mAChR/muscarinic acetycholine receptors

The pharmacokinetic experiments show that absorption of diphemanil methylsulphate is slow (tmax = 2 to 4 h), the mean half-life is 8.35 h, and the amount of the drug recovered in urine within 48 h ranges from 0.6 to 7.4% of the administered dose. Poorly absorbed from the gastrointestinal tract with an absolute bioavailability of 15 to 25%.

Parenterally administered diphemanil methylsulfate, a quarternary ammonium compound with both parasympatholytic and direct bronchial smooth muscle relaxing properties, has been found effective in the treatment of bronchial asthma. The present study was undertaken to test the effectiveness of inhaled diphemanil in preventing histamine induced bronchoconstriction in asymptomatic adult asthmatics. Twenty subjects, aged 19-40 years (average 25) were studied, each on three different days, observing an interval of at least 70 hours between testing. On day one, airway sensitivity to inhaled histamine was determined. On days two and three, histamine challenge was repeated 20 minutes after inhalation of either diphemanil (2 mg) or its vehicle in a double-blind crossover design. Airway sensitivity was assessed by determining cumulative log dose units of inhaled histamine required to provoke a 20% decline in FEV1 (log PD20 - FEV1). Diphemanil did not prevent histamine induced bronchoconstriction nor did it significantly affect log PD20 - FEV1 (p = 0.59). We conclude that a 2 mg dose of diphemanil, administered by oral inhalation 20 minutes before histamine challenge, is ineffective in protecting against induced bronchospasm in asymptomatic adult asthmatics.[1]

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Five infants aged 35 to 109 days (mean: 62 +/- 28) and weighing 3.5 to 5.3 kg (mean: 4.3) were included in the study with the formal consent of their parents. All suffered from vagal hyperreactivity. The sixth younger full-term infant was aged 10 days and weighed 4 kg. They were given a single dose (3 mg/kg) of diphemanil methylsulfate orally, after a minimal fast of 4 hours. Blood samples were collected at T0 and 3, 6, 8, 12 and 24 hours after administration. Urines were also collected from 1 hour before drug administration to 24 hours after. Plasma concentrations of diphemanil methylsulfate were measured by gas-exchange chromatography.[4]

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Serious undesirable cardiac side effects have been reported with treatment with diphemanil methylsulfate (Prantal) in premature babies or neonates. To understand the origin of this problem, the authors undertook an electrophysiological study of the effects of this product in vitro on rabbit Purkinje fibres. In three separate series (N = 5 to N = 8), the effects of increasing concentrations (0.1 microM-30 microM) of diphemanil methylsulfate, different frequencies of stimulation (0.2 Hz, 1 Hz, 2 Hz) and duration of exposition (60 min followed by 120 min washout) were observed on the properties of the action potential. The results show a clearcut antiarrhythmic Class III type action characterised by a concentration-dependent prolongation of the action potential duration with an inverse frequency dependency without significant changes of the other parameters. During stimulation at 0.2 Hz, early post-depolarizations and induced activity were observed in 3/8 of the fibres exposed to 10 microM and 8/8 fibres exposed to 30 microM. The effect did not attain a steady state after 60 min of exposition. It was not reversed by 120 min of washout of the preparation. These results were compatible with the reported cardiac arrhythmic effects of prolongation of the QT interval and torsades de pointe.[5]

The pharmacokinetic parameters of oral diphemanil methylsulphate have been evaluated in six healthy male volunteers. Absorption of the drug was slow (tmax = 2 to 4 h), the mean half-life was 8.35 h, and the amount of the drug recovered in urine within 48 h ranged from 0.6 to 7.4% of the administered dose. The results suggest low bioavailability, assuming that the drug is poorly metabolized.[2]

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The pharmacokinetics of diphemanil methylsulphate was evaluated after oral administration of a single 3 mg.kg-1 dose to 5 infants being treated for symptomatic bradycardia. The mean pharmacokinetic parameters of oral diphemanil methylsulphate in infants were similar to those in adults. The mean half-life was 8.6 h. This would allow administration three times a day in infants instead of four to six times a day, as currently prescribed. The mean residence time decreases significantly with age (Spearman's r' = -1), and there is a trend for the half-life to decrease with age (r' = -0.9; NS), suggesting an influence of maturation on its elimination.[3]

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The peak plasma concentration in the five infants occurred at 3.9 +/- 2.3 hours (range: 2.9-8 hours). Half-life was 8.6 +/- 2.4 hours and tended to decrease with age. All the other parameters were identical to those found in adults. The peak plasma concentration occurred in the sixth younger infant at 2.9 hours, with a half-life of 17.2 hours. Renal clearance was high (0.3 l/h/kg). Conclusion: The relatively long half-life of diphemanil methylsulfate allows this drug to be given every 8 hours. This longer interval is more comfortable for the patients and their parents. The high renal clearance suggests that this drug is excreted by both glomerular filtration and tubular secretion.[4]

rat LD50 intravenous 5 mg/kg SENSE ORGANS AND SPECIAL SENSES: MYDRIASIS (PUPILLARY DILATION): EYE; AUTONOMIC NERVOUS SYSTEM: SMOOTH MUSCLE RELAXANT (MECHANISM UNDEFINED, SPASMOLYTIC) Oyo Yakuri. Pharmacometrics., 23(461), 1982
mouse LD50 intraperitoneal 47 mg/kg Proceedings of the Society for Experimental Biology and Medicine., 78(576), 1951 [PMID:14911957]
dog LDLo intravenous 42 mg/kg LUNGS, THORAX, OR RESPIRATION: OTHER CHANGES Proceedings of the Society for Experimental Biology and Medicine., 78(576), 1951 [PMID:14911957]
guinea pig LD50 oral 404 mg/kg Proceedings of the Society for Experimental Biology and Medicine., 78(576), 1951 [PMID:14911957]
mouse LD50 intravenous 4012 ug/kg Archives Internationales de Pharmacodynamie et de Therapie., 103(100), 1955 [PMID:13259724]

[1]. Küng M, Diamond L. Effect of inhaled diphemanil methylsulfate, a parasympatholytic agent, on histamine induced bronchoconstriction in asymptomatic asthmatics. Ann Allergy. 1984 Jan;52(1):22-5.

[2]. Pharmacokinetics of diphemanil methylsulphate in healthy subjects. Eur J Clin Pharmacol. 1992;42(6):689-91.

[3]. Pharmacokinetics of diphemanil methylsulphate in infants. Eur J Clin Pharmacol. 1993;45(1):89-91.

[4]. [Pharmacokinetics of diphemanil methylsulfate in infants]. Arch Pediatr. 1994 Jan;1(1):33-7.

[5]. Adamantidis M, Dumotier B, Caron J, Dupuis B. [Electrophysiologic effects and arrhythmogenic potential of diphemanil methylsulfate on rabbit purkinje fibers. Correlations with clinical observations of QT prolongation in pediatrics]. Arch Mal Coeur Vaiss.

Diphemanil methylsulfate is the alkene resulting from the formal Wittig olefination of benzophenone and 1,1-dimethyl-4-bromopiperidinium methylsulfate. A quaternary ammonium anticholinergic, it binds muscarinic acetycholine receptors and thereby decreases secretory excretion of stomach acids, saliva and sweat, It is used topically in the treatment of hyperhidorsis (excessive sweating). It has a role as a muscarinic antagonist, a parasympatholytic and a bronchodilator agent. It is a quaternary ammonium salt and a member of piperidines.
See also: Diphemanil (has active moiety).

C20H24N.CH3O4S

389.51

389.166

C, 64.75; H, 6.99; N, 3.60; O, 16.43; S, 8.23

62-97-5

15394-62-4;62-97-5 (methylsulfate);

6126

White to off-white solid powder

194-195ºC

4.491

0

4

2

27

426

0

BREMLQBSKCSNNH-UHFFFAOYSA-M

InChI=1S/C20H24N.CH4O4S/c1-21(2)15-13-19(14-16-21)20(17-9-5-3-6-10-17)18-11-7-4-8-12-18;1-5-6(2,3)4/h3-12H,13-16H2,1-2H3;1H3,(H,2,3,4)/q+1;/p-1

4-(diphenylmethylene)-1,1-dimethylpiperidin-1-ium methyl sulfate

NSC41725; Diphemanil Methylsulfate; NSC 41725; DIPHEMANIL METHYLSULFATE; 62-97-5; Diphemanil metilsulfate; Prantal; Diphenmethanil; Nivelona; Demotil; Diphemanil methosulfate; NSC-41725; Prantal; Talpran;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: 50 mg/mL (128.37 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)