Methonium Compounds Research Articles

The channel‐blocking action of methonium compounds on rat submandibular ganglion cells

The channel‐blocking action of methonium compounds on rat submandibular ganglion cells

Curare-like action of polymethylene bis-quaternary ammonium salts. 1948.

Curare-like action of polymethylene bis-quaternary ammonium salts. 1948.

The channel‐blocking action of methonium compounds on rat submandibular ganglion cells

The effects of drugs of the polymethylene bis‐trimethylammonium (methonium) series on the characteristics of the synaptic currents (e.s.cs) recorded from voltage‐clamped rat submandibular ganglion cells have been studied. The drugs studied were from C4 to C10 (decamethonium). All of the drugs except C4 shortened the initial decay phase of the e.s.c.; C9 and C10 produced an additional slowly decaying component. These effects were interpreted in terms of an open channel block mechanism, the calculated rate constants for association with the open channel at − 80 mV being fairly similar (5.9 × 106 to 18.1 × 106M−1 s−1) for all of the compounds except C4, which had no effect on the e.s.c. decay. All of the compounds produced use‐dependent block when tested with short trains of stimuli at 10 Hz, or with trains of ionophoretic pulses of acetylcholine, consistent with their channel blocking property. Tubocurarine had a similar effect, but not trimetaphan or mecamylamine. Recovery from use‐dependent block with short chain methonium compounds, up to C8, was very slow in the absence of agonist, being incomplete even after several minutes. With C9 or C10 or tubocurarine, recovery from use‐dependent block was complete within a few seconds. With C6 recovery in the absence of agonist was unaffected by membrane potential, but could be accelerated by applying acetylcholine with the cell depolarized to − 40 mV. This persistent block was ascribed to the ability of the blocking molecule to become trapped by closure of the channel. With C9 and C10 it is assumed that their presence inhibits channel closure, so they can escape without the help of agonist. When use‐dependent block is avoided by leaving the ganglion unstimulated during equilibration with the blocking drug, the first e.s.c. elicited shows no appreciable reduction of amplitude, though with C6, C7 or C8 subsequent responses elicited at 0.1 Hz become progressively more blocked. Even at 1 Mm, C6 does not prevent acetylcholine from opening ionic channels. It is concluded that all of the effects on e.s.c. amplitude can be interpreted in terms of channel block, there being no evidence of any receptor blocking action.

Harold King

Harold King was an analytical chemist of distinction, who worked with Sir Henry Dale and his colleagues in the Medical Research Institute, later the Medical Research Council. He helped to quash the theory that the anaesthetic action of ether was attributable to its impurities. Interest in alkaloids led to the elucidation of the structure of hyoscine, the synthesis of muscarine and the first isolation of crystalline tubocurarine for which he proposed a structural formula, work which influenced Bovet in the synthesis of gallamine. He proposed the synthesis of the homologous series of methonium compounds which included relaxant and hypotensive drugs. His collaboration with Rosenheim was outstanding and opened the way for synthesis of cholesterol and the steroids. He was always encouraging clinicians, and gave a sample of tubocurarine to Ranyard West who was the first to inject d-tubocurarine into a human patient.

The channel-blocking action of methonium compounds on rat submandibular ganglion cells.

The effects of drugs of the polymethylene bis-trimethylammonium (methonium) series on the characteristics of the synaptic currents (e.s.cs) recorded from voltage-clamped rat submandibular ganglion cells have been studied. The drugs studied were from C4 to C10 (decamethonium). All of the drugs except C4 shortened the initial decay phase of the e.s.c.; C9 and C10 produced an additional slowly decaying component. These effects were interpreted in terms of an open channel block mechanism, the calculated rate constants for association with the open channel at -80 mV being fairly similar (5.9 X 10(6) to 18.1 X 10(6)M-1S-1) for all of the compounds except C4, which had no effect on the e.s.c. decay. All of the compounds produced use-dependent block when tested with short trains of stimuli at 10 Hz, or with trains of ionophoretic pulses of acetylcholine, consistent with their channel blocking property. Tubocurarine had a similar effect, but not trimetaphan or mecamylamine. Recovery from use-dependent block with short chain methonium compounds, up to C8, was very slow in the absence of agonist, being incomplete even after several minutes. With C9 or C10 or tubocurarine, recovery from use-dependent block was complete within a few seconds. With C6 recovery in the absence of agonist was unaffected by membrane potential, but could be accelerated by applying acetylcholine with the cell depolarized to -40 mV. This persistent block was ascribed to the ability of the blocking molecule to become trapped by closure of the channel. With C9 and C10 it is assumed that their presence inhibits channel closure, so they can escape without the help of agonist. When use-dependent block is avoided by leaving the ganglion unstimulated during equilibration with the blocking drug, the first e.s.c. elicited shows no appreciable reduction of amplitude, though with C6, C7 or C8 subsequent responses elicited at 0.1 Hz become progressively more blocked. Even at 1 mM, C6 does not prevent acetylcholine from opening ionic channels. It is concluded that all of the effects on e.s.c. amplitude can be interpreted in terms of channel block, there being no evidence of any receptor blocking action.

The uptake of methonium compounds by isolated slices of rat cerebral cortex.

Abstract— The uptakes of a series of methonium compounds, C2, C4, C6, C7, C8, C9 and C10, by isolated slices of rat cerebral cortex were measured.Analyses of the kinetics of uptake of C7, C8, C9 and C10 indicate that their initial influxes consist of two components. A Michaelis‐Menten type uptake by carrier can account for the saturable fraction. C7 had the lowest affinity for the carrier, with values increasing for C8, C9 and C10, while C10 had the smallest maximum influx with values increasing for C9, C8 and C7. The unsaturable fraction corresponded to the slow continuous swelling of the tissue.The uptake of C8 was inhibited by other methonium compounds, choline, ACh, physostigmine, ouabain and morphine. C8 could be counter‐transported by C7.There is evidence that the main driving force for uptake is the transmembrane potential, but the steric factor may be a restricting influence.

SOME EFFECTS OF ALTERING ONIUM SUBSTITUENTS ON THE INTERNITROGEN DISTANCE IN GANGLIONIC AND NEUROMUSCULAR BLOCKING AGENTS.

Abstract The conductances of butaethonium chloride and bromide, hexaethonium chloride and bromide, and hexadecaethonium iodide have been measured in water at 25°. The limiting equivalent cationic conductances have been interpreted to give a measure of the internitrogen distances, which are larger than in the corresponding methonium compounds, being 5.7–6.7 Å for butaethonium, 6.5–8.7 Å for hexaethonium, and 13.6–14.9 Å for hexadecaethonium. The changes of potency observed on changing the onium substituents are attributed to changes in internitrogen distance and of molecular geometry.

N-Methylation of Nicotine and Cotinine in Vivo

In studies on the metabolism of randomly labeled ( -)-nicotine-C4 in the anesthetized dog, it has been observed (2, 3) that the major part of the administered radioactivity, approximately 80 to 90$&, appears in the urine. Approximately one-tenth of this radioactivity is present as nicotine. From various experiments in which unlabeled (-)-nicotine and one of its metabolites, (-)-cotinine, have been employed (4-7), it can be deduced that another fraction, approximately one-third, is composed of derivatives of nicotine in which the pyrrolidine ring has undergone fragmentation or oxidative changes. Since N-demethylation of (-)-nicotine leads to carbon dioxide (8), and loss of 2 of the 4 carbon atoms of the pyrrolidine ring leads to 3-pyridylacetic acid (2), many of the urinary metabolites lack unique features and possess only those that are common to the metabolism of 1 and 2 carbon compounds. Indeed, radioactive urea is one of the products of the metabolism of nicotine-methyl-Cl4 in the rat (8). Our attention, therefore, has been directed to metabolites in which the pyridine ring remains intact. During the separation of urinary metabolites arising from randomly labeled ( -)-nicotine-Cl4 administered to the dog, it was observed (2) that the major portion (essentially 95%) of the radioactivity of the urine was retained on Dowex 50 (H+). An exhaustive elution with 4 M ammonia served to remove 65% of the activity from t,he column. Further quantities of radioactivity were removed (1) by elution with strong hydrochloric acid. The material so obtained had properties consistent with those of a strong base. Quaternary ammonium compounds derived from methylation of the pyridine ring of nicotine and its metabolites were at once suggested. The present report describes the isolation and identification of the methonium compounds formed by the biological methylation of the pyridine rings of (-)-nicotine and ( -)-cotinine in oivo.

CURARE-LIKE ACTION OF POLYMETHYLENE BIS-QUATERNARY AMMONIUM SALTS

CURARE-LIKE ACTION OF POLYMETHYLENE BIS-QUATERNARY AMMONIUM SALTS

PARALYTIC ILEUS SIMULATING ACUTE INTESTINAL OBSTRUCTION DUE TO PENTOLINIUM TARTRATE (ANSOLYSEN)

Case Reports1 February 1961PARALYTIC ILEUS SIMULATING ACUTE INTESTINAL OBSTRUCTION DUE TO PENTOLINIUM TARTRATE (ANSOLYSEN)KENNETH L. BECKER, ALTON I. SUTNICKKENNETH L. BECKERSearch for more papers by this author, ALTON I. SUTNICKSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-54-2-313 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptIn recent years pentolinium tartrate has become one of the most widely used drugs in the treatment of severe hypertension. The case described below illustrates dramatically a side effect of this drug, ileus mimicking acute intestinal obstruction, a result of pentolinium-induced parasympatholysis.CASE REPORTThe patient was a 58-year-old white retired Army officer with known hypertension of eight years' duration. Two years prior to admission he had noticed the onset of intermittent claudication, occasional nosebleeds, dyspnea on effort, orthopnea, and occasional angina. At one time he experienced a sudden coldness of his left leg lasting several hours. He had nocturia...Bibliography1. FreisPartenopeLilienfieldRose EDEALSJC: A clinical appraisal of pentapyrrolidinium (M&B 2050) in hypertensive patients. Circulation 9: 540, (Apr.) 1954. CrossrefMedlineGoogle Scholar2. Schroeder HA: Hypertensive vascular disease: therapy with modern drugs and its limits. J. Chron. Dis. 1: 497 (May) 1955. CrossrefMedlineGoogle Scholar3. Sheldon MB: The status of present-day drug therapy of hypertension. Amer. Practit. 7: 33 (Jan.) 1956. Google Scholar4. GunnCooke JAAM: Pilocarpine as an antagonist to the undesired effects of ganglion-blocking agents in the treatment of hypertension. Brit. Med. J. 1: 1473 (June 26) 1954. CrossrefMedlineGoogle Scholar5. WaldmanPelner SL: Treatment of the ambulatory hypertensive patient with pentolinium tartrate. Amer. J. Med. Sci. 231: 140 (Feb.) 1956. CrossrefMedlineGoogle Scholar6. GiffordAllenBirkhead RWEVNC: Pentapyrrolidinium observations. Proc. Mayo Clin. 29: 496 (Sept. 1) 1954. MedlineGoogle Scholar7. Gibson DS: A case of intestinal obstruction following the administration of pentapyrrolidinium bitartrate ("Ansolysen"), Med. J. Aust. 2: 860, 1957. CrossrefGoogle Scholar8. EttmanBouchillonHalford IKCDHH: Gastrointestinal roentgen findings due to untoward effects of hexamethonium. Radiology 68: 673 (May) 1957. CrossrefMedlineGoogle Scholar9. Goldstone B: Death associated with methonium treatment. S. Afr. Med. J. 26: 552 (July) 1952. MedlineGoogle Scholar10. ThomasWilliams OMRG: Paralytic ileus after hexamethonium. Brit. Med. J. 1: 1331 (June 9) 1951. CrossrefGoogle Scholar11. BourneHosford GJ: Methonium compounds in hypertension; letter to the editor. Lancet 1: 527 (Mar. 3) 1951. CrossrefGoogle Scholar12. Goldsmith HJ: Death from hexamethonium ileus. Brit. Med. J. 1: 522 (Feb. 26) 1955. CrossrefMedlineGoogle Scholar13. LyonsLord WGPJ: Paralytic ileus after hexamethonium. Brit. Med. J. 2: 176 (July 21) 1951. CrossrefGoogle Scholar14. GrantBoyd APJS: Mecamylamine ileus as a surgical emergency. Lancet 1: 713 (Apr. 6) 1957. CrossrefGoogle Scholar15. McCallaCreechFord LHORV: Hexamethonium ileus. Amer. Surg. 19: 115 (Feb.) 1953. MedlineGoogle Scholar16. FurstePhelpsTaylor WDP: Antihypertensive drugs as a cause of the acute abdomen. J. A. M. A. 166: 2111 (Apr. 26) 1958. CrossrefMedlineGoogle Scholar17. Waldron JF: Ileus due to mecamylamine hydrochloride simulating an acute surgical condition of the abdomen. Minnesota Med. 41: 499 (July) 1958. Google Scholar18. Estes JE: Hypertension in 1958: a tale of pills, philosophy, and perplexity. Med. Clin. N. Amer. 42: 899-915, 1958. CrossrefMedlineGoogle Scholar19. MackeyShaw WAGB: Paralytic ileus after hexamethonium. Brit. Med. J. 1: 1205 (May 26) 1951. CrossrefGoogle Scholar20. FreisWilson EDIM: Mecamylamine, a new, orally effective, hypotensive agent. Arch. Intern. Med. 97: 551 (May) 1956. CrossrefGoogle Scholar21. FreisFinnertySchnaperJohnson EDRAHWRL: The treatment of hypertension with hexamethonium. Circulation 5: 20 (Jan.) 1952. CrossrefMedlineGoogle Scholar22. FreisWilsonParrish EDIMAE: Enhancement of antihypertensive activity with chlorothiazide. Circulation 16: 882 (Nov.) 1957. Google Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: *Received for publication September 17, 1959.†From 196th Station Hospital, Neuilly-sur-Seine, Paris, France.Requests for reprints should be addressed to Kenneth L. Becker, M.D., 427 Seventh Avenue, Southwest, Rochester, Minnesota. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byThe radiology of drug-induced disorders in the gastrointestinal tractNeuromuscular Disease of the Gastrointestinal TractChronic Intestinal Pseudo-Obstruction SyndromesPhenothiazine effect on gastrointestinal tract functionChronic intestinal pseudoobstructionMegacolon associated with administration of an anticholinergic drug in a patient with ulcerative colitisPostoperative Intestinal Obstruction 1 February 1961Volume 54, Issue 2Page: 313-319KeywordsConstipationDiarrheaDrugsDyspneaElectrocardiographyHypertensionHypotensionIntoxicationNauseaUrea ePublished: 1 December 2008 Issue Published: 1 February 1961 PDF downloadLoading ...

Sympathetic blockade in treatment of hypertension. Clinical trial of bretylium tosylate.

Ten years ago, in papers on medical sympathectomy and the clinical use of methonium compounds, early experience in this unit with ganglion-blocking drugs was recorded (Turner, 1950, 1951). Recently the indications for treatment, method of administration, and the problems of tolerance and side-effects were reviewed (Turner, 1959). At an early stage it was decided that to initiate life long treatment with potent and potentially dangerous drugs was a major decision and that it was best first to make a detailed and standardized assessment of each patient in hospital. If treatment was indicated we tried to achieve a steady state with the appropriate drug, and then further treatment was supervised on a long-term basis in a special clinic organized for the purpose. This procedure has helped to ensure the proper and uniform selection of patients suitable for treatment, has facili tated the maintenance of good control over the blood pressure as well as the collection and correlation of data, and has made possible comparative assessments of different drugs. Numerous ganglion-blocking agents have been investigated, all potent in lowering the blood pressure, but none free from difficulties of administra tion, particularly as regards tolerance and side-effects. None, in fact, has been satisfactory. Although the blood-pressure can be reduced to almost any desired level this can rarely be achieved without troublesome side-effects from concomitant parasympa thetic blockade. Some improvement results from combining the ganglion-blocking drug with chloro thiazide or rauwolfia, but in some degree most patients complain of constipation, dryness of the mouth, diffi culty with accommodation, delay in micturition, or impotence. In many individuals these effects are asso ciated with a feeling of general malaise. Because of all this, physicians have looked forward to the day when research workers would be rewarded by the finding of a compound with selective blocking action on the sympathetic nervous system. Recently, in the laboratories of the Wellcome Founda tion in England and the Ciba Foundation in Switzer land, compounds have been isolated which do selectively block the peripheral sympathetic nervous system by accumulating in sympathetic ganglia and post-ganglionic fibres. The first of these has been given the name of bretylium tosylate ( darenthin ), and has the formula N-o-bromobenzyl-N-ethyl : N : N-dimethylammonium p toluenesulphonate. The second substance has been given the name of guanethidine ( ismelin ) and has the formula 2-(octahydro-L-azocinyl-ethyl) guanidine sulphate. This paper is principally concerned with a clinical trial of bretylium, which we have used for 15 months in the treatment of 43 patients with hypertension.

Treatment of severe arterial hypertension: results from long-term use of methonium compounds with and without the addition of reserpine.

Australasian Annals of MedicineVolume 5, Issue 4 p. 274-290 Article TREATMENT OF SEVERE ARTERIAL HYPERTENSION RESULTS FROM LONG-TERM USE OF METHONIUM COMPOUNDS WITH AND WITHOUT THE ADDITION OF RESERPINE A. J. BARNETT, A. J. BARNETT From the Baker Medical Research Institute and Alfred Hospital Clinical Research Unit, Melbourne, AustraliaAssociate Director, Clinical Research Unit, Alfred Hospital.Search for more papers by this author A. J. BARNETT, A. J. BARNETT From the Baker Medical Research Institute and Alfred Hospital Clinical Research Unit, Melbourne, AustraliaAssociate Director, Clinical Research Unit, Alfred Hospital.Search for more papers by this author First published: November 1956 https://doi.org/10.1111/imj.1956.5.4.274Citations: 5 AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume5, Issue4November 1956Pages 274-290 RelatedInformation

Management of the patient with primary (essential) hypertension

The blood pressure of many patients with primary hypertension may be lowered by low-sodium diets, antihypertensive drugs, or sympathectomy. Some of these patients treated with such measures are benefited. The physician must base and evaluate his treatment on an understanding of the natural history of primary hypertension in untreated patients. The possible benefits of treatment must be weighed against the disadvantages and dangers peculiar to each regimen in the various stages of the disease. The choice of treatment represents an experiment in each patient. Neither the antihypertensive effect nor the disadvantageous effects of any treatment can be predicted with confidence before trial in the individual. The choice of which agent to try first is made principally on an evaluation of the rapidity of progression of the disease process and on the patient's ability and willingness to follow the necessary regimen. Emphasis is placed on avoiding, when possible, the more complex and hazardous forms of therapy until the simpler and less hazardous ones have been found inadequate. Current experience permits certain generalizations: 1. 1. No specific treatment other than education is recommended for the patient in the asymptomatic uncomplicated phase. Symptoms, in the absence of demonstrable organ involvement, are treated conservatively. The alkaloids of Rauwolfia are sometimes useful. 2. 2. Progression of essential hypertension into the complicated phase implies the existence of atherosclerosis. All induced reductions in blood pressure in such patients carry the risk of significant local alterations in arterial blood supply. Changes are therefore made as slowly as possible. 3. 3. In the complicated phase of essential hypertension, even asymptomatic cardiac enlargement or any degree of decompensation justifies an attempt to lower the blood pressure. The possible hazards of the various forms of treatment and of lowered pressure are a limiting factor. 4. 4. Renal damage, without uremia, is considered an indication for antihypertensive therapy; the potential benefit far outweighs the disadvantages of treatment. The rate of progression of the disease determines the choice of therapeutic agents and the rapidity of pressure change desired. 5. 5. Acute hypertensive encephalopathic crises call for immediate lowering of the blood pressure by parenterally administered methonium compounds, if the facilities for their controlled administration are available. 6. 6. The value of prolonged antihypertensive therapy for most patients with cerebral damage has not been demonstrated. It is now sometimes possible to help patients with hypertension. It is more possible than ever before to hurt them.

Development of tolerance to ganglion blockade by methonium compounds.

THE clinical observation that tolerance follows the repeated administration of hexamethonium salts was reported by Smirk and others1 ; and Smirk2 has reported that the tolerance to hexamethonium salts was effective also in reducing the effects of other methonium salts. No reports concerning similar phenomena in animals have been found, and I have not found published observations as to the mechanism whereby tolerance occurs. This preliminary report is concerned with the mechanism by which tolerance is developed to the ganglion-blocking action of methonium salts.

METHONIUM COMPOUNDS IN THE ANGINA OF HYPERTENSION

METHONIUM COMPOUNDS IN THE ANGINA OF HYPERTENSION

The structure of the active surface of serum cholinesterase

1. 1. Purified human serum cholinesterase combines in its active surface an anionic and an esteratic site, similar to true cholinesterase. The differences between the two types of cholinesterases can be ascribed to a) the presence of at least two negative sites in the true enzyme, b) the lack of spatial restrictions around the active center of the serum enzyme. 2. 2. Methonium compounds show quantitative differences in their inhibitory power towards the two enzymes. The lower members, C 5 and C 6, are active only against the serum enzyme, the higher ones, e.g. C 10, also against true cholinesterase. These differences suggest an explanation of the curious “localization” of the pharmacological effects of lower and higher methonium compounds. 3. 3. The results indicate that serum cholinesterase behaves principally similar to the true enzyme and thus can play a similar role in nerve conduction, although it participates probably only in relatively slow conductive processes.

The management of malignant hypertension.

Excerpt INTRODUCTION Hypertension varies strikingly in its clinical course. One of the unexplained vagaries of this condition is the fact that in some instances the disease may be most benign, with...

Ganglionic Blockade with Methonium Compounds

Ganglionic Blockade with Methonium Compounds

Electrocardiographic changes in hypertension treated by methonium compounds

Serial electrocardiograms recorded before and after treatment with the methonium compounds in seventy-five patients suffering from arterial hypertension have been examined. Electrocardiographic appearances consisting of S-T and T-wave changes and increased voltage in leads influenced mainly by the left ventricle improved progressively during the time that treatment was maintained, all abnormal electrocardiograms improving after treatment for a year or more. Electrocardiograms from fifty-four patients with S-T or T-wave abnormalities showed a return to normal in twenty-six patients and a return toward normality in twenty. Electrocardiograms from fifty patients with abnormally high QRS voltage showed a return to normal in thirty-two and a return in the direction of normal in six. Improvements in the electrocardiogram appeared to be directly related to the degree of control of blood pressure achieved.

Postural Ischaemia and the Use of the Methonium Compounds.

Postural Ischaemia and the Use of the Methonium Compounds.