THE PHARMACOLOGICAL ACTIONS OF POLYMETHYLENE BISTRIMETHYLAMMONIUM SALTS (1997)

Since the classical work of Crum Brown and Fraser, the curariform action of many onium salts has been recognized, and other activities exerted by these compounds have been described, such as those commonly called nicotine-like or muscarine-like. In the present paper an account is given of the actions of members of a polymethylene bistrimethylammonium series, whose general formula is (CH3)3 N+(CH2)n N+(CH3)3.2I. The compounds will be referred to by the value of n; thus C10 is the decane derivative, where n = 10. Our attention was drawn to the series during a test of the power of the octamethylene compound to liberate histamine. After the injection of a small dose into a cat, there was no depressor response, such as histamine-liberators cause (Macintosh and Paton, 1949); on the contrary, the blood pressure rose. This rise was evidently asphyxial, since the respiration had simultaneously ceased; but there were no gasps or convulsive movements such as usually accompany asphyxia, and the sequence of events suggested some form of neuromuscular block. This series has also been independently studied by Barlow and Ing, with whom a simultaneous preliminary report was arranged (Barlow and Ing, 1948a; Paton and Zaimis, 1948a), and who have now reported their results more fully (Barlow and Ing, 1948b). Following a further note (Paton and Zaimis, 1948b), preliminary clinical trials of the decane derivative as a substitute for d-tubocurarine chloride in anaesthesia and convulsion therapy were instituted. These have proved successful, and the name “decamethonium iodide” has been approved by the British Pharmacopoeia Commission as the official name for the compound. Our investigations of the pharmacological actions of these compounds have been chiefly directed to studying their activity in blocking neuromuscular transmission. Particular attention has been paid also to describing how the pharmacological activity varies with the length of the polymethylene chain. Later papers will report more fully experiments on other pharmacological actions. Cats anaesthetized with chloralose (80 mg./kg.), after induction with ether, were used in most of the experiments. For recording the tension of muscle twitch, tibialis anterior was prepared; the preparation was mounted on the Brown-Schuster myograph stand, and an isometric steel spring myograph was used for recording on the smoked drum. The muscle was excited either by slightly supra-maximal shocks to the sciatic nerve through shielded silver electrodes, or directly by induction coil break shocks. The nerve was tied centrally, above the point of stimulation and above the point of entry of its blood supply. Injections were made either intravenously through a cannula tied into the femoral or jugular vein, or by the method of close arterial injection into the anterior tibial artery (Brown, 1938a). A few animals were anaesthetized with pentothal infused at a rate of 0.3–0.5 mg./min., or with ether from an “Oxford vaporizer” adapted for animal use, using 6–7 per cent ether. For experiments on unanaesthetized animals, injections of volumes of 0.01 c.c./g. were made into the tail vein of mice (white, male, weight 18–20 g.) and rats (male, weight 100–150 g.). (The effective dose was that the animal on its (male, weight were used for the method and or injections in the and a injections in the were as by In anaesthetized with the of the was on the smoked drum. The was excited to by to the of the and from the in the a rate of stimulation of per a In other the preparation by and was action was on or small in chloride was used as an The in was in to test for nicotine-like stimulation of The was as by and and for the of activity was using a with and or and as of and for or The and were in the of the that into simultaneous with the of the were made for The tension of of the compounds was with a for the tension of of at were on the respiration were at by the of the animal of into a from a was and the pressure by a were made with the respiration by Paton pressure was in the a cannula with and with into the to for recording action from the nerve and tibialis muscle for in experiments. The most activity of series is that by the members in neuromuscular block. the of the injection of a small dose of C10 most compound in on the of tibialis muscle excited through its the tension is and the of the muscle be (The other of the animal also these the tension to with the is the muscle is to stimulation through its is of to stimulation of of tibialis excited by shocks to the sciatic nerve C10 and to chloride intravenously C10 C10 nerve injection of C10 stimulation of the of such a the action of the nerve to tibialis the muscle action and tension and The of be in the or in the nerve to sciatic nerve of action of nerve by after and of action of tibialis after = as in muscle action after for such a be of the of by the nerve as has been for and suggested for (Brown, have that the of given by close arterial injection as as more the of a nerve by a dose of as by A of the to is in nerve injections of C10 nerve shocks at at The blocking action of C10 be by an with of The was on the blood the there was no depressor activity in the stimulation of the nerve at a rate of per for the of depressor in a to per in the and the activity of depressor was by the injection of into the was by C10 to the to a of The and the of the neuromuscular to test these compounds for since and experiments in that C10 and its some activity of work that action a in these such a is The of the be and is with of such that the neuromuscular is small to the such an a of the tension be the that C10 has been was to test the neuromuscular be since these compounds onium salts and have there is no to a Since the is there is no to action such as that to the that be was directly in in the tibialis anterior muscle of a was and in with a of activity or nerve shocks C10 The dose was given is and that and other cause neuromuscular has been to the of an of in the of the neuromuscular such the of a or the close arterial injection of the for the and have used as a test of the of the by and that there is no such action by a or by injection of on the of a muscle with and has been that be to from the that a had been or an injection of the by in was to of C10 from the the rate of stimulation and the of the block. with a dose of C10 after a is that to C10 is the of the of at the to the of some of to those from injections of and but is that some of the a by their Our experiments in also that a muscle a at a with the tension with is that the muscle experiments on will be reported In the anaesthetized cat, the or of tibialis that an dose of of C10 usually to in and is in a tension the be for a few of the the to the The of the is for some after the tension has to since the dose given after the injection a with of of and be for many the commonly a of the with the of Our also that C10 has a a dose of was on tension in an animal in a block. to from a C10 is chloride in a of action for a given action and in the of its in unanaesthetized and in animals, after a dose of C10 to in d-tubocurarine chloride has a more In the the is the and with effective C10 has a of action to that of d-tubocurarine have given C10 by other in a few experiments. by C10 is in and in the effective but a dose of a be in an animal for The an or more to the in the the dose is for and the for for slightly and the of is have studied the for by the in and the is the of an in the was simultaneously with the of the tibialis muscle to nerve shocks. the muscle was the was but slightly This has been a and an in the has been a of the of of the muscle has been of of be but is how of respiration of the muscle of respiration and of nerve shocks C10 d-tubocurarine chloride In is also the of a with d-tubocurarine In to was with an on the tibialis Our has been of that with d-tubocurarine or of the tibialis The the in that will be reported more fully most of experiments were made with anaesthetized with have also used ether and pentothal In the with pentothal C10 to be more effective with for of the tibialis twitch, respiration was slightly with the above preliminary or were ether per on the other C10 was effective with and the fully dose of C10 from to in of the and were with of respiration was in the animal anaesthetized with were as with d-tubocurarine the of ether be to those of a dose of d-tubocurarine to the of these compounds at to the of a with For the of the experiments of were used with the in more in with for d-tubocurarine experiments on a few of the compounds that in the method of for a small of the as a that dose after injection by the into unanaesthetized animals, of the to in the In was close to the dose to the tension of tibialis by per cent in the animal anaesthetized with in was per cent the dose and was per cent the in mice and The for were of those for on some preliminary trials Paton, and Zaimis, and the dose that made the to or or of their the activity of C10 in the is to of its in these and in The results of on also but be that the of injection used was from that in the other of of bistrimethylammonium with length of polymethylene and of d-tubocurarine of in chain. dose in of the to has been The actions of these on also in the of the and In the the of was an to the above the after of and of the and with was the to In the more and and to but an and was the of the for as the the of after an in of the further of the and The was of C10 to weight was from a and was to be After the injection of C10 at a rate of mg./min., after had been by respiration was of of of and of the C10 was the most of the series by test for neuromuscular block. in general in The of the to for the polymethylene from to more of the series from the that activities were The of in in the of and the of the with of Since and for neuromuscular is that the other pharmacological actions of the series in an with the members of the series in neuromuscular block. A point of in the activity of to these A dose of intravenously into a an on tibialis with that of of This is that of and to neuromuscular in of Our results with and that and or more in Our to the of these on the tibialis was that C10 was effective d-tubocurarine chloride had been given and point on also be on the and a is in In the preliminary dose of was such as of the a dose of C10 was to The of C10 its the of d-tubocurarine but to a to the the injections This of d-tubocurarine chloride is in the for an and in the for a The of the and its as the dose is In the and by C10 These actions to d-tubocurarine have also with its ether, and with and on the neuromuscular to C10 and its the of to such in the tibialis is an of an effective by a dose to d-tubocurarine (The of to C10 by in was at other but was with the a dose of per the of d-tubocurarine chloride from to in the dose of C10 from nerve shocks nerve shocks d-tubocurarine chloride on the in C10 a that members of the series, in neuromuscular and in a action of and were effective in This suggested that such also at the neuromuscular a of an to test the point on the tibialis with that was the results of a with using the also that has no action to d-tubocurarine chloride but its action The action of is to some by their action and with there is no that a of blood pressure is to of This the of neuromuscular is during a to A action be in and where the dose of is that of the dose of and these of from is and to is the tibialis a of to C10 is usually and be for a The action of is by the dose of and the of neuromuscular be by further of there is a to and with of more from neuromuscular be after of C10 is to as is effective after of has been to the neuromuscular to and have a to C10 will be that there is no the dose is given to the to a of the to be A few after the injection of of into a that its and and have the of and to cause a of blood The of these that these compounds The for will be in For the present to the experiments made to the of and its in The excited to a by stimulation of the at a of shocks per a test for activity of these compounds on in the a in and and were a of those of these compounds and of of the was a and and in their of the more and their action to as as the for of of excited by stimulation of of and test the on used the of by and and the of the compounds was by the with be that and were more in their action of length and by rise of pressure of to and d-tubocurarine The injection of or in commonly a of blood pressure of and The of the was to the blood pressure A was made for stimulation of by these of the series, a of the blood pressure or of rate of the in those of or for more a of the In the there was a for the members to but action was and be to their was at that be to on the an by C10 of the of to that exerted by d-tubocurarine was that C10 the to in or and to or for no of other activity from usually its of The by C10 and its in from that by has a and a after C10 has been a is to to that of and in that its action is also by d-tubocurarine chloride and by of by of to by and were made of the of the members of the series with to other and to of the the above that the in were an action on the since the by the compounds The to C10 was a with by the of the members per cent of was also that and the by of to C10 by and The stimulation of muscle also be in the and In these experiments a few of C10 were into the artery of a tibialis for close arterial during an of as after a injection of there was a of the muscle the injection as to with After the is there is a small for a few is by the of neuromuscular block. the dose of C10 to a of the muscle is a neuromuscular in and a to be with dose by to of stimulation by the injection After injections of C10 have the but a small of a few with other members of the series has been in experiments with the of in on activity was by in to the activities of the compounds the and For the and were for the and as of The compounds had activity and was to their actions at The in the members had and were made to be to the of per cent of the for of the series is given in and has been in for in is more C10 of activity of bistrimethylammonium compounds with length of polymethylene chain. of in polymethylene chain. for per cent of the A point of some is the of no is a of the the of is by be that C10 is more and have referred to the of the during the of a by of the muscle action of the in to to that for and The be that in as an more effective of its of for in is also that the action of C10 on the muscle be into account in the of the twitch, and Zaimis, has a and was of to these compounds also such activity as is and be on the or the most compound was in a of in the to these depressor action be these compounds were on the blood pressure in to the of the A depressor action of histamine-liberators is was also made for an with the of the blood pressure to as a test A dose of C10 the action of but that the action of C10 be a The was in an that of be C10 was but was to of the to by the injection of a on the The of the by in the was by the or of C10 to a of a to cause a of the to the C10 was made at the of paper that series is in the depressor of the blood of This be and a of the action of with by d-tubocurarine chloride and for and Paton, have studied activity since is with that in neuromuscular transmission. that is a more C10 in d-tubocurarine chloride was intravenously in a dose of into of and in a dose of into of a for a of to and a there was no in to the at other a The through the injections were made the in cat, of the in and the animals their weight and and cat, after a injection of their of was be that is to animals for respiration was as as to at a that an of was in animal those of the In the other animals there were no of was into the vein of of in a dose of a for a This dose is more a the dose is effective in of the was but there was no in or weight of the animals, and was in of the animals to the injections into vein given these compounds be of the for compound in of and was no either of these or of other action be to the of these were from small and and In the and of the was with small of These were also in animals, and were as of but no other after other during of in and of other after and other and of of by other after injection of The an of of and accompany many of the of and the of in the to blood to or to is other there was no to that series of compounds an of to how activity varies with the length of the polymethylene chain. to for for the of the compounds in at of and The activity is from to and is with with the the activity is of The of pharmacological action with polymethylene length these compounds the as to how be to in the of to in the The of tension at an a method for studying the for the of the tension of by members of the series, in of most of the compounds there was of the tension of the and a was with was to the for the was to a the of tension with for many was with of The of tension is to some an after had from the but to be per cent of the from these that to in activity to in pharmacological actions of members of the most of the members of series, and of was the in their activity to the of animal on were a is and in the with d-tubocurarine of has been for many other onium but its for to a compound of activity in the to be of activity in the few The in the to the to in that and mice and rats in to a in the of these is that those with in be to since be to such onium been and have no of to the of there to be no of the its of be made with more with of be to that the with and with of will be to be that the test used to the The of C10 a for experiments on at an in since trials have that of the the most Paton, and Zaimis, The of be as is a to the action of compound by a but These and the other have of by For the of to of C10 is as to to a of to C10 for to neuromuscular of is to be a in the of neuromuscular block. have in for will be from that of for most but for those neuromuscular in the as have the of the reported in in the activities of the members of the series there their to their is no in the of the for activity on the the on the of but is that the of the at with the of the of the tension of of the of the pharmacological actions of the bistrimethylammonium of in polymethylene chain. of with These results be as for pharmacological for action at for neuromuscular blocking action at and a for stimulation of and activity These and to The of these to is that in the of compounds of length whose activities and in those of the salts by a is and in other has been with that the members = or of and the members = or activity but for and and Paton that the with n = had a and depressor on the blood of the and of the the other as the length of these salts of the salts have by their activity in the tension of more is that activity to at the point at in pharmacological activity on and that the an in activity as the compounds to an and a in activity as the of the to the action of the compound. The of a as series at directly the in for the recognized, and the activity and is by and In a is the at at a point where in activity the rate of of with is the in the of length by a in by a of is of that the the in C10 as in d-tubocurarine chloride and in compounds and the C10 and these be is for activity at the neuromuscular n = is for by (Macintosh and Paton, and is the most of its series in The of the the as to the length of the polymethylene be and be C10 is at more in neuromuscular or salts and to that of C10 the of the in the is that the other to since is to that the is on some is to the that the of the activity of the series to some the and its is to that the effective the the of for some of of the to the of some or to the in a of A on a an of the a the of the at with its at and from for a the length be to the a at be to a with its of to the for but is such compounds to the and by the activities of and will be referred to in is that C10 and and of the of activities in neuromuscular and block. A dose of C10 more a that for neuromuscular to the a dose of more a that for to the neuromuscular In the to since of the compounds studied is the most as a neuromuscular blocking but have no to and to the that its in the The experiments have that C10 those as d-tubocurarine neuromuscular and the muscle to to the of a close arterial injection of with the of from these there to be to in some These more those d-tubocurarine its ether or other and the compounds studied by and these there in in of in activity in in or in from these also and there no that the of action of these compounds in actions in neuromuscular those of into the that by with the at the nerve for on the This is for the of its be suggested that is C10 the the but the of C10 as an and the of action by C10 to that of d-tubocurarine that more a small of the is by the of C10 the other is a in a of a C10 for with and with C10 for the be to with and a blocking action at the given in a dose effective in in by the of the of be with a of the action of in the of C10 to in those in is with the that is an to C10 muscle and neuromuscular that the of C10 is that of an with but that is in some at the neuromuscular have the in a in has been by its to of its is of the muscle that a is of to fully of be to some by d-tubocurarine chloride has been but also the that the by C10 is at some other of the that at d-tubocurarine chloride block. The the compounds the the of the of d-tubocurarine chloride to and of the of C10 to the to d-tubocurarine is to account for these on the that the compounds at the The have that C10 neuromuscular by some in the or muscle and that at a of the from that by d-tubocurarine of the suggested been as a of the muscle (Brown, Paton, and 1949); and an of C10 from have in The of to the neuromuscular to be at the to no more attention to the the and to the of a in their of be the in the and The to a is Paton, as a to and stimulation of to be of and to and to on to be of d-tubocurarine of the compounds studied cause neuromuscular and its and with with that of and its the other of d-tubocurarine the and many of the compounds studied by and d-tubocurarine is and that is also compounds of on the on the compounds The pharmacological of a series of polymethylene with and in the polymethylene have been The decane derivative neuromuscular in the in of and is the most of the series in such the of nerve and muscle is the of and by nerve is of the nerve or injection of or the block. A of of the muscle twitch, of the and to nerve the block. a of the muscle to a In the cat, neuromuscular of the tibialis muscle be by of d-tubocurarine chloride or of C10 is by by activity in anaesthetized with chloralose or pentothal is to that in the unanaesthetized but ether to to C10 varies with in of the series is For d-tubocurarine chloride by the the in is and The action of C10 is by The and effective the to be by of d-tubocurarine chloride also the of C10 and its a of the and the by and such a but the actions of C10 and of C10 also a of tibialis muscle a small dose is given by close arterial of the series, and to transmission. members a is more also a a power of and a or to was the of members of the series activity in the tension of The pharmacological of the series have been to the length of the polymethylene chain. This a for in at a for in neuromuscular at a for stimulation of and activity a rise in activity and activity and at The of the of the of for of the of activity with length of polymethylene and of the C10 and d-tubocurarine chloride is is a to to for and and to for many and also to for on to for in these and to for the