News muscle relaxants 2003

Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)

C ’è qualche cosa di nuovo nel campo della

miorisoluzione???

Claudio MelloniServizio Anestesia e Rianimazione

Ospedale di Faenza(RA)


PORC: Post Operative Residual Curarization !

I\


Frequency of residual curarization

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3035

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Viby 1979

Beemer

Pedersen

Bevanpanc


Viby Mogensen et al,AAS 1997

• 693 paz.randomizzati,cieco

• chir elettiva

• monitoraggio periop con Myotest e Tof

• confronto fra 1-5-2 ED95 diatrac,vecu,panc.

• Antagonismo se necessario;

• estubaz a tof eguale, tattile e resp adeguata.


Paralisi residua e % di tof<0.40 in RR,subito dopo trasferimento

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Residual neuromuscular block and POPC

TOFR Panc Atrac & vecu

>0.7 4,8% 5,4%

<0.7 16,9%* 4,2%


Andamento temporale del tof <0.80 nella RR

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Risk of POPC following abdominal surgery

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Fattori di rischio per POPC nello studio AAS 1997

Tipo di chirurgia;freq * 2-10(addominale) età:ogni 10 anni * 1.68 durata di anestesia(> o < 200 min)*3.3 panc e tof<0.70:*5


Postoperative pulmonary complications

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Kopman et al.Relationship of the train of four fade ratio to clinical signes and symptoms of

residual paralysis in awake volunteers.Anesthesiology,1997;86:765-71.

Volontari sani infusione di mivacurium monitoraggio Datex 221 NMT valutazione;stretta di mano sollev,testa & gamba per 5 sec. Ritenzione di abbassalingua


Osservazioni cliniche sulla relazione fra tof e correlati di forza:

disturbi visivi sempre con tof di 0.90(diplopia,diff.seguire oggetti in moto,ecc)

forza dei masseteri ridotta sempre sollev.testa e gamba sempre possibile > 0.60 stretta di mano variabile,ma 83% del basale a tof

0.90 per tof < 0.75 tutti disturbati


Conclusioni delle correlazioni fra segni clinici di forza muscolare e tof

Capacità di ritenzione dell’abbassalingua è un test più sensibile del sollevamento del capo

tof <1 ancora residuano disturbi visivi e senso generalizzato di fatica

tof = 1 (o altri monitoraggi) per dimissione in chirurgia ambulatoriale??

0,000,100,200,300,400,500,600,700,800,90

lowest tof highest tof

at which test passed or failed

head lift

leg lift

retain tonguedepressor


Assiomi della ripresa nm.

TOF > 0.70 sicuro indice della ripresa nm……….. Ali HH, Wilson RS, Savarese JJ, Kitz RJ: The effect of tubocurarine on indirectly elicited train-of-four muscle response and respiratory measurements in humans. Br J Anaesth 47:570-4, 1975

Brand JB, Cullen DJ, Wilson NE, Ali HH: Spontaneous recovery from nondepolarizing neuromuscular blockade: Correlation between clinical and evoked responses. Anesth Analg 56:55-8, 1977


Mutazioni occorse

Esplosione della chirurgia ambulatoriale pressione per la diminuzione della

spesa sanitaria aumento delle persone anziane e

debilitate anche in chir amb. Disponibilità di nuovi farmaci


Rivalutazione della pratica clinica

Età e stato di salute differiscono fra volontari sani e pazienti!

La prassi clinica e l’utilizzo dei miorilassanti variano fra i diversi centri ambulatoriali

il monitoraggio degli effetti nm non è praticato in ospedale,figurarsi nei centri ambulatoriali!

I metodi di monitoraggio usati da Kopman et al si applica ad una ampia gamma di situazioni cliniche.

Esistono pesanti pressioni economiche per la diminuzione della spesa sanitaria.


Implicazioni del lavoro di Kopman:1

I paz chirurgici sono in genere più anziani e ammalati dei volontari sani dello studio di Kopman/( ASA 1, entro il 15% del peso ideale,tra 23—33 anni….)

gli effetti residui dei miorilassanti è probabile possano essere + significativi nella pratica ambulatoriale con pazienti + anziani e debilitati.

Si potrebbe arguire che i paz.con sedazione residua siano meno attenti a disturbi visivi e

debolezza dei muscoli facciali;ma è anche vero che dal punto di vista della sicurezza i paz postop siano esposti a rischio maggiore di aumento della morbilità,poichè la debolezza residua nm può essere aggravata da residui dell’anestesia.


Conclusions form Kopman,Brull,Erikkson…..

indicators of recovery of nm function should be changed.

The TOF ratio <0.9 was also associated with functional impairment of the pharynx and upper correlated volunteers' subjective feelings of partial neuromuscular weakness with the clinical counterpart of neuromuscular recovery. All subjects had significant signs and symptoms of residual paralysis at a TOF ratio of 0.7 and satisfactory recovery of neuromuscular function after mivacurium-induced neuromuscular block required return of the TOF ratio to >0.9 . According to these studies, the absence of muscle relaxant-induced clinical effects may be defined as the return to a TOF ratio ³0.9 at the AP.


Kim KS, Lew SH, Cho HY, Cheong MA. Residual paralysis induced by either vecuronium or

rocuronium after reversal with pyridostigmine.Anesth Analg. 2002 95:1656-60

125/602125/602

Vecu>rocu

Estubazione nel 94% dei paz.prima di entrare nella RR


Fattori di rischio di PORC (Kim et al.Residual paralysis induced by either vecuronium or

rocuronium after reversal with pyridostigmine.Anesth Analg. 2002 95:1656-60 )

Dose cumulativa di vecu maggiore Più breve distanza dall’ultima iniezione Paz con blocco residuo più ipotermici Sollevamento testa> 5 sec più sensibile della

depressione della lingua?


McCaul, C.; Tobin, É.; Boylan, J. F.; McShane, A. J.*Atracurium is associated with postoperative residual curarization.BJA 2002;89:766-769

65% patients TOFR <0.7 at extubation Risk factors:

» shorter procedures» more profound neuromuscular block at the time of neostigmine administration» shorter time intervals from administration of last dose of atracurium to

administration of antagonist» Shorter times from administration of antagonist to extubation » TOFR at the time of antagonism was positively correlated with time elapsed since

last dose of atracurium 19 patients had clinical evidence of impaired neuromuscular function as

evidenced by a total of 40 clinical events:» . uncoordinated movements» oxygen desaturation» upper airway obstruction» ptosis » diplopia/blurring of vision.


McCaul, C.; Tobin, É.; Boylan, J. F.; McShane, A. J.*Atracurium is associated with postoperative residual curarization.BJA 2002;89:766-769

» A peripheral nerve stimulator was used in 50% (20/40) of patients.» Trainees who did not use nerve stimulators were more experienced

than those who did [6.3 (0.8) vs 4.5 (0.4) yr, P=0.04]. » Use of nerve stimulators was not associated with altered atracurium

dosage, depth of blockade before antagonism, time interval from antagonism of neuromuscular block to tracheal extubation, or incidence of PORC.

The sole multivariate predictor of residual neuromuscular block was duration of surgical procedure, which correlated inversely with PORC


Dilly M P,Plaud B.,Thery V, Debaene B.Incidence of residual neuromuscular block in the PACU after a single intubating dose of intermediate duration

muscvle relaxant.BJA 1999;82 suppl 1.526 patients single intubating dose 2ED 95 of vecuronium,

rocuronium or atracurium. a clinical evaluation and a qualitative measurement of

the TOF count were performed At the admission in the PACU, TOF ratio at the AP

was measured using an accelerometry method (TOF-Watch, Organon Tecknica).

TOFR< 70% in 16,2%;TOFR< 90% in 44,9%.


Dilly et al.Incidence of residual neuromuscular block in the PACU after a single intubating dose of intermediate duration muscvle relaxant.BJA

1999;82 suppl 1.

2 hrs after the a single intubating dose (2 x ED95) of non-depolarizing MR of intermediate duration (n = 238), 10% of the patients had a TOFR< 70% +TOFR< 90% in 36,6% of the cases.

Conclusions: The incidence of RNMB two hours after a single dose (2 x DA95) of MR of intermediate duration is about 36% (TOF ratio <90%) These results argue for a quantitative measurement of the TOF using accelerometry to assess residual paralysis in the PACU. This measurement needs to be performed even after the administration of a single dose of non-depolarizing MR, and whatever the duration of the anesthetic procedure.


Cammu G, de Baerdemaeker L, den Blauwen N, de Mey JC, Struys M, Mortier E. Postoperative

residual curarization with cisatracurium and rocuronium infusions.Eur J Anaesthesiol.

2002;19:129-34.

Chir maggiore di durata 3-4 h Infusioni terminate all’inizio della sutura

cutanea Monitoraggio nm:EMG Datex;tof ogni

min Anestesia mant:propofol/sufent Miorisoluz mant al 10% di T1 Estubaz a TOF 0.90


Cammu et al. Postoperative residual curarization with cisatracurium and rocuronium infusions.Eur

J Anaesthesiol. 2002;19:129-34.

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neostigm in tof at reversal tempo finechir-tof 0.90

fine chir-estubaz

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Rocuronium


PR. Freund KL Posner, DJ. Dalgleish. Decrease in Emergent Reintubation after Establishing a Standard for Monitoring and Documenting

Reversal of Neuromuscular Blockade.Anesthesiology 2002 ;96:A1125

: There is no ASA standard for documentation of adequate return of neuromuscular (NM) function. Our continuous quality improvement program1 identified several cases of emergent reintubation for inadequate return of NM function. We hypothesized that setting a standard for confirming and documenting return of NM function would decrease the incidence of emergent reintubation in PACU.

Methods: After IRB approval, 100 consecutive records for open intra-abdominal surgery were retrospectively reviewed (baseline). Adequate documentation was defined as a note of any one of commonly used criteria for return of NM function: no fade on train of four, sustained tetanic contraction at 50Hz for 5 seconds, or negative inspiratory force > -35cm H2O. Inadequate documentation was defined as mention of any one criteria without documentation of adequacy (e.g., note of train of four without mention of fade or sustained tetanus). A departmental educational program of lectures plus a written and email bulletin explaining the service standards for monitoring the return of NM function was then implemented. A 2nd set of 100 consecutive records was examined over a five week intervention period. Inadequate documentation during this period prompted a verbal or electronic reminder to the primary care giver. After an interlude of 2 months without reminders, a final consecutive 100 records were reviewed (post intervention).


Freund et al.. Decrease in Emergent Reintubation after Establishing a Standard for Monitoring and

Documenting Reversal of Neuromuscular Blockade.Anesthesiology 2002 ;96:A1125

Results: During the baseline period, only 13% of records had adequate documentation and 40% had no documentation at all (Figure). In the post intervention period, compliance with the service standard was 50% (Figure). During the baseline period, 4% of anesthetics administered by residents and 31% of those by CRNAs had adequate documentation, increasing to 57% for the residents and 44% for the CRNAs in the post interventionperiod. There were no emergent reintubations in the PACU during the study period.

Discussion: Our CQI system identified a problem with emergent reintubation in the PACU. Initial chart review confirmed inadequate documentation of the return of NM function after the use of NM blocking drugs. The educational program has improved documentation and emergent reintubations in our PACU have decreased.


Effetti di un programma di incentivazione qualitativa sulla annotazione diligente della

ripresa della funzione nm.(chir.add.)

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baseline intervento post intervento

adeguatainadeguatasenza documentazione

LettureBollettino scritto

E mail


NEW DRUGS



White PF .Rapacuronium:why did it fail as a replacement for

succinylcholine?Br.J.Anaesth.2002;88;163-65



TETRAIDROCHINOLINA CLOROFUMARATO


Belmont MR. Lien C A, Savarese , Patel S,Fischer G,Mook R.Neuromuscular blocking effects of

GW280430A at the adductor pollicis and larynx in human.BJA 1999;82:suppl A 419

20 pts Midaz/fent/propofol N2O/O2/propofol

infusion+ fent qb. IOT senza mioriiassanti Monitoraggio:

» forza all’AP » pressione cuffia del ETT con stimolaz

transcutanea sulla faccia lat della tiroide.


GW280340A The structure of this mixed-tetrahydroisoquinolinium

chlorofumarate is given in . The similarity in structure to mivacurium is demonstrated. The presence of three methyl groups between the quaternary nitrogen and oxygen atom at each end of the carbon chain suggests that, similar to mivacurium, this compound will not undergo Hofmann degradation. Little is known as yet about its metabolism. It is said to be degraded by chemical mechanisms in vitro. It is possible that the chloride substituted double bond in the carbon chain is its weak point. The molecule appears to be in the trans—trans configuration similar to one of the active isomers of mivacurium and in contrast to cisatracurium. It is the trans isomers of mivacurium and atracurium that undergo ester hydrolysis.


GW280430A:tetraidrochinolinio clrofumarato 1 ED95:0.18 mg/kg

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GW280430A 2 ED 95:0.36 mg/kg

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GW280430A 3 ED 95:0.54 mg/kg

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Belmont,Lien.... Asa abstracts 2003.GW280430A,now 430A

40 ASA 1 ,male and female volunteers, aged 18-50, Anesthesia: midazolam, fentanyl, propofol: maintained with an infusion of propofol and N2O

70%/O2 30%. ulnar nerve was stimulated at the wrist with a train-of-four (TOF) every 10 seconds and

MMG responses were recorded from the adductor pollicis. data were analyzed for onset of maximum block and recovery times. ED95 calculated from the first 15 volunteers' doses, and accounting for TOF monitoring, is

approximately 0.125mg/kg Mean onsets decreased from 122 to 54 seconds for doses ranging from 1.5 to 7XED95. Mean total durations, 95%T1 recovery, were 10.9-15.9 minutes for these doses. Mean clinical durations, 25%T1 recovery, ranged from 3.5 to 9.8 minutes No fasciculations were observed and fade of TOF during recovery was noted. Cardiovascular changes observed through the 5XED95 dose were minimal (<20%), and

rare.Conclusions: 430A is a potent non-depolarizing neuromuscular blocking agent with a rapid

onset and an ultra-short duration of action. Further study of this experimental compound is warranted.


Farmacodinamica del GW430A ;da Belmont,Lien.... Asa abstracts 2003.

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Lien CA et al.Pharmacodynamics of spontaneous and edrophonium facilitated recovery following

administration of GW 430A.Anesthesiology 2003;A1154

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BISTROPINIL DIESTERE


Struttura del G 1-64 bis N clorobenzil tropanium 3

alfa gamma glutarato dibromuro :bistropinil diestere


Gyermek L, Lee C, Nguyen N. Pharmacology of G-1-64, a new non-depolarising neuromuscular

blocking agent with rapid onset and short duration of action. Acta Anaesthesiol Scand 1999;

43:651-7. G-1-64 is a promising prototype of a new series of bis-quaternary ammonium salt of

bistropinyl diester derivatives we have synthesized and studied in the laboratory. METHODS: Neuromuscular block (NMB) and autonomic and cardiovascular side effects were studied on appropriate preparations of anesthetized rats, rabbits, cats, ferrets, pigs and monkeys. Neuromuscular blocking characteristics, cumulativeness, and pharmacological reversibility were determined. Cardiac vagal block was evaluated by the inhibition of the bradycardic response to stimulation of the vagus in the cat, rat, ferret, and pig. Sympathetic ganglion block was evaluated on the cat's superior cervical ganglion/nictitating membrane preparation. Arterial blood pressure and heart rate were determined in all species. RESULTS: G-1-64 produced nondepolarizing NMB with train-of-four (TOF) and tetanic fades, and reversible with anticholinesterases. Its ED50 ranged between 60 and 800 microg/kg in these species. It showed a significantly faster onset (0.9-2.1 min) and/or shorter duration of action (5-12 min) than either atracurium or mivacurium. It did not show cumulativeness on repeated doses or infusion. A varying degree of cardiac vagal block was present, dependent on the species at doses exceeding the ED80 for NMB. Cardiovascular changes, ganglion block or signs suggesting histamine release were absent. CONCLUSION: With favorable neuromuscular blocking characteristics and modest side effects, G-1-64 and similar derivatives may have clinical potential.


Pharmacology

This is a bis-quaternary ammonium salt of a bistropinyl diester derivative. The molecule was selected from more than 200 tropinyl diester compounds. These agents are characterized by:

1. A connecting chain of acid diesters attached to the C3 atom of two tropine molecules.

2. Bulky quaternary substitutes on the tropine N atoms. 3. Varying interonium distances between the terminal groups. G-1-64 is the prototype of this series of compounds, with an

interonium distance of 14.74 Å. It is not yet known how this compound is metabolized. Such diesters could be predicted to undergo hydrolysis in the plasma. Another tropinyl diester compound, N-(3,4-diacetoxybenzyl)-tropinium-3a-yl] glutarate dibromide (TAAC3), has also undergone investigation in animals and appears to undergo non-organ dependent elimination.


Gyermek L, Lee C, Cho YM, Nguyen N, Tsai SK. Neuromuscular pharmacology of TAAC3, a new nondepolarizing muscle

relaxant with rapid onset and ultrashort duration of action. Anesth Analg. 2002 Apr;94(4):879-85,

We selected bis [N-(3,4-diacetoxybenzyl) tropanium-3a-yl] glutarate dibromide (TAAC3) from many new tropinyl diester derivatives to evaluate its neuromuscular blocking (NMB) and autonomic side effects on anesthetized rats, rabbits, guinea pigs, cats, pigs, dogs, and monkeys. NMB potency, onset, recovery index, and duration of action were determined. Comparisons of these pharmacologic variables were made between TAAC3 and rocuronium. In the cat, the degrees of train-of-four and tetanic fade, posttetanic potentiation, and pharmacologic antagonism were evaluated. For determination of the NMB maintenance dose, TAAC3 was also given to rabbits and pigs in the initial dose/maintenance infusion mode. Cardiac vagal block was evaluated in the rat, pig, cat, and guinea pig on the basis of the inhibition of the bradycardia to stimulation of the vagus nerve. Sympathetic ganglion block was studied on the superior cervical ganglion-nictitating membrane preparation of the cat. TAAC3 produced nondepolarizing NMB. Its NMB 90% effective doses ranged from 90 to 425 mg/kg, depending on the species. TAAC3 had a faster onset (0.8–1.0 min), shorter recovery index (0.6–1.1 min), and shorter duration of action (1.8–3.5 min) than rocuronium. It produced a slight cumulative effect on infusion, but not on repeated single-dose administration. Cardiac vagal block was present at doses exceeding the NMB 90% effective dose. In the cat and pig at equipotent NMB doses, the degree of cardiac vagal block was similar to that of rocuronium. There was no demonstrable sympathetic ganglion block in the cat. In view of its favorable NMB characteristics, TAAC3 is now undergoing detailed preclinical studies.


bis [N-(3,4-diacetoxybenzyl) tropanium-3a-yl] glutarate dibromide (TAAC3) :

BISTROPINIL DIESTERE


bis [N-(3,4-diacetoxybenzyl) tropanium-3a-yl] glutarate

dibromide (TAAC3)


bis [N-(3,4-diacetoxybenzyl) tropanium-3a-yl] glutarate

dibromide (TAAC3)


Durate comparative (min) TAAC3,Rocuronium,rapacuronium nel maiale

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TAAC3ROCURAPA


SZ 1677


E. S. VIZI , Z. TUBA S. MAHO , F. F. FOLDES , 0. NAGANO , M. D0DA , S. TAKAG, , A. CHAUDHRy , A. J. SAUBERMANN ,

H. NAGASHIMA A new short‑acting non‑depolarizing muscle relaxant (SZ1677) without cardiovascular side‑effects.Acta Anesth Scand 2003;47:291-300

Background: In order to facilitate rapid tracheal intubation, the development of a rapid onset, short duration, non‑depolarizing muscle relaxant without cardiovascular side‑effects would be a significant accomplishment in the field of anesthesiology. The aim of the present study was to test the action of a new non‑depolarizing muscle relaxant (SZ1677) on neuromuscular transmission, muscarinic (M2, IV13) receptors and cardiovascular reactions and to compare it with clinically used muscle relaxants.

Methods: Neuromuscular transmission was studied by recording muscle contractions elicited by indirect electrical stimulation, using (i) in vitro isolated phrenic nerve‑hemidiaphragm preparation of mice, rats and guinea pigs and (ii) in vivo sciatic nerve‑anterior tibial muscle preparation of anesthetized rats, guinea pigs and cats. Cardiovascular effects of muscle relaxants were evaluated on the grounds of their effects on changes of blood pressure and heart rate induced by electrical stimulation of the right vagal nerve in anesthetized cats. To study postsynaptic antimuscarinic affinity of muscle relaxants on M3 receptors, oxotremorine‑induced contractions of longitudinal muscle strip of guinea pig ileum were registered in their presence and absence.

Results: One of more than 120 newly synthesized non‑depolarizing muscle relaxants compounds, 1‑3[C~ hydroxy‑17P‑acetyloxy‑2f'‑(1,4‑dioxa‑8‑azaspiro[4,5]dec‑8‑yl)‑50~‑androstane‑l6P‑ilI

‑1‑(2propenyl)pyrrolidinium bromide (SZ1677), excelled with its advantageous pharmacological properties: relatively short duration of action, no accumulation and lack of unwanted side‑effects. Pharmacodynamic studies show that SZ1 677 is a non‑depolarizing neuromuscular blocking agent with a relatively short duration and rapid onset of action in a variety of laboratory animal species. It is without cumulative effect, does not reduce blood pressure, and fails to produce tachycardia. Significant cardiac vagal blocking effects were not observed even at concentrations or dosages of 8 times the ED9o. This compound, unlike many other muscle relaxants, does not have atropine‑like effects on human atrial tissue; it does not increase the release of NA from sympathetic innervation in the heart. In all practical ways, at least from the vantage point of the preclinical study, SZ1 677 compares favorably with all presently available short‑acting muscle relaxants, including rapacuronium.

Conclusion: In experiments, SZ1677 proved to be a short‑acting neuromuscular blocking compound having a large safety margin between the doses required to produce neuromuscular block and those likely to lead to cardiovascular side‑effects.


Struttura chimica dell’SZ 1677 e del suo principale

metabolita


SZ 1677:farmacodinamica((VIZI et al .A new short‑acting non‑depolarizing muscle relaxant

(SZ1677) without cardiovascular side‑effects.Acta Anesth Scand 2003;47:291-300)


SZ 1677:Effetto sulla trasmissione nm.nel preparato nervo frenico- emidiaframma di cavia.(VIZI et al .A new short‑acting non‑depolarizing muscle relaxant (SZ1677)

without cardiovascular side‑effects.Acta Anesth Scand 2003;47:291-300)


SZ 1677;farmacodinamica e antagonizzazione(VIZI et al .A new short‑acting

non‑depolarizing muscle relaxant (SZ1677) without cardiovascular side‑effects.Acta Anesth Scand 2003;47:291-300


Effetti temporali dei vari miorilassanti(ED 90) negli animali da esperimento. (VIZI et al .A new short‑acting

non‑depolarizing muscle relaxant (SZ1677) without cardiovascular side‑effects.Acta Anesth Scand 2003;47:291-300)

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SZ1823

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author species drug onset Duration

(min)

Belmont Animals

humans

GW280430A

<2 min 6-9

Gyermek animals TAAC 3 <2min 5-10

Vizi animals Sz1677 <2 min <12


Adverse effects

HeerdtHeerdt PM, Hashim MA, Wastilla W, Mook RA, Savarese JJ. Cardiopulmonary effects of the ultrashort neuromuscular blocking drug GW280430A in dogs. Anesthesiology 1999; 91:A1024.

has studied the effect of GW280430A on the respiratory system of six male beagles; he measured pulmonary artery pressures, peak inspiratory pressure and pulmonary compliance. He found no change in these variables at doses up to 25xED95


Cardiac effects of TAAC 3

Studies of the cardiovascular properties of the tropinyl diesters have considered only the degree of vagal block produced. This is evaluated by studying the inhibition of the bradycardic response to peripheral stimulation of the cut right vagus nerve with 15–20 Hz supramaximal impulses delivered every 2 min. Gyermek found that all the tropinyl diesters studied produced vagal block in the rat. The least potent compounds (which have the slowest onset of action and longest duration of effect), produced 70–90% vagal block, whereas the more potent tropinyl diesters (the most rapid onset of action and the most rapid offset) produced only 40% vagal block. Investigation of TAAC3 in anaesthetized cats also suggests that this tropinyl ester has the potential to produce changes in heart rate and arterial pressure. The fact that as potency increases, the side-effect profile of these drugs becomes more favourable is encouraging, as it is these more potent agents which promise to be of most clinical benefit.


Cardiovascular side-effects of GW280430A

The cardiovascular side-effects of GW280430A have been investigated in dogs, cats, and human volunteers. Heerdt measured heart rate, systemic and pulmonary artery pressures, left ventricular pressure, end-diastolic pressure, and cardiac index in beagles given increasing doses of GW280430A. Other than a transient decrease in arterial pressure at 25xED95, GW280430A did not alter any of the variables. When Belmont examined the effect of GW280430A on the cardiovascular system of cats by measuring heart rate, arterial pressure and per cent vagal inhibition, he was able to give 10xED95 before producing a transient but significant decrease in arterial pressure and a rise in heart rate. Forty per cent vagal block was produced at 16xED95. Lein has reported the effects of GW280430A in 16 male volunteers using doses up to 3xED95 and measuring maximal heart rate and arterial pressure changes in the 5 min following administration. She found that no volunteer had a maximal change in heart rate or arterial pressure of greater than 10% from baseline.

Belmont MR, Apperley G, Hashim MA, Patel S, Savarese JJ. The neuromuscular and cardiovascular profile of GW280430A, a new ultrashort-acting muscle relaxant in cats. Anesthesiology 1999; 91:A 1025.

54: Heerdt PM, Hashim MA, Wastilla W, Mook RA, Savarese JJ. Cardiopulmonary effects of the ultrashort neuromuscular blocking drug GW280430A in dogs. Anesthesiology 1999; 91:A1024.

55: Heerdt PM, Hashim MA, Wastilla W, Mook RA, Savarese JJ. Pharmacodynamics of the novel neuromuscular blocking drug GW280430A in dogs. Anesthesiology 1999; 91:A1023.

78: Lien CA, Belmont MR, Tjan J, Fisher GR, Savarese JJ. Determination of the cardiovascular effects of GW280430A in anesthetized male volunteers. Anesthesiology 1999; 91:A1015.


I nuovi antagonisti decurarizzanti


New reversal agents:i nuovi antagonisti

AChE hanno effetti cardiovascolari ed intestinali indesiderati

Concetto della chelazione chimica Cyclodextrins are a group of cyclic

oligosaccharides, which are recognized to encapsulate lipophilic molecules including steroids. Org 25969 has been investigated in monkeys and been found to antagonize residual block produced by rocuronium more rapidly than neostigmine, without any significant cardiovascular changes.


Referenze in Pubmed.(sept 2003)

Bom A, Bradley M, Cameron K, Clark JK, Van Egmond J, Feilden H, MacLean EJ, Muir AW, Palin R, Rees DC, Zhang MQ.A novel concept of reversing neuromuscular block: chemical encapsulation of rocuronium bromide by a cyclodextrin-based synthetic host.Angew Chem Int Ed Engl. 2002 Jan 18;41(2):266-70.

Sparr HJ. Cyclodextrin. A new concept for antagonizing muscle relaxants]

Anaesthesist. 2002 Nov;51(11):929-30.


Referenze in Pubmed.(sept 2003)

Epemolu O, Mayer I, Hope F, Scullion P, Desmond P. Liquid chromatography/mass spectrometric bioanalysis of a modified

gamma-cyclodextrin (Org 25969) and Rocuronium bromide (Org 9426) in guinea pig plasma and urine: its application to determine the plasma pharmacokinetics of Org 25969.Rapid Commun Mass Spectrom. 2002;16(20):1946-52.

Adam JM, Bennett DJ, Bom A, Clark JK, Feilden H, Hutchinson EJ, Palin R, Prosser A, Rees DC, Rosair GM, Stevenson D, Tarver GJ, Zhang MQ.

Cyclodextrin-derived host molecules as reversal agents for the neuromuscular blocker rocuronium bromide: synthesis and structure-activity relationships.J Med Chem. 2002 Apr 25;45(9):1806-16.

Tarver GJ, Grove SJ, Buchanan K, Bom A, Cooke A, Rutherford SJ, Zhang MQ.

2-O-substituted cyclodextrins as reversal agents for the neuromuscular blocker rocuronium bromide.Bioorg Med Chem. 2002 Jun;10(6):1819-27.


ORG 25969


Rocuronium incapsulato nella gammaciclodestrina


Bom AH,Hope H. Rapid reversal of rocuronium induced neuromuscular block by ORG 25969 in

the guinea pig is not modified by occlusion of the blood supply to one kidney.Eur J,Anesth.20003;20:suppl A 486

0

2

4

6

8

10

12

min

spont org 25969 69mmol/kg

org 25969 230mmol/kg

org 25969 460mmol/kg

2 kidneys1 kidney


Bom et al.Rapid reversal of rocuronium inducd neuromuscular block by ORG 25969 is

independent of renal perfusion.Anesthesiology 2003;A1158

BOM


Epemolu 0, Bom A, Hope F, Mason R. Reversal of neuromuscular blockade and simultaneous

increase in plasma rocuronium concentration after the intravenous infusion of the novel

reversal agent Org 25969. The purpose of this study was to determine the changes in the plasma concentration of

rocuronium and the reversal of its neuromuscular blockade after the intravenous infusion of Org 25969, the novel neuromuscular block‑reversal agent, in anesthetized guinea pigs. METHODS: Rocuronium was infused for I h at a rate of 12‑19 nmol.kg‑l.min‑I to produce a steady‑state 90% neuromuscular block. After 30 min, a concomitant infusion of either the reversal agent Org 25969 at a rate of 50 nmol.kg‑l.min‑I or an infusion of an equivalent volume of saline was started. The time course of plasma concentrations of rocuronium was determined by use of liquid chromatography‑mass spectrometry/mass spectrometry. RESULTS: In both treatment groups, a steady‑state plasma concentration of rocuronium was obtained after 30 min. In the saline‑treated group, the plasma concentration of rocuronium and depth of block remained constant. In the Org 25969 group, neuromuscular block was reversed while the rocuronium infusion was ongoing. Simultaneously, an increase in the total plasma concentration of rocuronium (free and complexed) was observed, even though the infusion rate of rocuronium was not changed. Compared with the saline‑treated group, a small increase in the postmortem bladder concentration of rocuronium was detected. CONCLUSIONS: The authors propose that the capture of rocuronium by Org 25969 causes the rapid reversal of neuromuscular block. The reversal can be explained by the rapid transfer of free rocuronium from the effect compartment (neuromuscular junction) to the central compartment, in which it is bound to Org 25969. This explains the increase in total plasma concentration of rocuronium (free and bound to Org 25969).sz


1)White PF rapacuronium:why did it fail as a replacement for succinylcholine?Br.J.Anaesth.2002;88;163-65. 2) Baillard C, Gehan G, Reboul‑Marty J, etal. Residual curarization in the recovery room after vecuronium. Br J Anaesth 2000; 84:394‑395.

3) Hayes AH, Mirakhur RK, Breslin DS, et al. Postoperative residual block after intermediate‑acting neuromuscular blocking drugs. Anaesthesia 2001; 56:312‑318. 6)Palin R, Clark JK, Cowley P, Muir AW, Pow E, Prosser AB, Taylor R, Zhang MQ. Novel piperidinium and pyridinium agents as water-soluble acetylcholinesterase

inhibitors for the reversal of neuromuscular blockade. Bioorg Med Chem Lett. 2002 Sep 16;12(18):2569-72 7)Cameron KS, Fielding L, Mason R, Muir AW, Rees DC, Thorn S, Zhang MQ.Anionic cyclophanes as potential reversal agents of muscle relaxants by

chemicalchelation.Bioorg Med Chem Lett. 2002 Mar 11;12(5):753-5. 8)Adam JM, Bennett DJ, Bom A, Clark JK, Feilden H, Hutchinson EJ, Palin R, Prosser,A, Rees DC, Rosair GM, Stevenson D, Tarver GJ, Zhang MQ.Cyclodextrin-derived host molecules as reversal agents for the neuromuscularblocker rocuronium bromide: synthesis and structure-activity relationships.J Med Chem. 2002 Apr 25;45(9):1806-16.

9) Fuchs-Buder T, Mencke T. Use of reversal agents in day care procedures (with special reference to postoperative nausea and vomiting.Eur J Anaesthesiol Suppl. 2001;23:53-9. 10) Berg H, Viby‑Mogensen J, Roed J, et al. Residual neuromuscular block is a risk factor for postoperative pulmonary complications: a prospective, randomised and blinded study of postoperative pulmonary complications after atracurium, vecuronium and pancuronium. Acta Anaesthesiol Scand 1997; 41:1095-1103.

11) Kirkegaard H, Heier T, Caldwell JE.Efficacy of tactile-guided reversal from cisatracurium-induced neuromuscular block.Anesthesiology. 2002 ;96:45-50. 12) Eikermann, M,Groeben H,Husing,J,Peters J. Accelerometry of Adductor Pollicis Muscle Predicts Recovery of Respiratory Function from Neuromuscular Blockade.

Anesthesiology 2003 ;. 98:1333-1337.. 13) Lysakowski C, Fuchs-Buder T, Tassonyi E. Mivacurium or vecuronium for paediatric ENT surgery. Clinical experience and cost analysis.Anaesthesist. 2000 ;49:387-

91. 14)Plaud B, Debaene B, Donati F, The corrugator superciIii, not the orbicularis oculi, reflects rocuronium neuromuscular blockade at the laryngeal adductor muscles.

Anesthesiology 2001; 95:96‑101. 15) Hemmerling TM, Schmidt J, Wolf T, et al. Intramuscular versus surface electromyography of the diaphragm for determining neuromuscular blockade. Anesth Analg 2001; 92:106‑111. 16) Itoh H, Shibata K, Yoshida M, eta], Neuromuscular monitoring at the orbicularis oculi may overestimate the blockade in myasthenic patients. Anesthesiology 2000;

93:1194‑1197. 17)Hemmerling TM, Schmidt J, Hanusa Q et al. Simultaneous determination of neuromuscular block at the larynx, diaphragm, adductor pollicis, orbicularis oculi and

corrugator supercilii muscles. Br J Anaesth 2000;85: 856-860. 18)Hemmerling TM, Schurr C, Walter S, et al. A new method of monitoring the effect of muscle relaxants on laryngeal muscle using surface laryngeal electromyography.

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2001; 48:356‑360. 22)Bellemare F, Couture J, Donati F. Temporal relation between acoustic and force responses at the adductor pollicis during nondepolarizing neuromuscular block.

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Pharmacodynamics of GW280430A:AP dataPharmacodynamics of GW280430A:AP dataBelmont et al.BJA 1999Belmont et al.BJA 1999

onset

25% rec

75% rec

95% rec

0246810121416

02468

10121416

14,6

15,2

12,5

9,3

1,5

11,9

12,2

9,5

7

1,7

9,8

9,9

7,4

4,7

2,6

Legend0,18 mg/kg0,36 mg/kg0,54 mg/kg

New lead-inNew lead-in


Pharmacodynamics of GW 280430A:larynxPharmacodynamics of GW 280430A:larynxBElmont et al BJA 1999BElmont et al BJA 1999

onset

25% rec

75% rec

95% rec

024681012141618

02468

1012141618

1516,1

12,7

9,3

0,9

11,212,9

9,6

7,2

1,1

9,411,3

7,7

5,6

1,6

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