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{{drugbox |
{{Drugbox
| IUPAC_name       =  
| Verifiedfields = changed
| image             = Sugammadex sodium.svg
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| image2           = Sugammadex sodium 3D front view.png
| verifiedrevid = 470472707
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| DrugBank          =
<!--Clinical data-->
| C = 72 | H = 104 | Na = 8 | O = 48 | S = 8
| tradename =   
| molecular_weight = 2178 g/mol
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| elimination_half-life =
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| ATC_suffix = AB35
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<!--Chemical data-->
| C=72 | H=104 | Na=8 | O=48 | S=8
| molecular_weight = 2178 g/mol
|  smiles = [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].O=C([O-])CCSC[C@H]8O[C@@H]7O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@@H]1CSCCC(=O)[O-])O[C@H]2[C@H](O)[C@@H](O)[C@H](O[C@@H]2CSCCC(=O)[O-])O[C@H]3[C@H](O)[C@@H](O)[C@H](O[C@@H]3CSCCC(=O)[O-])O[C@H]4[C@H](O)[C@@H](O)[C@H](O[C@@H]4CSCCC(=O)[O-])O[C@@H]9[C@H](O[C@H](O[C@H]5[C@H](O)[C@@H](O)[C@H](O[C@@H]5CSCCC(=O)[O-])O[C@H]6[C@H](O)[C@@H](O)[C@H](O[C@@H]6CSCCC([O-])=O)O[C@H]8[C@H](O)[C@H]7O)[C@H](O)[C@H]9O)CSCCC(=O)[O-]
|  InChI = 1/C72H112O48S8.8Na/c73-33(74)1-9-121-17-25-57-41(89)49(97)65(105-25)114-58-26(18-122-10-2-34(75)76)107-67(51(99)43(58)91)116-60-28(20-124-12-4-36(79)80)109-69(53(101)45(60)93)118-62-30(22-126-14-6-38(83)84)111-71(55(103)47(62)95)120-64-32(24-128-16-8-40(87)88)112-72(56(104)48(64)96)119-63-31(23-127-15-7-39(85)86)110-70(54(102)46(63)94)117-61-29(21-125-13-5-37(81)82)108-68(52(100)44(61)92)115-59-27(19-123-11-3-35(77)78)106-66(113-57)50(98)42(59)90;;;;;;;;/h25-32,41-72,89-104H,1-24H2,(H,73,74)(H,75,76)(H,77,78)(H,79,80)(H,81,82)(H,83,84)(H,85,86)(H,87,88);;;;;;;;/q;8*+1/p-8/t25-,26-,27-,28-,29-,30-,31-,32-,41-,42-,43-,44-,45-,46-,47-,48-,49-,50-,51-,52-,53-,54-,55-,56-,57-,58-,59-,60-,61-,62-,63-,64-,65-,66-,67-,68-,69-,70-,71-,72-;;;;;;;;/m1......../s1
|  InChIKey = KMGKABOMYQLLDJ-HYEGWRPHBL
|  StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 1S/C72H112O48S8.8Na/c73-33(74)1-9-121-17-25-57-41(89)49(97)65(105-25)114-58-26(18-122-10-2-34(75)76)107-67(51(99)43(58)91)116-60-28(20-124-12-4-36(79)80)109-69(53(101)45(60)93)118-62-30(22-126-14-6-38(83)84)111-71(55(103)47(62)95)120-64-32(24-128-16-8-40(87)88)112-72(56(104)48(64)96)119-63-31(23-127-15-7-39(85)86)110-70(54(102)46(63)94)117-61-29(21-125-13-5-37(81)82)108-68(52(100)44(61)92)115-59-27(19-123-11-3-35(77)78)106-66(113-57)50(98)42(59)90;;;;;;;;/h25-32,41-72,89-104H,1-24H2,(H,73,74)(H,75,76)(H,77,78)(H,79,80)(H,81,82)(H,83,84)(H,85,86)(H,87,88);;;;;;;;/q;8*+1/p-8/t25-,26-,27-,28-,29-,30-,31-,32-,41-,42-,43-,44-,45-,46-,47-,48-,49-,50-,51-,52-,53-,54-,55-,56-,57-,58-,59-,60-,61-,62-,63-,64-,65-,66-,67-,68-,69-,70-,71-,72-;;;;;;;;/m1......../s1
|  StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = KMGKABOMYQLLDJ-VKHHSAQNSA-F
}}
}}
'''Sugammadex''' (designation Org 25969) is a novel agent for reversal of [[neuromuscular blocking drugs|neuromuscular blockade]] by the agent [[rocuronium]] in [[general anaesthesia]]. Sugammadex is currently in Phase 3 study and has not been approved for use. It is the first [[selective relaxant binding agent]] (SRBA). <ref>Naguib M (2007). "Sugammadex: another milestone in clinical neuromuscular pharmacology.". ''Anesth Analg'' '''104'''(3): 575–81. PMID 17312211</ref>


Sugammadex is a modified γ-[[cyclodextrin]], with a lipophilic core and a hydrophilic periphery. This gamma cyclodextrin has been modified from its natural state by placing eight carboxyl thio ether groups at the sixth carbon positions.  These extensions extend the cavity size allowing greater encapsulation of the rocuronium molecule. These negatively charged extensions electrostatically bind to the positively charged ammonium group as well as contribute to the aqueous nature of the cyclodextrin. Sugammadex's binding encapsulation of rocuronium has been found to be one of the strongest among cyclodextrin and their guest molecules. The rocuronium molecule (a modified [[steroid]]) bound within sugammadex's lipophilic core, is rendered unavailable to bind to the [[acetycholine receptor]] at the [[neuromuscular junction]]. Sugammadex binding to rocuronium has been found to be very strong.
__Notoc__
<div class="thumb tleft" style="background-color: #f9f9f9; border: 1px solid #CCCCCC; margin:0em;">
{{SI}}
{{CMG}}
 
==Overview==
 
'''Sugammadex ''' ('''Org 25969''', tradename '''Bridion''') is an agent for reversal of [[neuromuscular blocking drugs|neuromuscular blockade]] by the agent [[rocuronium]] in [[general anaesthesia]]. It is the first [[selective relaxant binding agent]] (SRBA) .
 
==History==
Sugammadex was discovered at the [[Newhouse Research Site|Newhouse research site]] in [[Scotland]].<ref>Naguib M (2007). "Sugammadex: another milestone in clinical neuromuscular pharmacology.". ''Anesth Analg'' '''104'''(3): 575–81. PMID 17312211</ref>  These scientists who discovered Sugammadex worked for the pharmaceutical company Organon.  Organon was acquired by Schering-Plough in 2007; Schering-Plough merged with Merck in 2009.  Sugammadex is now owned and sold by Merck.
 
On January 3, 2008, Schering-Plough submitted a [[New Drug Application]] to the US [[Food and Drug Administration]] for sugammadex, but the FDA rejected the application on August 2008.<ref>{{cite press release
  | title = U.S. FDA Issues Action Letter for Sugammadex
  | publisher = [[Schering-Plough]]
  | date = 2008-08-01
  | url = http://www.schering-plough.com/schering_plough/news/release.jsp?releaseID=1182475
  | accessdate = 2008-08-02
}}</ref>
It was approved for use in the [[European Union]] on July 29, 2008.<ref>{{cite press release
  | title = BRIDION(R) (sugammadex) Injection - First and Only Selective Relaxant Binding Agent - Approved in European Union
  | publisher = [[Schering-Plough]]
  | date = 2008-07-29
  | url = http://www.schering-plough.com/schering_plough/news/release.jsp?releaseID=1180933
  | accessdate = 2008-08-02
}}</ref>
 
==Mechanism of action ==
Sugammadex is a modified γ-[[cyclodextrin]], with a lipophilic core and a hydrophilic periphery. This gamma cyclodextrin has been modified from its natural state by placing eight carboxyl thio ether groups at the sixth carbon positions.  These extensions extend the cavity size allowing greater encapsulation of the rocuronium molecule. These negatively charged extensions electrostatically bind to the quaternary nitrogen of the target as well as contribute to the aqueous nature of the cyclodextrin. Sugammadex's binding encapsulation of rocuronium is one of the strongest among cyclodextrins and their guest molecules. The rocuronium molecule (a modified [[steroid]]) bound within sugammadex's lipophilic core, is rendered unavailable to bind to the [[acetylcholine receptor]] at the [[neuromuscular junction]]. <div class="thumb tleft" style="background-color: #f9f9f9; border: 1px solid #CCCCCC; margin:0em;">
{|border="0" width=475px border="0" cellpadding="0" cellspacing="0" style="font-size: 85%; border: 1px solid #CCCCCC; margin: 0.3em;"
{|border="0" width=475px border="0" cellpadding="0" cellspacing="0" style="font-size: 85%; border: 1px solid #CCCCCC; margin: 0.3em;"
|[[Image:Sugammadex encaps rocuronium.jpg|300px|Schematic diagram of sugammadex encapsulating a rocuronium molecule]]
|[[Image:Sugammadex encaps rocuronium.jpg|300px|Schematic diagram of sugammadex encapsulating a rocuronium molecule]]
Line 38: Line 92:
<!--Table adapted from DNA article, feel free to replace with cleaner one-->
<!--Table adapted from DNA article, feel free to replace with cleaner one-->


The main advantage of sugammadex is reversal of neuromuscular blockade without relying on inhibition of [[acetylcholinesterase]]. Therefore it does not cause the autonomic instability produced by anticholinesterases such as [[neostigmine]], and [[antimuscarinic]] agents such as [[atropine]] do not need to be co-administered. Its administration is therefore associated with much greater cardiovascular and autonomic stability than the traditional reversal agents. The use of the depolarizing neuromuscular agent [[suxamethonium]] (Celucurin) is often preferred when a fast onset and short duration is needed. The short effect of suxamethonium is of advantage when there is uncertainty of a successful endotracheal intubation. Some disadvantages with suxamethonium sometimes makes it less preferable i.e. electrolyte imbalances like high potassium, other serious cardiovascular side effects also may occur. The introduction of sugammadex will make rocuronium usable in these rare situations also. Since rocuronium has reasonably short onset with high dosage and sugammadex will abolish the effects of rocuronium and in reality make it as short acting as suxamethonium if the effect needs to be reversed.  
The main advantage of sugammadex is reversal of neuromuscular blockade without relying on inhibition of [[acetylcholinesterase]]. Therefore it does not cause the autonomic instability produced by anticholinesterases such as [[neostigmine]], and [[antimuscarinic]] agents such as [[atropine]] do not need to be co-administered. Its administration is therefore associated with much greater cardiovascular and autonomic stability than the traditional reversal agents.  
 
In addition, when a fast onset and short duration of muscle relaxant is required, there has been little choice previously apart from the use of [[suxamethonium]]. However, suxamethonium is not ideal, as it has some undesirable side effects, such as anaphylaxis, increasing serum potassium levels and other cardiovascular properties. Since, in high doses, rocuronium has a reasonably rapid onset and now can be reversed with sugammadex, it can potentially be used instead.
 
'Recurarisation', a phenomenon of recurrence of neuromuscular block, may occur where the reversal agents wear off before a neuromuscular blocking drug is completely cleared. This is very unusual with all but the longest acting neuromuscular blocking drugs (such as [[gallamine]], [[pancuronium]] or [[tubocurarine]]). It has been demonstrated to occur only rarely with sugammadex, and only when insufficient doses were administered.<ref>{{cite journal |author=Miller R |title=Sugammadex: an opportunity to change the practice of anesthesiology? |journal=Anesth Analg |volume=104 |issue=3 |pages=477–8 |year=2007 |pmid=17312188 |doi=10.1213/01.ane.0000255645.64583.e8}}</ref>  The underlying mechanism is thought to be related to redistribution of relaxant after reversal. It may occur for a limited range of sugammadex doses which are sufficient for complex formation with relaxant in the central compartment, but insufficient for additional relaxant returning to central from peripheral compartments.<ref>{{cite journal |author=Eleveld DJ |title=A Temporary Decrease in Twitch Response During Reversal of Rocuronium-Induced Muscle Relaxation with a Small Dose of Sugammadex |journal=Anesth Analg |volume=104 |issue=3 |pages=582–4 |year=2008 |pmid=17312212  |doi=10.1213/01.ane.0000250617.79166.7f |last2=Kuizenga |first2=K |last3=Proost |first3=JH |last4=Wierda |first4=JM}}</ref>


'''Recurarisation''', a phenomenon of recurrence of neuromuscular block, may occur where the reversal agents wear off before a neuromuscular blocking drug is completely cleared. This is very unusual with all but the longest acting neuromuscular blocking drugs (such as [[gallamine]], [[pancuronium]] or [[tubocurarine]]). It has been demonstrated to occur only rarely with sugammadex, and only when insufficient doses were administered.<ref>{{cite journal |author=Miller R |title=Sugammadex: an opportunity to change the practice of anesthesiology? |journal=Anesth Analg |volume=104 |issue=3 |pages=477-8 |year=2007 |pmid=17312188}}</ref>
Sugammadex also has some affinity for other aminosteroid neuromuscular blocking agents such as [[vecuronium]] and [[pancuronium]]. Though sugammadex's affinity for vecuronium is lower than its affinity for rocuronium, reversal of vecuronium is still effective because fewer vecuronium molecules are present in vivo for equivalent blockade.  Vecuronium is approximately seven times more potent than rocuronium and overall requires fewer molecules to induce blockade. Sugammadex encapsulates with a 1:1 ratio and therefore will adequately reverse vecuronium as there are fewer molecules to bind compared to rocuronium.<ref>Welliver M (2006). "New drug sugammadex; A selective relaxant binding agent". ''AANA J'' '''74'''(5): 357–363. PMID 17048555</ref> Shallow Pancuronium blockade has been successfully reversed by sugammadex in phase III clinical trials.<ref>Decoopman M (2007). "Reversal of pancuronium-induced block by the selective relaxant binding agent sugammadex". ''Eur J Anaesthesiol.'' 24(Suppl 39)'':110-111.</ref>


γ-cyclodextrins have eight glucose units around the central ring of the molecule. Other cyclodextrins have different numbers, and correspondingly different properties.
==Efficacy==
A study was carried out in Europe looking at its suitability in [[rapid sequence induction]]. It found that sugammadex provides a rapid and dose-dependent reversal of neuromuscular blockade induced by high-dose [[rocuronium]].<ref>{{cite journal |author=Pühringer FK, Rex C, Sielenkämper AW, ''et al.'' |title=Reversal of profound, high-dose rocuronium-induced neuromuscular blockade by sugammadex at two different time points: an international, multicenter, randomized, dose-finding, safety assessor-blinded, phase II trial |journal=Anesthesiology |volume=109 |issue=2 |pages=188–97 |date=August 2008 |pmid=18648227 |doi=10.1097/ALN.0b013e31817f5bc7 }}</ref>


Sugammadex also has some affinity for the aminosteroid neuromuscular blocking agents [[vecuronium]] and [[pancuronium]]. Though sugammadex's affinity for vecuronium is lower than its affinity for rocuronium, reversal of vecuronium is still effective because less vecuronium molecules are present in vivo for equivalent blockade. Vecuronium is approximately seven times more potent than rocuronium and overall requires less molecules to induce blockade. Sugammadex encapsulates with a 1:1 ratio and therefore will adequately reverse vecuronium as there are less molecules to bind compared to rocuronium. <ref>Welliver M (2006). "New drug sugammadex; A selective relaxant binding agent". ''AANA J'' '''74'''(5): 357–363. PMID 17048555</ref> Shallow Pancuronium blockade has been successfully reversed by sugammadex in phase III clinical trials. <ref>Decoopman M (2007). "Reversal of pancuronium-induced block by the selective relaxant binding agent sugammadex". ''Eur J Anaesthesiol.'' 24(Suppl 39)'':110-111.</ref>  
A Cochrane systematic review on sugammadex has been recently published by Abrishami et al. This review article included 18 randomized controlled trials on the efficacy and safety of sugammadex. The trials included a total of 1321 patients. The review concluded that "sugammadex was shown to be more effective than placebo (no medication) or neostigmine in reversing muscle relaxation caused by neuromuscular blockade during surgery and is relatively safe. Serious complications occurred in less than 1% of the patients who received sugammadex. The results of this review article (especially the safety results) need to be confirmed by future trials on larger patient populations".<ref>{{cite journal |author=Abrishami A, Ho J, Wong J, Yin L, Chung F. |editor1-last=Abrishami |editor1-first=Amir|title=Sugammadex, a selective reversal medication for preventing postoperative residual neuromuscular blockade |journal=Cochrane Database of Systematic Reviews |issue=4 |pages=CD007362 |date=October 2009 |pmid=19821409  |doi=10.1002/14651858.CD007362.pub2}}</ref>
 
==Tolerability==
Sugammadex was generally well tolerated in clinical trials in surgical patients or healthy volunteers.  In pooled analyses, the tolerability profile of sugammadex was generally similar to that of placebo or neostigmine plus [[glycopyrrolate]].<ref name="sugamma">Yang LPH, Keam SJ.[http://adisonline.com/drugs/abstract/2009/69070/Sugammadex__A_Review_of_its_Use_in_Anaesthetic.8.aspx].Drugs 2009;69(7):919-942. {{doi|10.2165/00003495-200969070-00008}}.</ref>


==References==
==References==
{{reflist|2}}
{{reflist}}
 
{{Antidotes}}


[[Category:Anesthesia]]
[[Category:Anesthesia]]
[[Category:Polysaccharides]]
[[Category:Polysaccharides]]

Revision as of 14:23, 8 April 2015

Sugammadex
File:Sugammadex sodium.svg
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E number{{#property:P628}}
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FormulaC72H104Na8O48S8
Molar mass2178 g/mol
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]

Overview

Sugammadex (Org 25969, tradename Bridion) is an agent for reversal of neuromuscular blockade by the agent rocuronium in general anaesthesia. It is the first selective relaxant binding agent (SRBA) .

History

Sugammadex was discovered at the Newhouse research site in Scotland.[1] These scientists who discovered Sugammadex worked for the pharmaceutical company Organon. Organon was acquired by Schering-Plough in 2007; Schering-Plough merged with Merck in 2009. Sugammadex is now owned and sold by Merck.

On January 3, 2008, Schering-Plough submitted a New Drug Application to the US Food and Drug Administration for sugammadex, but the FDA rejected the application on August 2008.[2] It was approved for use in the European Union on July 29, 2008.[3]

Mechanism of action

Sugammadex is a modified γ-cyclodextrin, with a lipophilic core and a hydrophilic periphery. This gamma cyclodextrin has been modified from its natural state by placing eight carboxyl thio ether groups at the sixth carbon positions. These extensions extend the cavity size allowing greater encapsulation of the rocuronium molecule. These negatively charged extensions electrostatically bind to the quaternary nitrogen of the target as well as contribute to the aqueous nature of the cyclodextrin. Sugammadex's binding encapsulation of rocuronium is one of the strongest among cyclodextrins and their guest molecules. The rocuronium molecule (a modified steroid) bound within sugammadex's lipophilic core, is rendered unavailable to bind to the acetylcholine receptor at the neuromuscular junction.

Schematic diagram of sugammadex encapsulating a rocuronium molecule
Left: Schematic of a sugammadex molecule encapsulating a rocuronium molecule.
Right: Space-filling model of a sugammadex sodium molecule in the same orientation.


The main advantage of sugammadex is reversal of neuromuscular blockade without relying on inhibition of acetylcholinesterase. Therefore it does not cause the autonomic instability produced by anticholinesterases such as neostigmine, and antimuscarinic agents such as atropine do not need to be co-administered. Its administration is therefore associated with much greater cardiovascular and autonomic stability than the traditional reversal agents.

In addition, when a fast onset and short duration of muscle relaxant is required, there has been little choice previously apart from the use of suxamethonium. However, suxamethonium is not ideal, as it has some undesirable side effects, such as anaphylaxis, increasing serum potassium levels and other cardiovascular properties. Since, in high doses, rocuronium has a reasonably rapid onset and now can be reversed with sugammadex, it can potentially be used instead.

'Recurarisation', a phenomenon of recurrence of neuromuscular block, may occur where the reversal agents wear off before a neuromuscular blocking drug is completely cleared. This is very unusual with all but the longest acting neuromuscular blocking drugs (such as gallamine, pancuronium or tubocurarine). It has been demonstrated to occur only rarely with sugammadex, and only when insufficient doses were administered.[4] The underlying mechanism is thought to be related to redistribution of relaxant after reversal. It may occur for a limited range of sugammadex doses which are sufficient for complex formation with relaxant in the central compartment, but insufficient for additional relaxant returning to central from peripheral compartments.[5]

Sugammadex also has some affinity for other aminosteroid neuromuscular blocking agents such as vecuronium and pancuronium. Though sugammadex's affinity for vecuronium is lower than its affinity for rocuronium, reversal of vecuronium is still effective because fewer vecuronium molecules are present in vivo for equivalent blockade. Vecuronium is approximately seven times more potent than rocuronium and overall requires fewer molecules to induce blockade. Sugammadex encapsulates with a 1:1 ratio and therefore will adequately reverse vecuronium as there are fewer molecules to bind compared to rocuronium.[6] Shallow Pancuronium blockade has been successfully reversed by sugammadex in phase III clinical trials.[7]

Efficacy

A study was carried out in Europe looking at its suitability in rapid sequence induction. It found that sugammadex provides a rapid and dose-dependent reversal of neuromuscular blockade induced by high-dose rocuronium.[8]

A Cochrane systematic review on sugammadex has been recently published by Abrishami et al. This review article included 18 randomized controlled trials on the efficacy and safety of sugammadex. The trials included a total of 1321 patients. The review concluded that "sugammadex was shown to be more effective than placebo (no medication) or neostigmine in reversing muscle relaxation caused by neuromuscular blockade during surgery and is relatively safe. Serious complications occurred in less than 1% of the patients who received sugammadex. The results of this review article (especially the safety results) need to be confirmed by future trials on larger patient populations".[9]

Tolerability

Sugammadex was generally well tolerated in clinical trials in surgical patients or healthy volunteers. In pooled analyses, the tolerability profile of sugammadex was generally similar to that of placebo or neostigmine plus glycopyrrolate.[10]

References

  1. ↑ Naguib M (2007). "Sugammadex: another milestone in clinical neuromuscular pharmacology.". Anesth Analg 104(3): 575–81. PMID 17312211
  2. ↑ "U.S. FDA Issues Action Letter for Sugammadex" (Press release). Schering-Plough. 2008-08-01. Retrieved 2008-08-02.
  3. ↑ "BRIDION(R) (sugammadex) Injection - First and Only Selective Relaxant Binding Agent - Approved in European Union" (Press release). Schering-Plough. 2008-07-29. Retrieved 2008-08-02.
  4. ↑ Miller R (2007). "Sugammadex: an opportunity to change the practice of anesthesiology?". Anesth Analg. 104 (3): 477–8. doi:10.1213/01.ane.0000255645.64583.e8. PMID 17312188.
  5. ↑ Eleveld DJ; Kuizenga, K; Proost, JH; Wierda, JM (2008). "A Temporary Decrease in Twitch Response During Reversal of Rocuronium-Induced Muscle Relaxation with a Small Dose of Sugammadex". Anesth Analg. 104 (3): 582–4. doi:10.1213/01.ane.0000250617.79166.7f. PMID 17312212.
  6. ↑ Welliver M (2006). "New drug sugammadex; A selective relaxant binding agent". AANA J 74(5): 357–363. PMID 17048555
  7. ↑ Decoopman M (2007). "Reversal of pancuronium-induced block by the selective relaxant binding agent sugammadex". Eur J Anaesthesiol. 24(Suppl 39):110-111.
  8. ↑ Pühringer FK, Rex C, Sielenkämper AW; et al. (August 2008). "Reversal of profound, high-dose rocuronium-induced neuromuscular blockade by sugammadex at two different time points: an international, multicenter, randomized, dose-finding, safety assessor-blinded, phase II trial". Anesthesiology. 109 (2): 188–97. doi:10.1097/ALN.0b013e31817f5bc7. PMID 18648227.
  9. ↑ Abrishami A, Ho J, Wong J, Yin L, Chung F. (October 2009). Abrishami, Amir, ed. "Sugammadex, a selective reversal medication for preventing postoperative residual neuromuscular blockade". Cochrane Database of Systematic Reviews (4): CD007362. doi:10.1002/14651858.CD007362.pub2. PMID 19821409.
  10. ↑ Yang LPH, Keam SJ.[1].Drugs 2009;69(7):919-942. doi:10.2165/00003495-200969070-00008.
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