Fear God (UNDER CONSTRUCTION)

FEAR GOD

Revelation 14: 7 And I saw another angel fly in the midst of heaven, having the everlasting gospel to preach unto them that dwell on the earth, and to every nation, and kindred, and tongue, and people, 7Saying with a loud voice, Fear God, and give glory to him; for the hour of his judgment is come: and worship him that made heaven, and earth, and the sea, and the fountains of waters. 8And there followed another angel, saying, Babylon is fallen, is fallen, that great city, because she made all nations drink of the wine of the wrath of her fornication. 8And there followed another angel, saying, Babylon is fallen, is fallen, that great city, because she made all nations drink of the wine of the wrath of her fornication. 9And the third angel followed them, saying with a loud voice, If any man worship the beast and his image, and receive his mark in his forehead, or in his hand, 10The same shall drink of the wine of the wrath of God, which is poured out without mixture into the cup of his indignation; and he shall be tormented with fire and brimstone in the presence of the holy angels, and in the presence of the Lamb: 11And the smoke of their torment ascendeth up for ever and ever: and they have no rest day nor night, who worship the beast and his image, and whosoever receiveth the mark of his name. 12Here is the patience of the saints: here are they that keep the commandments of God, and the faith of Jesus.

Ecclesiastes 12:13 Let us hear the conclusion of the whole matter: Fear God, and keep his commandments: for this is the whole duty of man.14For God shall bring every work into judgment, with every secret thing, whether it be good, or whether it be evil.

Universality and Cosmology

ANALYZING UNDERLYING IMPETUSES AS REFLECTED IN HISTORY (1840's-present)
Religion Civil Rights Science and Technology Space Forms of government Wars and conflicts
Crimes against humanity Literature Entertainment

Universitarianism reflected in religions, military, and politics. (1800's) III

Friday, October 15, 2010

Abilify (Phi)(ability)

Double play on words (Phi, Ability), comp. lexapro

 Aripiprazole

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Aripiprazole
Systematic (IUPAC) name
7-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy}-3,4-dihydroquinolin-2(1H)-one
Identifiers
CAS number 129722-12-9
ATC code N05AX12
PubChem CID 60795
IUPHAR ligand ID 34
DrugBank APRD00638
ChemSpider 54790
UNII 82VFR53I78
Chemical data
Formula C23H27Cl2N3O2 
Mol. mass 448.385
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 87%
Protein binding >99%
Metabolism liver
Half-life 75h (active metabolite : 94h)
Excretion feces and urine
Therapeutic considerations
Licence data EU EMA:LinkUS FDA:link
Pregnancy cat. C (USA)
Legal status Prescription only
Routes oral (via tablets, orodispersable tablets, and oral solution); intramuscular
 Yes(what is this?)  (verify)Y
Aripiprazole (pronounced /ˌɛərɨˈpɪprəzoʊl/ AIR-i-PIP-rə-zohl; brand names: Abilify, Abilify Discmelt, Aripiprex) is an atypical antipsychotic and antidepressant used in the treatment of schizophrenia, bipolar disorder, and clinical depression. It was approved by the US Food and Drug Administration (FDA) for schizophrenia on November 15, 2002, for acute manic and mixed episodes associated with bipolar disorder on October 1, 2004, as an adjunct for major depressive disorder on November 20, 2007 and to treat irritability in children with autistic disorder in children on 20 November 2009.[1][2] Aripiprazole was developed by Otsuka in Japan, and in the United States, Otsuka America markets it jointly with Bristol-Myers Squibb.

Contents

[show]

[edit] Indications and usage

[edit] Schizophrenia

Aripiprazole has been approved by the FDA for the treatment of schizophrenia.[3]

[edit] Bipolar disorder

Aripiprazole has been approved by the FDA for the treatment of acute manic and mixed episodes, in both pediatric patients aged 10–17 and in adults.[4] Several double-blind, placebo-controlled trials support this use.[5][6][7][8] In addition, it is often used as maintenance therapy, either on its own or in conjunction with a mood stabilizer such as lithium or valproate. This use is also supported by a handful of studies.[9][10]haloperidol at reducing manic symptoms,[11][unreliable source?] and is much better tolerated by patients.[12] Aripiprazole is at least as effective as
Aripiprazole's use as a monotherapy in bipolar depression is more controversial. While a few pilot studies have found some effectiveness[13][14] (with one finding a reduction in anhedonia symptoms[15]), two large, double-blind, placebo-controlled studies found no difference between aripiprazole and placebo.[16] One study reported depression as a side effect of the drug.[17]

[edit] Major depression (Unipolar depression)

In 2007, aripiprazole was approved by the FDA for the treatment of unipolar depression when used adjunctively with an antidepressant medication.[18] It has not been FDA-approved for use as monotherapy in unipolar depression.

[edit] Autism

In 2009, the United States FDA approved Abilify to treat irritability in persons with autism.[19] It was approved on the basis of two studies that showed it reduced aggression towards others, self-injury, quickly changing moods, irritability, and temper tantrums in autistic males and females 6–17 years of age.

[edit] Cocaine dependency

Perhaps owing to its mechanism of action relating to dopamine receptors, there is some evidence to suggest that aripiprazole blocks cocaine-seeking behaviour in animal models without significantly affecting other rewarding behaviours (such as food self-administration). [20]

[edit] Pharmacology

  • D2 Partial Agonist (Ki = 0.34 nM)
  • D3 Antagonist (?)
  • 5-HT1A Partial Agonist (Ki = 0.34 nM)
  • 5-HT2A Antagonist (Ki = 0.8 nM)
  • 5-HT2C Partial Agonist (Ki = 15 nM)
  • 5-HT7 Antagonist (Ki = 39 nM)
  • SRI (?)
  • Antihistamine (Ki = 61 nM)
  • α-adrenergic antagonist (Ki = 57 nM)
  • mACh receptor antagonist (?)
Aripiprazole's mechanism of action is different from those of the other FDA-approved atypical antipsychoticsclozapine, olanzapine, quetiapine, ziprasidone, and risperidone). Rather than antagonizing the D2 receptor, aripiprazole acts as a D2 partial agonist (Ki = 0.34 nM).[21][22] Aripiprazole is also a partial agonist at the 5-HT1A receptor (Ki = 1.65 nM), and like the other atypical antipsychotics displays an antagonist profile at the 5-HT2A receptor (Ki = 0.8 nM).[23][24] It also antagonizes the 5-HT7 receptor (Ki = 39 nM) and acts as a partial agonist at the 5-HT2C receptor (Ki = 15 nM), both with high affinity. The latter action may underlie the minimal weight gain seen in the course of therapy.[25] Aripiprazole has moderate affinity for histamine (Ki = 61 nM) and α-adrenergic (Ki = 57 nM) receptors and for the serotonin transporter, and no appreciable affinity for cholinergic muscarinic receptors.[26] (e.g.,
D2 and D3 receptor occupancy levels are high, with average levels ranging between ~71% at 2 mg/day to ~96% at 40 mg/day.[27][28] Most atypical antipsychotics bind preferentially to extrastriatal receptors, but aripiprazole appears to be less preferential in this regard, as binding rates are high throughout the brain.[29]
Recently, it has been demonstrated that in 5-HT7 receptor knockout mice, aripiprazole does not reduce immobility time in the forced swim test (FST), and actually increases it.[30][31] This implicates 5-HT7amisulpride.[30][31][32] antagonism as playing a major role in aripiprazole's antidepressant effects, similarly to
Aripiprazole produces 2,3-dichlorophenylpiperazine (DCPP) as a metabolite similarly to how trazodone and nefazodone reduce to 3-chlorophenylpiperazine (mCPP) and niaprazine converts to 4-fluorophenylpiperazine[33] It is unknown whether DCPP contributes to aripiprazole's pharmacology in any way, but the possibility cannot be excluded. (pFPP).

[edit] Pharmacokinetics

Aripiprazole displays linear kinetics and has an elimination half-life of approximately 75 hours. Steady-state plasma concentrations are achieved in about 14 days. Cmax (maximum plasma concentration) is achieved 3–5 hours after oral dosing. Bioavailability of the oral tablets is about 90% and the drug undergoes extensive hepatic metabolization (dehydrogenation, hydroxylation, and N-dealkylation), principally by the enzymes CYP2D6 and CYP3A4. Its only known active metabolite is dehydro-aripiprazole, which typically accumulates to approximately 40% of the aripiprazole concentration. The parenteral drug is excreted only in traces, and its metabolites, active or not, are excreted via feces and urine.[26] When dosed daily, brain concentrations of aripiprazole will increase for a period of 10–14 days, before reaching stable constant levels. This phenomenon is due to the long half life of aripiprazole, and is responsible for many of the adverse side effects that appear after multiple days of dosing (whereas the first dose normally does not cause these side effects).

[edit] Patent status

Otsuka's US patent on aripiprazole expires on October 20, 2014;[34] however, due to a pediatric extension, a generic will not become available until at least April 20, 2015.[4] Barr Laboratories (now Teva Pharmaceuticals) initiated a patent challenge under the Hatch-Waxman Act in March 2007.[35] As of 14 August 2009, this challenge is still in court. (2009 -08-14)

[edit] Side effects

Akathisia[36], headache, unusual tiredness or weakness, nausea, vomiting, an uncomfortable feeling in the stomach, constipation, light-headedness, insomnia, sleepiness, shaking, and blurred vision.
Uncontrollable twitching or jerking movements, tremors, seizure, and weight gain. Some people may feel dizzy, especially when getting up from a lying or sitting position, or may experience a fast heart rate.
Neuroleptic malignant syndrome (Combination of fever, muscle stiffness, faster breathing, sweating, reduced consciousness, and sudden change in blood pressure and heart rate.)
Aripiprazole also causes sexual dysfunction.
Tardive dyskinesia (As with all antipsychotic medication, patients using aripiprazole may develop the permanent neurological disorder tardive dyskinesia.[37][38][39])
Stroke (While taking aripiprazole some elderly patients with dementia have suffered from stroke or 'mini' stroke.)
Other elderly patients may experience high blood sugar or the onset or worsening of diabetes.
Allergic reaction (such as swelling in the mouth or throat, itching, rash), increased production of saliva, speech disorder, nervousness, agitation, fainting, reports of abnormal liver test values, inflammation of the pancreas, muscle pain, weakness, stiffness, or cramps.

[edit] Overdosage

Children or adults who ingested acute overdoses have usually manifested central nervous system depression ranging from mild sedation to coma; serum concentrations of aripiprazole and dehydroaripiprazole in these patients were elevated by up to 3-4 fold over normal therapeutic levels, yet no deaths have yet been recorded.[40]

[edit] Drug interactions

Aripiprazole is a substrate of CYP2D6 and CYP3A4. Coadministration with medications that inhibit (e.g. paroxetine, fluoxetine) or induce (e.g. carbamazepine) these metabolic enzymes are known to increase and decrease, respectively, plasma levels of aripiprazole.[41] As such, anyone taking Abilify should be aware that their dosage of Abilify may need to be decreased.
Aripiprazole may change the subjective effects of alcohol. One study[42] found that aripiprazole increased the sedative effect and reduced the sense of euphoria normally associated with alcohol consumption. However, another alcohol study[43] found that there was no difference in subjective effect between a placebo group and a group taking aripiprazole.

[edit] Dosage forms

  • Intramuscular injection, solution: 7.5 mg/mL (1.3 mL)
  • Solution, oral: 1 mg/mL (150 mL) [contains propylene glycol, sucrose 400 mg/mL, and fructose 200 mg/mL; orange cream flavor]
  • Tablet: 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg
  • Tablet, orally disintegrating: 10 mg [contains phenylalanine 1.12 mg; creme de vanilla flavor]; 15 mg [contains phenylalanine 1.68 mg; creme de vanilla flavor]

[edit] Synthesis

Aripiprazole synth.png
U.S. Patent 5,006,528


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