International Programme on Chemical Safety (WHO/ILO/UNEP) Evaluation. Antidotes for Poisoning by Organophosphorus Pesticides. Completed May 2004. FDA prescribing information, side effects and uses. Valium (diazepam) is a benzodiazepine derivative. The chemical name of diazepam is 7- chloro- 1,3- dihydro- 1- methyl- 5- phenyl- 2. H- 1,4- benzodiazepin- 2- one. It is a colorless to light yellow crystalline compound, insoluble in water. The empirical formula is C1. H1. 3Cl. N2. O and the molecular weight is 2. The structural formula is as follows: Valium is available for oral administration as tablets containing 2 mg, 5 mg or 1. Readbag users suggest that etimologia-e-abreviatura-de-termos-medicos.pdf is worth reading. The file contains 381 page(s) and is free to view, download or print. Roche Products Inc: Valium is indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety. Anxiety or tension. CYP3A4 is a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in. Valium official prescribing information for healthcare professionals. Includes: indications, dosage, adverse reactions, pharmacology and more. In addition to the active ingredient diazepam, each tablet contains the following inactive ingredients: anhydrous lactose, corn starch, pregelatinized starch and calcium stearate with the following dyes: 5- mg tablets contain FD& C Yellow No. D& C Yellow No. FD& C Blue No. Valium 2- mg tablets contain no dye. Valium - Clinical Pharmacology. Diazepam is a benzodiazepine that exerts anxiolytic, sedative, muscle- relaxant, anticonvulsant and amnestic effects. Most of these effects are thought to result from a facilitation of the action of gamma aminobutyric acid (GABA), an inhibitory neurotransmitter in the central nervous system. Pharmacokinetics. Absorption. After oral administration > 9. Absorption is delayed and decreased when administered with a moderate fat meal. In the presence of food mean lag times are approximately 4.
There is also an increase in the average time to achieve peak concentrations to about 2. This results in an average decrease in Cmax of 2. AUC (range 1. 5% to 5. Distribution. Diazepam and its metabolites are highly bound to plasma proteins (diazepam 9. Diazepam and its metabolites cross the blood- brain and placental barriers and are also found in breast milk in concentrations approximately one tenth of those in maternal plasma (days 3 to 9 post- partum). In young healthy males, the volume of distribution at steady- state is 0. L/kg. The decline in the plasma concentration- time profile after oral administration is biphasic. The initial distribution phase has a half- life of approximately 1 hour, although it may range up to > 3 hours. Metabolism. Diazepam is N- demethylated by CYP3. A4 and 2. C1. 9 to the active metabolite N- desmethyldiazepam, and is hydroxylated by CYP3. A4 to the active metabolite temazepam. N- desmethyldiazepam and temazepam are both further metabolized to oxazepam. Temazepam and oxazepam are largely eliminated by glucuronidation. Elimination. The initial distribution phase is followed by a prolonged terminal elimination phase (half- life up to 4. The terminal elimination half- life of the active metabolite N- desmethyldiazepam is up to 1. Diazepam and its metabolites are excreted mainly in the urine, predominantly as their glucuronide conjugates. The clearance of diazepam is 2. L/min in young adults. Diazepam accumulates upon multiple dosing and there is some evidence that the terminal elimination half- life is slightly prolonged. Pharmacokinetics in Special Populations. Children. In children 3 - 8 years old the mean half- life of diazepam has been reported to be 1. Newborns. In full term infants, elimination half- lives around 3. In both premature and full term infants the active metabolite desmethyldiazepam shows evidence of continued accumulation compared to children. Longer half- lives in infants may be due to incomplete maturation of metabolic pathways. Geriatric. Elimination half- life increases by approximately 1 hour for each year of age beginning with a half- life of 2. This appears to be due to an increase in volume of distribution with age and a decrease in clearance. Consequently, the elderly may have lower peak concentrations, and on multiple dosing higher trough concentrations. It will also take longer to reach steady- state. Conflicting information has been published on changes of plasma protein binding in the elderly. Reported changes in free drug may be due to significant decreases in plasma proteins due to causes other than simply aging. Hepatic Insufficiency. In mild and moderate cirrhosis, average half- life is increased. The average increase has been variously reported from 2- fold to 5- fold, with individual half- lives over 5. There is also an increase in volume of distribution, and average clearance decreases by almost half. Mean half- life is also prolonged with hepatic fibrosis to 9. In chronic active hepatitis, clearance is decreased by almost half. INDICATIONSValium is indicated for the management of anxiety disorders or for the short- term relief of the symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. In acute alcohol withdrawal, Valium may be useful in the symptomatic relief of acute agitation, tremor, impending or acute delirium tremens and hallucinosis. Valium is a useful adjunct for the relief of skeletal muscle spasm due to reflex spasm to local pathology (such as inflammation of the muscles or joints, or secondary to trauma), spasticity caused by upper motor neuron disorders (such as cerebral palsy and paraplegia), athetosis, and stiff- man syndrome. Oral Valium may be used adjunctively in convulsive disorders, although it has not proved useful as the sole therapy. The effectiveness of Valium in long- term use, that is, more than 4 months, has not been assessed by systematic clinical studies. The physician should periodically reassess the usefulness of the drug for the individual patient. Contraindications. Valium is contraindicated in patients with a known hypersensitivity to diazepam and, because of lack of sufficient clinical experience, in pediatric patients under 6 months of age. Valium is also contraindicated in patients with myasthenia gravis, severe respiratory insufficiency, severe hepatic insufficiency, and sleep apnea syndrome. It may be used in patients with open- angle glaucoma who are receiving appropriate therapy, but is contraindicated in acute narrow- angle glaucoma. Warnings. Concomitant use of benzodiazepines, including Valium, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug- related mortality compared to use of opioids alone. If a decision is made to prescribe Valium concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. In patients already receiving an opioid analgesic, prescribe a lower initial dose of Valium than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking Valium, prescribe a lower initial dose of the opioid and titrate based upon clinical response. Advise both patients and caregivers about the risks of respiratory depression and sedation when Valium is used with opioids. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see Drug Interactions). Valium is not recommended in the treatment of psychotic patients and should not be employed instead of appropriate treatment. Since Valium has a central nervous system depressant effect, patients should be advised against the simultaneous ingestion of alcohol and other CNS- depressant drugs during Valium therapy. As with other agents that have anticonvulsant activity, when Valium is used as an adjunct in treating convulsive disorders, the possibility of an increase in the frequency and/or severity of grand mal seizures may require an increase in the dosage of standard anticonvulsant medication. Abrupt withdrawal of Valium in such cases may also be associated with a temporary increase in the frequency and/or severity of seizures. Pregnancy. An increased risk of congenital malformations and other developmental abnormalities associated with the use of benzodiazepine drugs during pregnancy has been suggested. There may also be non- teratogenic risks associated with the use of benzodiazepines during pregnancy. There have been reports of neonatal flaccidity, respiratory and feeding difficulties, and hypothermia in children born to mothers who have been receiving benzodiazepines late in pregnancy. In addition, children born to mothers receiving benzodiazepines on a regular basis late in pregnancy may be at some risk of experiencing withdrawal symptoms during the postnatal period. Diazepam has been shown to be teratogenic in mice and hamsters when given orally at daily doses of 1. Cleft palate and encephalopathy are the most common and consistently reported malformations produced in these species by administration of high, maternally toxic doses of diazepam during organogenesis. Rodent studies have indicated that prenatal exposure to diazepam doses similar to those used clinically can produce long- term changes in cellular immune responses, brain neurochemistry, and behavior. In general, the use of diazepam in women of childbearing potential, and more specifically during known pregnancy, should be considered only when the clinical situation warrants the risk to the fetus. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Patients should also be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physician about the desirability of discontinuing the drug. Labor and Delivery. CYP3. A4 - Wikipedia. CYP3. A4. Available structures. PDBHuman Uni. Prot search: PDBe. RCSBList of PDB id codes. TQN, 1. W0. E, 1. W0. F, 1. W0. G, 2. J0. D, 2. V0. M, 3. NXU, 3. TJS, 3. UA1, 4. I3. Q, 4. I4. G, 4. I4. H, 4. K9. T, 4. K9. U, 4. K9. V, 4. K9. W, 4. K9. X, 4. NY4, 5. A1. P, 5. A1. R, 4. D6. Z, 4. D7. 5, 4. D7. 8, 4. D7. DIdentifiers. Aliases. CYP3. A4, CP3. CP3. 4, CYP3. A, CYP3. A3, CYPIIIA3, CYPIIIA4, HLP, NF- 2. P4. 50. C3, P4. 50. PCN1, cytochrome P4. A member 4. External IDs. OMIM: 1. 24. 01. 0Homolo. Gene: 1. 11. 39. 1Gene. Cards: CYP3. A4. EC number. RNA expression pattern. More reference expression data. Orthologs. Species. Human. Mouse. Entrez. Ensembl. Uni. Prot. Ref. Seq (m. RNA)Ref. Seq (protein)Location (UCSC)Chr 7: 9. Mbn/a. Pub. Med search. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from the body. While many drugs are deactivated by CYP3. A4, there are also some drugs which are activated by the enzyme. Some substances, such as grapefruit juice and some drugs, interfere with the action of CYP3. A4. These substances will therefore either amplify or weaken the action of those drugs that are modified by CYP3. A4. CYP3. A4 is a member of the cytochrome P4. Several other members of this family are also involved in drug metabolism, but CYP3. A4 is the most common and the most versatile one. Like all members of this family, it is a hemoprotein, i. In humans, the CYP3. A4 protein is encoded by the CYP3. A4gene. The cytochrome P4. The CYP3. A4 protein localizes to the endoplasmic reticulum, and its expression is induced by glucocorticoids and some pharmacological agents. This enzyme is involved in the metabolism of approximately half the drugs that are used today, including acetaminophen, codeine, ciclosporin (cyclosporin), diazepam, and erythromycin. The enzyme also metabolizes some steroids and carcinogens. Also, many substances are bioactivated by CYP3. A4 to form their active compounds, and many protoxins being toxicated into their toxic forms (for examples - see table below). CYP3. A4 also possesses epoxygenase activity in that it metabolizes arachidonic acid to epoxyeicosatrienoic acids (EETs), i. CYP3. A4 promotes the growth of various types of human cancer cell lines in culture by producing (. CYP3. A4 is absent in fetal liver but increases to approximately 4. CYP3. A4 in the intestine plays an important role in the metabolism of certain drugs. Often this allows prodrugs to be activated and absorbed - as in the case of the histamine H1- receptor antagonistterfenadine. Recently CYP3. A4 has also been identified in the brain, however its role in the central nervous system is still unknown. These include hydroxylation, epoxidation of olefins, aromatic oxidation, heteroatom oxidations, N- and O- dealkylation reactions, aldehyde oxidations, dehydrogenation reactions, and aromatase activity. The first published report on grapefruit drug interactions was in 1. Lancet entitled . The effects of grapefruit last from 3–7 days, with the greatest effects when juice is taken an hour previous to administration of the drug. It can be supposed that this may be due to the induction of CYP3. A4 on exposure to substrates. CYP3. A4 alleles which have been reported to have minimal function compared to wild- type include CYP3. A4*6 (an A1. 77. 76 insertion) and CYP3. A4*1. 7 (F1. 89. S). Both of these SNPs led to decreased catalytic activity with certain ligands, including testosterone and nifedipine in comparison to wild- type metabolism. The ERMBT estimates in vivo CYP3. A4 activity by measuring the radiolabelled carbon dioxide exhaled after an intravenous dose of (1. C- N- methyl)- erythromycin. These ligands bind to the pregnane X receptor (PXR). The activated PXR complex forms a heterodimer with the retinoid X receptor (RXR), which binds to the XREM region of the CYP3. A4 gene. XREM is a regulatory region of the CYP3. A4 gene, and binding causes a cooperative interaction with proximal promoter regions of the gene, resulting in increased transcription and expression of CYP3. A4. Activation of the PXR/RXR heterodimer initiates transcription of the CYP3. A4 promoter region and gene. Ligand binding increases when in the presence of CYP3. A4 ligands, such as in the presence of aflatoxin B1, M1, and G1. Indeed, due to the enzyme’s large and malleable active site, it is possible for the enzyme to bind multiple ligands at once, leading to potentially detrimental side effects. Evidence shows an increased drug clearance by CYP3. A4 in women, even when accounting for differences in body weight. A study by Wobold et al. CYP3. A4 m. RNA transcripts were found in similar proportions, suggesting a pre- translational mechanism for the up- regulation of CYP3. A4 in women. The exact cause of this elevated level of enzyme in women is still under speculation, however studies have elucidated other mechanisms (such as CYP3. A5 or CYP3. A7 compensation for lowered levels of CYP3. A4) that affect drug clearance in both men and women. Certain ligands activate human PXR, which promotes CYP3. A4 transcription, while showing no activation in other species. For instance, mouse PXR is not activated by rifampicin and human PXR is not activated by pregnenalone 1. Although humanized h. CYP3. A4 mice successfully expressed the enzyme in their intestinal tract, low levels of h. CYP3. A4 were found in the liver. Indeed, in fatheaded minnows, unfed female fish were shown to have increased PXR and CYP3. A4 expression, and displayed a more pronounced response to xenobiotic factors after exposure after several days of starvation. For hepatic CYP3. A4, in vivo methods yield estimates of enzyme half- life mainly in the range of 7. Co- crystallization is difficult since the substrates tend to have a low Kd (between 5- 1. In addition to LSPR, CYP3. A4- Nanodisc complexes have been found helpful in other applications including solid- state NMR, redox potentiometry, and steady- state enzyme kinetics. Where classes of agents are listed, there may be exceptions within the class. Inhibitors of CYP3. A4 can be classified by their potency, such as: Strong inhibitor being one that causes at least a 5- fold increase in the plasma AUC values, or more than 8. European Journal of Biochemistry / FEBS. PMID 8. 26. 99. 49. The Japanese Journal of Human Genetics. PMID 1. 39. 19. 68. Annual Review of Nutrition. PMID 2. 48. 19. 32. Pharmacological Reviews. PMID 2. 52. 44. 93. British Journal of Pharmacology. PMC 1. 57. 28. 03 . PMID 1. 13. 75. 24. Pharmacogenetics and Genomics. PMID 2. 01. 47. 83. Drug Metabolism and Disposition. PMC 2. 68. 36. 93 . PMID 1. 92. 99. 52. Clinical Pharmacokinetics. PMID 1. 69. 28. 15. Clinical Pharmacology and Therapeutics. PMID 1. 80. 43. 69. Molecular Pharmacology. PMID 1. 28. 15. 15. Decreased enterocyte CYP3. A4 concentration and mechanism- based inactivation by furanocoumarins. Drug Metabolism and Disposition. PMID 9. 35. 18. 97. Biochimica et Biophysica Acta. PMC 3. 40. 42. 18 . PMID 2. 26. 77. 14. Chemical Reviews. PMID 1. 53. 52. 78. Chemical Research in Toxicology. PMID 9. 54. 87. 95. British Journal of Clinical Pharmacology. PMC 1. 87. 36. 72 . PMID 9. 72. 38. 17. Clinical Pharmacology and Therapeutics. PMID 9. 75. 71. 52. American Journal of Cardiovascular Drugs. PMID 1. 54. 49. 97. Exploring mechanisms of this interaction and potential toxicity for certain drugs. PMID 1. 71. 12. 30. Clinical Pharmacology and Therapeutics. PMID 1. 10. 61. 57. Memorial Sloan- Kettering Cancer Center. Retrieved 2. 01. 3- 0. Drug Metabolism and Disposition. PMID 1. 56. 73. 59. Pharmacogenomics. PMID 1. 60. 04. 55. Pharmacogenetics. PMID 7. 98. 74. 01. Toxicology Letters. PMID 2. 16. 41. 98. PMID 1. 45. 12. 88. Journal of Biochemical and Molecular Toxicology. PMID 1. 79. 36. 92. Comparative Biochemistry and Physiology. Toxicology & Pharmacology. PMID 2. 16. 64. 29. Current Drug Metabolism. PMID 1. 85. 37. 57. The Journal of Biological Chemistry. PMC 3. 27. 10. 04 . PMID 2. 21. 57. 00. Analytical Chemistry. PMC 4. 75. 74. 37 . PMID 1. 93. 64. 13. Indiana University School of Medicine. Retrieved July 2. Metabolized primarily by CYP3. A4 and, to a lesser degree, by CYP1. A2 and the extrahepatic isoform CYP1. A1 ^. Drug Metabolism and Disposition. PMC 2. 78. 47. 02 . PMID 1. 97. 73. 54. British Journal of Clinical Pharmacology. PMC 1. 88. 44. 56 . PMID 1. 49. 98. 42. Clinical Pharmacokinetics. PMID 1. 55. 09. 18. British Journal of Clinical Pharmacology. PMC 2. 01. 44. 43 . PMID 1. 12. 59. 98. Pharmacogenetics. PMID 1. 27. 24. 61. Circulation. 1. 07 (1): 3. PMID 1. 25. 15. 73. Analytical and Bioanalytical Chemistry. PMID 2. 37. 74. 83. Rang; Maureen M. Dale; Ritter, James M. Rang & Dale's pharmacology. Edinburgh: Churchill Livingstone. ISBN 0- 4. 43- 0. Antimicrobial Agents and Chemotherapy. PMC 2. 53. 79. 5 . PMID 1. 45. 76. 10. Drug Metabolism and Disposition. PMID 1. 27. 56. 21. Drug Metabolism and Disposition. PMID 1. 51. 55. 54. Biochemical and Biophysical Research Communications. PMID 1. 50. 81. 43. Food and Chemical Toxicology. PMID 1. 98. 83. 71. Ginko Biloba has been shown to contain the potent inhibitor amentoflavone ^Bhardwaj RK, Glaeser H, Becquemont L, Klotz U, Gupta SK, Fromm MF (August 2. The Journal of Pharmacology and Experimental Therapeutics. PMID 1. 21. 30. 72. European Journal of Clinical Pharmacology. PMID 1. 18. 68. 80. Phytotherapy Research. PMID 2. 56. 84. 70. ISSN 0. 01. 3- 9. PMID 1. 46. 36. 32. Planta Medica. 8. PMID 2. 63. 66. 75. Molecular Nutrition & Food Research. PMID 2. 26. 48. 62.
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