chloramphenicol, coumadin and probenecid) may potentiate the hypoglycemic action of glimepiride. Thiazides, other diuretics, phothiazides, thyroid products, oral contraceptives, and phenytoin tend to produce hyperglycemia.

Amantadine

Amantadine (trade name Symmetrel, by Endo Pharmaceuticals) is a drug that has U.S. Food and Drug Administration approval for use both as an antiviral and an antiparkinsonian drug. It is the organic compound 1-adamantylamine or 1-aminoadamantane, meaning it consists of an adamantane backbone that has an amino group substituted at one of the four methyne positions. Rimantadine is a closely related derivative of adamantane with similar biological properties.

Apart from medical uses, this compound is useful as a building block, allowing the insertion of an adamantyl group.

According to the U.S. Centers for Disease Control and Prevention, 100% of seasonal H3N2 and 2009 pandemic flu samples tested have shown resistance to adamantanes, and amantadine is no longer recommended for treatment of influenza in the United States. Additionally, its effectiveness as an antiparkinsonian drug is undetermined, with a 2003 Cochrane Review concluding that there was insufficient evidence in support or against its efficacy and safety.
Medical uses[edit]
Parkinson's disease[edit]
Amantadine is a weak antagonist of the NMDA-type glutamate receptor, increases dopamine release, and blocks dopamine reuptake.[3] This makes it a weak therapy for Parkinson's disease. Although, as an antiparkinsonian, it can be used as monotherapy, or together with L-DOPA to treat L-DOPA-related motor fluctuations (i.e., shortening of L-DOPA duration of clinical effect, probably related to progressive neuronal loss) and L-DOPA-related dyskinesias (choreiform movements associated with long-term L-DOPA use, probably related to chronic pulsatile stimulation of dopamine receptors).

A 2003 Cochrane review of the scientific literature concluded evidence was inadequate to support the use of amantadine for Parkinson's disease.[2]

Influenza[edit]
Amantadine is no longer recommended for treatment of influenza A infection. For the 2008/2009 flu season, the United States' Centers for Disease Control and Prevention (CDC) found that 100% of seasonal H3N2 and 2009 pandemic flu samples tested have shown resistance to adamantanes.[4] The CDC issued an alert to doctors to prescribe the neuraminidase inhibitors oseltamivir and zanamivir instead of amantadine and rimantadine for treatment of flu.[5][6] A 2014 Cochrane review did not find benefit for the prevention or treatment of influenza A.[7]

Fatigue in multiple sclerosis[edit]
Amantadine also seems to have moderate effects on multiple sclerosis (MS) related fatigue.[8]

Adverse effects[edit]
Amantadine has been associated with several central nervous system (CNS) side effects, likely due to amantadine's dopaminergic and adrenergic activity, and to a lesser extent, its activity as an anticholinergic. CNS side effects include nervousness, anxiety, agitation, insomnia, difficulty in concentrating, and exacerbations of pre-existing seizure disorders and psychiatric symptoms in patients with schizophrenia or Parkinson's disease. The usefulness of amantadine as an anti-parkinsonian drug is somewhat limited by the need to screen patients for a history of seizures and psychiatric symptoms.

Rare cases of severe skin rashes, such as Stevens-Johnson syndrome,[9] and of suicidal ideation have also been reported in patients treated with amantadine.[10][11]

Livedo reticularis is a possible side effect of amantadine use for Parkinson's disease.[12]

Mechanism of action[edit]
Question book-new.svg
This section relies too much on references to primary sources. Please improve this article by adding secondary or tertiary sources. (June 2014)
Influenza[edit]
The mechanisms for amantadine's antiviral and antiparkinsonian effects are unrelated. The mechanism of amantadine's antiviral activity involves interference with the viral protein, M2, a proton channel.[13][14] After entry of the virus into cells via endocytosis, it is localized in acidic vacuoles; the M2 channel functions in transporting protons with the gradient from the vacuolar space into to interior of the virion. Acidification of the interior results in disassociation of ribonucleoproteins, and the onset of viral replication. Amantadine and rimantadine function in a mechanistically identical fashion in entering the barrel of the tetrameric M2 channel, and blocking pore function (i.e., proton translocation). Resistance to the drug class is a consequence of mutations to the pore-lining residues of the channel, leading to the inability of the sterically bulky adamantane ring that both share in entering in their usual way, into the channel.[citation needed]

Influenza B strains possess a structurally distinct M2 channels with channel-facing side chains that fully obstruct the channel vis-a-vis binding of adamantine-calss channel inhibitors, while still allowing proton flow and channel function to occur; this constriction in the channels is responsible for the ineffectiveness of this drug and rimantadine towards all circulating Influenza B strains.

Parkinsons disease[edit]
Amantadine appears to act through several pharmacological mechanisms, but no dominant mechanism of action has been identified. It is a dopaminergic, noradrenergic and serotonergic substance, blocks monoamine oxidase A and NMDA receptors, and seems to raise beta-endorphin/beta-lipotropin levels.[citation needed] Moreover, the mechanism of its antiparkinsonian effect is poorly understood.[citation needed] The drug has many effects in the brain, including release of dopamine and norepinephrine from nerve endings. It appears to be a weak NMDA receptor antagonist[15][16] as well as an anticholinergic, specifically a nicotinic alpha-7 antagonist like the similar pharmaceutical memantine.

History[edit]
Amantadine was approved by the U.S. Food and Drug Administration in October 1966 as a prophylactic agent against Asian influenza, and eventually received approval for the treatment of influenzavirus A[17][18][19][20] in adults. In 1969, the drug was also discovered by accident to help reduce symptoms of Parkinson's disease, drug-induced extrapyramidal syndromes, and akathisia.

Research[edit]
In a 2012 study, 184 patients with severe traumatic brain injury were treated with amantadine or placebo for four weeks. In this study, the drug accelerated functional brain recovery during treatment. However, the placebo group had improved just as much as the amantadine group at six weeks — two weeks after the drug administration ended.[21]

Veterinary misuse[edit]
In 2005, Chinese poultry farmers were reported to have used amantadine to protect birds against avian influenza.[22] In Western countries and according to international livestock regulations, amantadine is approved only for use in humans. Chickens in China have received an estimated 2.6 billion doses of amantadine.[22] Avian flu (H5N1) strains in China and southeast Asia are now resistant to amantadine, although strains circulating elsewhere still seem to be sensitive. If amantadine-resistant strains of the virus spread, the drugs of choice in an avian flu outbreak will probably be restricted to the scarcer and costlier oseltamivir and zanamivir, which work by a different mechanism and are less likely to trigger resistance.

Alemtuzumab

Alemtuzumab is a drug used in the treatment of chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma (CTCL) and T-cell lymphoma under the trade names Campath, MabCampath and Campath-1H, and in the treatment of multiple sclerosis as Lemtrada. It is also used in some conditioning regimens for bone marrow transplantation, kidney transplantation and islet cell transplantation.

It is a monoclonal antibody that binds to CD52, a protein present on the surface of mature lymphocytes, but not on the stem cells from which these lymphocytes are derived. After treatment with alemtuzumab, these CD52-bearing lymphocytes are targeted for destruction.

Alemtuzumab is used as second-line therapy for CLL. It was approved by the US Food and Drug Administration for CLL patients who have been treated with alkylating agents and who have failed fludarabine therapy. It has been approved by Health Canada for the same indication, and additionally for CLL patients who have not had any previous therapies.

(Mab)Campath was withdrawn from the markets in the US and Europe in 2012 to prepare for a higher-priced relaunch of Lemtrada aimed at multiple sclerosis.[1]

A complication of therapy with alemtuzumab is that it significantly increases the risk for opportunistic infections, in particular, reactivation of cytomegalovirus.
Medical uses[edit]
Chronic lymphocytic leukemia[edit]
Alemtuzumab is indicated for the treatment of B-cell chronic lymphocytic leukemia (B-CLL) in patients who have been treated with alkylating agents and who have failed fludarabine therapy. It is an unconjugated antibody, thought to work via the activation of antibody-dependent cell-mediated cytotoxicity (ADCC).[2]

Multiple sclerosis[edit]
In 2008 early tests at Cambridge University suggest that alemtuzumab might be useful in treating and even reversing the effects of multiple sclerosis.[3] Promising results were reported in 2011 from a phase III trial against interferon beta 1a. A combination trial with glatiramer acetate (Copaxone) is being considered, and is expected to work synergistically.[4]

In September 2013 alemtuzumab was approved for first-line use in the EU.

In November 2013, the US FDA issued a comprehensive briefing on alemtuzumab for an agency review meeting. The document highlighted numerous serious safety and efficacy concerns, including substantial doubts about the adequacy of relevant clinical trials.[5] In December 2013, the US FDA indicated that the Lemtrada application is not ready for approval, due to lack of evidence from "adequate and well-controlled studies" that demonstrate that the benefits of the drug outweigh the risks.[6] The CEO of Genzyme, David Meeker, strongly disagreed with this decision and indicated that the company would file an appeal.

On November 2014 Alemtuzumab was finally approved by the FDA[7]

On December 1,2014 the first treatments with Lemtrada (or almtuzumab) were administered to the first patients outside clinical trials. Dr. Christopher LaGanke was the attending physician and was also instrumental in having the FDA reconsider the approval. [8]

Contraindications[edit]
Alemtuzumab is contraindicated in patients who have active systemic infections, underlying immunodeficiency (e.g., seropositive for HIV), or known Type I hypersensitivity or anaphylactic reactions to the substance.

Adverse effects[edit]
Alemtuzumab has been associated with infusion-related events including hypotension, rigors, fever, shortness of breath, bronchospasm, chills, and/or rash. In post-marketing reports, the following serious infusion-related events were reported: syncope, pulmonary infiltrates, ARDS, respiratory arrest, cardiac arrhythmias, myocardial infarction and cardiac arrest. The cardiac adverse events have resulted in death in some cases.[9]

It can also precipitate autoimmune disease through the suppression of suppressor T cell populations and/or the emergence of autoreactive B-cells.[10][11]

Biochemical properties[edit]
Alemtuzumab is a recombinant DNA-derived humanized IgG1 kappa monoclonal antibody that is directed against the 21–28 kDa cell surface glycoprotein CD52.[12]

History[edit]
The origins of alemtuzumab date back to Campath-1 which was derived from the rat antibodies raised against human lymphocyte proteins by Herman Waldmann and colleagues in 1983.[13] The name "Campath" derives from the pathology department of Cambridge University.

Initially, Campath-1 was not ideal for therapy because patients could, in theory, react against the foreign rat protein determinants of the antibody. To circumvent this problem, Greg Winter and his colleagues humanised Campath-1, by extracting the hypervariable loops that had specificity for CD52 and grafting them onto a human antibody framework. This became known as Campath-1H and serves as the basis for alemtuzumab.[14]

While alemtuzumab started life as a laboratory tool for understanding the immune system, within a short time it was clinically investigated for use to improve the success of bone marrow transplants and as a treatment for leukaemia, lymphoma, vasculitis, organ transplants, rheumatoid arthritis and multiple sclerosis.[15]

Campath as medication was first approved for B-cell chronic lymphocytic leukemia in 2001. It is marketed by Genzyme, which acquired the world-wide rights from Bayer AG in 2009. Genzyme was bought by Sanofi in 2011. In August/September 2012 Campath was withdrawn from the markets in the US and Europe. This was done to prevent off-label use of the drug to treat multiple sclerosis and to prepare for a relaunch under the trade name Lemtrada, with a different dosage aimed at multiple sclerosis treatment, this is expected to be much higher-priced.[1]

Bayer reserves the right to co promote Lemtrada for 5 years, with the option to renew for an additional five years.

Sanofi acquisition and change of license controversy[edit]
In February 2011, Sanofi-Aventis, since renamed Sanofi, acquired Genzyme, the manufacturer of alemtuzumab.[16] The acquisition was delayed by a dispute between the two companies regarding the value of alemtuzumab. The dispute was settled by the issuance of Contingent Value Rights, a type of stock warrant which pays a dividend only if alemtuzumab reaches certain sales targets. The contingent value rights (CVR) trade on the NASDAQ-GM market with the ticker symbol GCVRZ.

In August 2012, Genzyme surrendered the licence for all presentations of alemtuzumab,[17] pending regulatory approval to re-introduce it as a treatment for multiple sclerosis. Concerns[18] that Genzyme would later bring to market the same product at a much higher price proved correct.

Research and off-label use[edit]
Graft-versus-host disease[edit]
A 2009 study of alemtuzumab in 20 patients with severe steroid-resistant acute intestinal graft-versus-host disease after allogeneic hematopoietic stem cell transplantation (HSCT) demonstrated improvement. Overall response rate was 70%, with complete response in 35%. In this study, the median survival was 280 days. Important complications following this treatment included cytomegalovirus reactivation, bacterial infection, and invasive aspergillosis infection.[19]

Aleglitazar

Aleglitazar is a peroxisome proliferator-activated receptor agonist (hence a PPAR modulator ) with affinity to PPARα and PPARγ, which was under development by Hoffmann–La Roche for the treatment of type II diabetes.[1] It is no longer in phase III clinical trials.

Iduronidase

Iduronidase (EC 3.2.1.76, L-iduronidase, alpha-L-iduronidase) is an enzyme with the system name glycosaminoglycan alpha-L-iduronohydrolase.[1][2][3] This enzyme catalyses the hydrolysis of unsulfated alpha-L-iduronosidic linkages in dermatan sulfate.

It is involved in the degeneration of glycosaminoglycans such as dermatan sulfate and heparan sulfate. It is found in the lysosomes of cells.

Pathology[edit]
Its deficiency is associated with mucopolysaccharidoses (MPS). MPS, a type of lysosomal storage disease, is typed I through VII. Type I is known as Hurler syndrome and type I,S is known as Scheie syndrome, which has a milder prognosis compared to Hurler's. In this syndrome, glycosaminoglycans accumulate in the lysosomes and cause substantial disease in many different tissues of the body.

The defective alpha-L-iduronidase results in an accumulation of heparan and dermatan sulfate within phagocytes, endothelium, smooth muscle cells, neurons, and fibroblasts. Under electron microscopy these structures present as laminated structures called Zebra bodies.

Prenatal diagnosis of this enzyme deficiency is possible.

Aldosterone

Aldosterone is a steroid hormone (mineralocorticoid family) produced by the outer section (zona glomerulosa) of the adrenal cortex in the adrenal gland.[1][2] It plays a central role in the regulation of blood pressure mainly by acting on the distal tubules and collecting ducts of the nephron, increasing reabsorption of ions and water in the kidney, to cause the conservation of sodium, secretion of potassium, increase in water retention, and increase in blood pressure and blood volume.[1] When dysregulated, aldosterone is pathogenic and contributes to the development and progression of cardiovascular and renal disease.[2] Aldosterone has exactly the opposite function of the atrial natriuretic hormone secreted by the heart.[1]

Drugs that interfere with the secretion or action of aldosterone are in use as antihypertensives, like lisinopril, which lowers blood pressure by blocking the angiotensin-converting enzyme (ACE), leading to lower aldosterone secretion. The net effect of these drugs is to reduce sodium and water retention but increase retention of potassium. Aldosterone is part of the renin–angiotensin system. Another example is spironolactone, a potassium-sparing diuretic, which decreases blood pressure by releasing fluid from the body while retaining potassium.
Synthesis[edit]
The corticosteroids are synthesized from cholesterol within the zona glomerulosa of adrenal cortex. Most steroidogenic reactions are catalysed by enzymes of the cytochrome P450 family. They are located within the mitochondria and require adrenodoxin as a cofactor (except 21-hydroxylase and 17α-hydroxylase).

Aldosterone and corticosterone share the first part of their biosynthetic pathways. The last parts are mediated either by the aldosterone synthase (for aldosterone) or by the 11β-hydroxylase (for corticosterone). These enzymes are nearly identical (they share 11β-hydroxylation and 18-hydroxylation functions), but aldosterone synthase is also able to perform an 18-oxidation. Moreover, aldosterone synthase is found within the zona glomerulosa at the outer edge of the adrenal cortex; 11β-hydroxylase is found in the zona fasciculata and reticularis.


Steroidogenesis, showing aldosterone synthesis at upper-right corner
Note: aldosterone synthase is absent in other sections of the adrenal gland.

Stimulation[edit]
Aldosterone synthesis is stimulated by several factors:

increase in the plasma concentration of angiotensin III, a metabolite of angiotensin II
increase in plasma angiotensin II, ACTH, or potassium levels, which are present in proportion to plasma sodium deficiencies. (The increased potassium level works to regulate aldosterone synthesis by depolarizing the cells in the zona glomerulosa, which opens the voltage-dependent calcium channels.) The level of angiotensin II is regulated by angiotensin I, which is in turn regulated by renin, an enzyme secreted in the kidneys. Potassium levels are the most sensitive stimulator of aldosterone.
the ACTH stimulation test, which is sometimes used to stimulate the production of aldosterone along with cortisol to determine whether primary or secondary adrenal insufficiency is present. However, ACTH has only a minor role in regulating aldosterone production; with hypopituitarism there is no atrophy of the zona glomerulosa.
plasma acidosis
the stretch receptors located in the atria of the heart. If decreased blood pressure is detected, the adrenal gland is stimulated by these stretch receptors to release aldosterone, which increases sodium reabsorption from the urine, sweat, and the gut. This causes increased osmolarity in the extracellular fluid, which will eventually return blood pressure toward normal.
adrenoglomerulotropin, a lipid factor, obtained from pineal extracts. It selectively stimulates secretion of aldosterone.[4]
The secretion of aldosterone has a diurnal rhythm.[5]

Function[edit]
Aldosterone is the primary of several endogenous members of the class of mineralocorticoids in humans. Deoxycorticosterone is another important member of this class. Aldosterone tends to promote Na+ and water retention, and lower plasma K+ concentration by the following mechanisms:

Acting on the nuclear mineralocorticoid receptors (MR) within the principal cells of the distal tubule and the collecting duct of the kidney nephron, it upregulates and activates the basolateral Na+/K+ pumps, which pumps three sodium ions out of the cell, into the interstitial fluid and two potassium ions into the cell from the interstitial fluid. This creates a concentration gradient which results in reabsorption of sodium (Na+) ions and water (which follows sodium) into the blood, and secreting potassium (K+) ions into the urine (lumen of collecting duct).
Aldosterone upregulates epithelial sodium channels (ENaCs), increasing apical membrane permeability for Na+.
Cl− is reabsorbed in conjunction with sodium cations to maintain the system's electrochemical balance.
Aldosterone stimulates the secretion of K+ into the tubular lumen.[6]
Aldosterone stimulates Na+ and water reabsorption from the gut, salivary and sweat glands in exchange for K+.
Aldosterone stimulates secretion of H+ in exchange for K+ in the intercalated cells of the cortical collecting tubules, regulating plasma bicarbonate (HCO3−) levels and its acid/base balance.[7]
Aldosterone is responsible for the reabsorption of about 2% of filtered sodium in the kidneys, which is nearly equal to the entire sodium content in human blood under normal glomerular filtration rates.[8]

Aldosterone, probably acting through mineralocorticoid receptors, may positively influence neurogenesis in the dentate gyrus.[9]

Location of receptors[edit]
Steroid receptors are intracellular. The aldosterone mineralcorticoid receptor complex binds on the DNA to specific hormone response element, which leads to gene specific transcription.

Some of the transcribed genes are crucial for transepithelial sodium transport, including the three subunits of the epithelial sodium channel (ENaC), the Na+/K+ pumps and their regulatory proteins serum and glucocorticoid-induced kinase, and channel-inducing factor, respectively.

The mineralcorticoid receptor is stimulated by both aldosterone and cortisol, but a mechanism protects the body from excess aldosterone receptor stimulation by glucocorticoids (such as cortisol), which happen to be present at much higher concentrations than mineralcorticoids in the healthy individual. The mechanism consists of an enzyme called 11 β-hydroxysteroid dehydrogenase (11 β-HSD). This enzyme co-localizes with intracellular adrenal steroid receptors and converts cortisol into cortisone, a relatively inactive metabolite with little affinity for the MR. Liquorice, which contains glycyrrhetinic acid, can inhibit 11 β-HSD and lead to a mineralcorticoid excess syndrome.

Control of aldosterone release from the adrenal cortex[edit]

The renin-angiotensin system, showing role of aldosterone between the adrenal glands and the kidneys[10]
Major regulators[edit]
The role of the renin-angiotensin system[edit]
Angiotensin is involved in regulating aldosterone and is the core regulation.[11] Angiotensin II acts synergistically with potassium, and the potassium feedback is virtually inoperative when no angiotensin II is present.[12] A small portion of the regulation resulting from angiotensin II must take place indirectly from decreased blood flow through the liver due to constriction of capillaries.[13] When the blood flow decreases so does the destruction of aldosterone by liver enzymes.

Although sustained production of aldosterone requires persistent calcium entry through low-voltage-activated Ca2+ channels, isolated zona glomerulosa cells are considered nonexcitable, with recorded membrane voltages that are too hyperpolarized to permit Ca2+ channels entry.[2] However, mouse zona glomerulosa cells within adrenal slices spontaneously generate membrane potential oscillations of low periodicity; this innate electrical excitability of zona glomerulosa cells provides a platform for the production of a recurrent Ca2+ channels signal that can be controlled by angiotensin II and extracellular potassium, the 2 major regulators of aldosterone production.[2] Voltage-gated Ca2+ channels have been detected in the zona glomerulosa of the human adrenal, which suggests that Ca2+ channel blockers may directly influence the adrenocortical biosynthesis of aldosterone in vivo. [14]

The plasma concentration of potassium[edit]
The amount of aldosterone secreted is a direct function of the serum potassium[15][16] as probably determined by sensors in the carotid artery.[17][18]

ACTH[edit]
ACTH, a pituitary peptide, also has some stimulating effect on aldosterone, probably by stimulating the formation of deoxycorticosterone, a precursor of aldosterone.[19] Aldosterone is increased by blood loss,[20] pregnancy,[21] and possibly by other circumstances such as physical exertion, endotoxin shock, and burns.[22][23]

Miscellaneous regulators[edit]
The role of sympathetic nerves[edit]
The aldosterone production is also affected to one extent or another by nervous control, which integrates the inverse of carotid artery pressure,[17] pain, posture,[21] and probably emotion (anxiety, fear, and hostility)[24] (including surgical stress).[25] Anxiety increases aldosterone,[24] which must have evolved because of the time delay involved in migration of aldosterone into the cell nucleus.[26] Thus, there is an advantage to an animal's anticipating a future need from interaction with a predator, since too high a serum content of potassium has very adverse effects on nervous transmission.

The role of baroreceptors[edit]
Pressure-sensitive baroreceptors are found in the vessel walls of nearly all large arteries in the thorax and neck, but are particularly plentiful in the sinuses of the carotid arteries and in the arch of the aorta. These specialized receptors are sensitive to changes in mean arterial pressure. An increase in sensed pressure results in an increased rate of firing by the baroreceptors and a negative feedback response, lowering systemic arterial pressure. Aldosterone release causes sodium and water retention, which causes increased blood volume, and a subsequent increase in blood pressure, which is sensed by the baroreceptors.[27] To maintain normal homeostasis these receptors also detect low blood pressure or low blood volume, causing aldosterone to be released. This results in sodium retention in the kidney, leading to water retention and increased blood volume.[28]



The plasma concentration of sodium[edit]
Aldosterone is a function of the inverse of the sodium intake as sensed via osmotic pressure.[29] The slope of the response of aldosterone to serum potassium is almost independent of sodium intake.[30] Aldosterone is much increased at low sodium intakes, but the rate of increase of plasma aldosterone as potassium rises in the serum is not much lower at high sodium intakes than it is at low. Thus, the potassium is strongly regulated at all sodium intakes by aldosterone when the supply of potassium is adequate, which it usually is in primitive diets.

Aldosterone feedback[edit]
Feedback by aldosterone concentration itself is of a nonmorphological character (that is, other than changes in the cells' number or structure) and is poor, so the electrolyte feedbacks predominate, short term.[22]

Associated clinical conditions[edit]
Hyperaldosteronism is abnormally increased levels of aldosterone, while hypoaldosteronism is abnormally decreased levels of aldosterone.

A measurement of aldosterone in blood may be termed a plasma aldosterone concentration (PAC), which may be compared to plasma renin activity (PRA) as an aldosterone-to-renin ratio.

Hyperaldosteronism[edit]
Primary aldosteronism, also known as primary hyperaldosteronism, is characterized by the overproduction of aldosterone by the adrenal glands,[31] when not a result of excessive renin secretion. It leads to arterial hypertension (high blood pressure) associated with hypokalemia, usually a diagnostic clue. Secondary hyperaldosteronism, on the other hand, is due to overactivity of the renin-angiotensin system.

Conn's syndrome is primary hyperaldosteronism caused by an aldosterone-producing adenoma.

Depending on cause and other factors, hyperaldosteronism can be treated by surgery and/or medically, such as by aldosterone antagonists.

Hypoaldosteronism[edit]
An ACTH stimulation test for aldosterone can help in determining the cause of hypoaldosteronism, with a low aldosterone response indicating a primary hypoaldosteronism of the adrenals, while a large response indicating a secondary hypoaldosteronism.