Loading presentation...

Present Remotely

Send the link below via email or IM

Copy

Present to your audience

Start remote presentation

  • Invited audience members will follow you as you navigate and present
  • People invited to a presentation do not need a Prezi account
  • This link expires 10 minutes after you close the presentation
  • A maximum of 30 users can follow your presentation
  • Learn more about this feature in our knowledge base article

Do you really want to delete this prezi?

Neither you, nor the coeditors you shared it with will be able to recover it again.

DeleteCancel

Make your likes visible on Facebook?

Connect your Facebook account to Prezi and let your likes appear on your timeline.
You can change this under Settings & Account at any time.

No, thanks

BBB482 Clonazepam and Alprazolam

Bhavana, Hiral, Lauren, Marisa, Rosa
by

Rosa Chen

on 6 October 2012

Comments (0)

Please log in to add your comment.

Report abuse

Transcript of BBB482 Clonazepam and Alprazolam

Bhavana, Hiral, Lauren, Marisa, Rosa Clonazepam and Alprazolam ` Animal models to demonstrate proof of concept Clonazepam Works Cited Alprazolam - History: Created by Upjohn Pharmaceutical Company, approved by FDA 1981, expired patent 1993- key marketing strategy- “rare drug to something mothers began to joke about”

- Brand Names: Niravam, Xanax

- Street Names: Z-bars, Zanies, Planks, Bars, Upjohns

- Basic Information: Anxiolytic, Triazolobenzodiazepine, GABA-A receptor activator, oral tablet

- Indications: Panic Disorder, General Anxiety Disorder, Anxiety associated with depression
Forbes # 1 selling Psychiatric drug in 2009 with 47.9 million prescriptions Economics and Controversy Aden GC, Thein SG Jr. Alprazolam compared to diazepam and placebo in the treatment of anxiety. J Clin Psychiatry. 1980 Jul;41(7):245-8. PMID: 6993446.
Bonnet MH, Kramer M, Roth T. A dose response study of the hypnotic effectiveness of alprazolam and diazepam in normal subjects. Psychopharmacology (Berl). 1981;75(3):258-61. PMID: 6798616.
Bourin M, et al. Comparison of behavioral effects after single and repeated administrations of four benzodiazepines in three mice behavioral models. J Psychiatry Neurosci. 1992 Jun;17(2):72-7. PMCID: PMC1188404.
Buckman. "How To Kill Someone Properly." Gomerville. N.p., 12 Oct. 2009. Web. 30 Sept. 2012. <http://gomerville.com/wp-content/uploads/2009/10/gaba.gif>.
Clancy B., Finlay BL., Darlington RB., Anand KJ. Extrapolating brain development from experimental species to humans. Neurotoxicology 2007; 28: 931-7.
Cohn JB. Multicenter double-blind efficacy and safety study comparing alprazolam, diazepam and placebo in clinically anxious patients. J Clin Psychiatry. 1981 Sep;42(9):347-51. PMID: 6115853.
Fabre LF Jr. Pilot open label study with alprazolam (U31, 889) in outpatients with neurotic depression. Curr Ther Res Clin Exp. 1976 Jun;19(6):661-8. PMID: 6216.
Fabre LF Jr, Gainey A, Kemple S. Pilot open-label study of alprazolam (U-31,889) in anxious alcoholic out-patients. J Int Med Res. 1977;5(1):26-32. PMID: 14038.
"Family Practice Notebook." Alprazolam. Family Practice Notebook, n.d. Web. 30 Sept. 2012. <http://www.fpnotebook.com/psych/pharm/Alprzlm.htm>.
Fernández-Teruel A, Escorihuela RM, Núñez JF, Zapata A, Boix F, Salazar W, Tobeña A. The early acquisition of two-way (shuttle-box) avoidance as an anxiety-mediated behavior: psychopharmacological validation. Brain Res Bull.
1991 Jan;26(1):173-6. PMID: 1673080.
File SE, Pellow S. The effects of triazolobenzodiazepines in two animal tests of anxiety and in the holeboard. Br J Pharmacol. 1985 Nov;86(3):729-35. PMCID: PMC1916742.
Fraser LM, et al. Measuring anxiety- and locomotion-related behaviours in mice: a new way of using old tests. Psychopharmacology (Berl). 2010 Jul;211(1):99-112. PMID: 20454890
GABAA Receptor Subunits and Ion Channel. Dir. Marykmoore. YouTube. YouTube, 8 Jan. 2010. Web. 30 Sept. 2012. <http://www.youtube.com/watch?v=ne-YWfTCxLk>.
Greiss KC, Fogari R. Double-blind clinical assessment of alprazolam, a new benzodiazepine derivative, in the treatment of moderate to severe anxiety. J Clin Pharmacol. 1980 Nov-Dec;20(11-12):693-9. PMID: 6112245.
Griebel G, et al. Further evidence that the mouse defense test battery is useful for screening anxiolytic and panicolytic drugs: effects of acute and chronic treatment with alprazolam. Neuropharmacology. 1995 Dec;34(12):1625-
33. PMID: 8788960.
Griebel G, et al. The use of the rat elevated plus-maze to discriminate between non-selective and BZ-1 (omega 1) selective, benzodiazepine receptor ligands. Psychopharmacology (Berl). 1996 Apr;124(3):245-54. PMID: 8740046.
Hascoët M, Bourin M. Anticonflict effect of alpidem as compared with the benzodiazepine alprazolam in rats. Pharmacol Biochem Behav. 1997 Feb;56(2):317-24. PMID: 9050091.
Itoh H, Takahashi R, Miura S. Alprazolam, a new type anxiolytic in neurotic patients. A pilot study. Int Pharmacopsychiatry. 1980;15(6):344-9. PMID: 6117534.
Jenck F, et al. Dorsal periaqueductal gray-induced aversion as a simulation of panic anxiety: elements of face and predictive validity. Psychiatry Res. 1995 Jul 28;57(2):181-91. PMID: 7480384.
Kaiser, C. Alprazolam Among Top Causes of Fatal Overdoes in Florida (2011). http://www.medpagetoday.com/PublicHealthPolicy/ PublicHealth/27463.
Kleven MS, Koek W. Effects of benzodiazepine agonists on punished responding in pigeons and their relationship with clinical doses in humans. Psychopharmacology (Berl). 1999 Jan;141(2):206-12. PMID: 9952046.
Kolin IS, Linet OI. Double-blind comparison of alprazolam and diazepam for subchronic withdrawal from alcohol. J Clin Psychiatry. 1981 Apr;42(4):169-73. PMID: 7009593.
Kulkarni SK, Sharma K. Alprazolam modifies animal behaviour on elevated plus-maze. Indian J Exp Biol. 1993 Nov;31(11):908-11. PMID: 7906673.
Laino CH, Cordoba NE, Orsingher OA. Perinatally protein-deprived rats and reactivity to anxiolytic drugs in the plus-maze test: an animal model for screening antipanic agents? Pharmacol Biochem Behav. 1993 Sep;46(1):89-94. PMID:
7902987.
Loscher W., Schmidt D., Which Animal models should be used in the search for new antiepileptic drugs? A propsal based on experimental and clinical considerations. Epilepsy Research 1988.2: 145-81
Maletzky BM. Anxiolytic efficacy of alprazolam compared to diazepam and placebo. J Int Med Res. 1980;8(2):139-43. PMID: 6102940.
Mikulecka, A., Mares, P., and Kubova, H. Rebound increase in seizure susceptibility but not isolation- induced calls after single administration of clonazepam and Ro 19-8022 in infant rats. Epilepsy and Behavior 2011; 20: 12-19.
Nakajima R, et al. Pharmacological studies on new potent central depressants, 8-chloro-6-phenyl-4H-s-triazolo [4,3a][1,4] benzodiazepine (D-40tA) and its 1-methyl analogue (D-65MT). Jpn J Pharmacol. 1971 Aug;21(4):497-
516. PMID: 5000774.
Olivier B, et al. Rat pup ultrasonic vocalization: effects of benzodiazepine receptor ligands. Eur J Pharmacol. 1998 Oct 2;358(2):117-28. PMID: 9808260.
Palit G, et al. A primate model of anxiety. Eur Neuropsychopharmacol. 1998 Aug;8(3):195-201. PMID: 9716313.
Prunell M, et al. Anxiolytic profiles of alprazolam and ethanol in the elevated plus-maze test and the early acquisition of shuttlebox avoidance. Pharmacol Res. 1994 Jan-Feb;29(1):37-46. PMID: 7911239.
Shimada T, et al. The modified light/dark transition test in mice: evaluation of classic and putative anxiolytic and anxiogenic drugs. Gen Pharmacol. 1995 Jan;26(1):205-10. PMID: 7713361.
Söderpalm B, Eriksson E, Engel JA. Anticonflict and rotarod impairing effects of alprazolam and diazepam in rat after acute and subchronic administration. Prog Neuropsychopharmacol Biol Psychiatry. 1989;13(1-2):269-83. PMID:
2748865.
Sunderland G, et al. Imipramine and alprazolam treatment of lactate-induced acute endogenous distress in nonhuman primates. Am J Psychiatry. 1989 Aug;146(8):1044-7. PMID: 2637682.
Warnick JE, et al. Modeling anxiety-like states: pharmacological characterization of the chick separation stress paradigm. Behav Pharmacol. 2006 Nov;17(7):581-7. PMID: 17021390.
Watson GS, et al. Benzodiazepine receptor function in the chick social separation-stress procedure. Exp Clin Psychopharmacol. 1999 May;7(2):83-9. PMID: 10340149.
Whiting, Paul J. "GABA-A Receptors: A Viable Target for Novel Anxiolytics?" Pharmacology 6th ser. (2006): 24-29. Print.
Zethof TJ, et al. Stress-induced hyperthermia as a putative anxiety model. Eur J Pharmacol. 1995 Dec 27;294(1):125-35. PMID: 8788424.
XANAX® [package insert]. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018276s045lbl.pdf General Information Clonazepam - History: First studied during the early 1970s as a benzodiazepine which had anticonvulsant properties (van Duijn H)

- Brand Names: Klonopin, Klonopin Wafer (US), Rivotril (World)

- Street Names: K-pin, Pin, Super Valium, K

- Basic Information: Anxiolytic, anticonvulsant, GABA-A agonist, benzodiazepine, oral tablet

- Indications: FDA approved for panic disorder (with or without agoraphobia) and some types of epilepsy (Lennox-Gastaut syndrome), akinetic and myoclonic seizures, as well as absence seizures.

-Off label use: Social phobia, mania, PTSD Clinical Trials Panic Disorder: 2 double blind, placebo controlled studies Study 1:
9 week, fixed dose
4 phases
Significant results only at 1mg dose - average approximately 1 panic attack less per week Study 2:
6 week, flexible dose
3 phases
Optimal dosing period was 2.3 mg/day, ~1 panic attack per week. Pentylenetetrazol (PTZ)-induced seizures (Loscher et al., 1988)
PTZ is a circulatory and respiratory stimulant that in high doses causes convulsions General Information Economics and Controversy Economics: Currently, Klonopin in the U.S. is manufactured and distributed widely by Roche Pharmaceuticals Limitations/Controversy Effectiveness of clonazepam in long term use >9 weeks has not been studied
Studies examining influence of gender and age have not been conducted
Studies examining effects of renal or liver disease have not been conducted (Clonazepam undergoes hepatic metabolism)
Recreational Use
Withdrawal
Suicidal thoughts and behavior OVERDOSE:
ANNA NICOLE SMITH Animals: male Sprague-Dawley rats
Modified Vogel’s conflict test
No. of shocks accepted during a 10-min session
Drinking motivation test
Shock threshold test
Montgomery’s conflict test
Total time spent in open or closed arms
No. of entries made into open or closed arms (entry defined as animal placing all 4 paws onto the arm)
Rotarod test Anticonflict and rotarod impairing effects of alprazolam and diazepam in rat after acute and subchronic administration. Söderpalm B, et al. (1988) Fig 2. Dose-response relationships with regard to anticonflict effects in the modified Vogel's conflict test after acute and subchronic treatment Results Fig 4. Dose-response relationships with regard to rotarod impairment after acute and subchronic treatment Fig 3. Acute effects in Montgomery’s conflict test • Early acquisition of shuttlebox avoidance (Fernández-Teruel A, 1991; Prunell M, 1994)

• Perinatally protein-deprived rats (Laino CH, 1993)

• Modified light/dark transition test (Shimada T, 1995)

• Dorsal periaqueductal gray-induced aversion (Jenck F, 1995)

• Mouse Defense Test Battery (Griebel, 1995)

• Stress-induced hyperthermia (Zethof, 1995)

• Pentylenetetrazol (PTZ) (Palit, 1998)

• Rat pup ultrasonic vocalizations (Olivier, 1998)

• Punished responding in pigeons (Kleven, 1999)

• Chick social separation-stress paradigm (Watson, 1999; Warnick, 2006) Validating animal models of anxiety… 16 diff. subunits

Pentamers (2 alphas, 2 betas)

gamma-2 subunit: BZ binding site

only 4 combinations = high affinity The GABA Receptor Subunits GABA-A Receptor
Subtype-Selective Anxiolytics higher receptor affinity vs. higher efficacy selectivity

awaiting translation into positive clinical data alpha-1:
sedative, amnesic,
antimyoclonic (anticonvulsant) We are considering novel ways to affect the GABA-A receptor, BUT... TAKE-HOME MESSAGE ...our methods for validation only allow us to grade our work based on old standards, THEREFORE... ...we can currently only produce products that are as good as we the products we already have.
Anxiety and Anxiety with Depression:
4-week placebo controlled studies, patients treated with Alprazolam much better on the following evaluations: Physician’s Global Impressions, Hamilton Anxiety Rating Scale, Target Symptoms, Patient’s Global Impressions, and Self-Rating Symptom Scale

Panic Disorder:
three short-term placebo trials (10 weeks) and patients treated with Alprazolam were superior to placebo on a variable defined as "the number of patients with zero panic attacks” and on a global improvement score

Side Effects:
drowsiness, light-headedness, impaired coordination Clinical Trials Economics Overdose: somnolence, confusion, impaired coordination, diminished reflexes and coma-very fast-acting compared to other benzodiazepines: Peak concentration is plasma: 1 to 2 hours after administration
Dependence- relatively short-term use at the doses recommended for the treatment of transient anxiety and anxiety disorder ( 0.75 to 4.0 mg per day), there is some risk of dependence
Withdrawal symptoms: heightened sensory perception, impaired concentration smell issues, clouded, sensorium, muscle cramps, muscle twitch, diarrhea, blurred vision, appetite decrease, and weight loss, seizures
suicide, mania, respiratory effects in children (pregnant women) Controversy/Problems Whitney Houston Clonazepam possessed marked efficacy against PTZ-induced seizures (Mikulecka, Mares and Kubova, 2011)

measurement instrument: 5 point scale on severity of observed epileptic phenomena within a 30 minute span

demonstrated withdrawal effects from single doses of agonist of GABA-A receptor anticonvulsant in immature rats

all other papers that use the same animal model and methods achieved similar results adverse effects of Clonazepam
demonstrated by animal models ultrasonic vocalizations sensorimotor tests passive avoidance tests anxiolytic muscle relaxant amnesic are these bad....? Search for preclinical studies… Fabre LF Jr. Pilot open label study with alprazolam (U31, 889) in outpatients with neurotic depression. Curr Ther Res Clin Exp. 1976.

Fabre LF Jr, et al. Pilot open-label study of alprazolam (U-31,889) in anxious alcoholic out-patients. J Int Med Res. 1977.

Maletzky BM. Anxiolytic efficacy of alprazolam compared to diazepam and placebo. J Int Med Res. 1980.

Itoh H, Takahashi R, Miura S. Alprazolam, a new type anxiolytic in neurotic patients. A pilot study. Int Pharmacopsychiatry. 1980.

Aden GC, Thein SG Jr. Alprazolam compared to diazepam and placebo in the treatment of anxiety. J Clin Psychiatry. 1980.

Greiss KC, Fogari R. Double-blind clinical assessment of alprazolam, a new benzodiazepine derivative, in the treatment of moderate to severe anxiety. J Clin Pharmacol. 1980.

Bonnet MH, Kramer M, Roth T. A dose response study of the hypnotic effectiveness of alprazolam and diazepam in normal subjects. Psychopharmacology (Berl). 1981.

Kolin IS, Linet OI. Double-blind comparison of alprazolam and diazepam for subchronic withdrawal from alcohol. J Clin Psychiatry. 1981

Cohn JB. Multicenter double-blind efficacy and safety study comparing alprazolam, diazepam and placebo in clinically anxious patients. J Clin Psychiatry. 1981. Nakajima R, Take Y, Moriya R, Saji Y, Yui T, Nagawa Y. Pharmacological studies on new potent central depressants, 8-chloro-6-phenyl-4H-s-triazolo [4,3a][1,4] benzodiazepine (D-40tA) and its 1-methyl analogue (D-65MT). Jpn J Pharmacol. 1971.

File SE, Pellow S. The effects of triazolobenzodiazepines in two animal tests of anxiety and in the holeboard. Br J Pharmacol. 1985.






Sunderland G, et al. Imipramine and alprazolam treatment of lactate-induced acute endogenous distress in nonhuman primates. Am J Psychiatry. 1989.

Bourin M, et al. Comparison of behavioral effects after single and repeated administrations of four benzodiazepines in three mice behavioral models. J Psychiatry Neurosci. 1992.

Kulkarni SK, Sharma K. Alprazolam modifies animal behaviour on elevated plus-maze. Indian J Exp Biol. 1993.

Griebel G, et al. The use of the rat elevated plus-maze to discriminate between non-selective and BZ-1 (omega 1) selective, benzodiazepine receptor ligands. Psychopharmacology (Berl). 1996.

Hascoët M, Bourin M. Anticonflict effect of alpidem as compared with the benzodiazepine alprazolam in rats. Pharmacol Biochem Behav. 1997. Limit results to "Other Animals"... Söderpalm B, et al. Anticonflict and rotarod impairing effects of alprazolam and diazepam in rat after acute and subchronic administration. Prog Neuropsychopharmacol Biol Psychiatry. 1989. •“Triple test” (Fraser, 2010) (Nakajima, et al., 1971) (dailymed.nlm.nih.gov) Limitations of the model: acute model

not all anticonvulsants are effective in PTZ model
carbamazepine, valproate, phenytoin

not predictive of efficacy in treatment of absence epilepsy gatekeepers of AED discovery standard AED to compare against newer drugs
polytherapy regimen studies alpha-2 (in alpha-beta-gamma2 Rs): anxiolytic effects of BZs alpha-1,2,3,5 (alpha-beta-gamma2 Rs): muscle relaxant effects of BZs
Full transcript