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Nonsymmetrical bisquaternary mono- and diesters combining the potency-enhancing properties of the (1R)-laudanosinium group with a second unhindered quaternary ammonium moiety have been studied as a means of promoting short action with high-potency neuromuscular block. Atracurium-related nonsymmetrical diesters showed high potency, freedom from vagal blockade at neuromuscular blocking doses, and short action. Nonsymmetrical monoesters were short acting but showed varying degrees of vagal block.

Plasma concentrations of total and unbound 11-hydroxysteroids in patients with rheumatoid arthritis have been determined using a fluorimetric method before and after administration of acetylsalicylic acid, phenylbutazone and indomethacin. Unbound 11-hydroxysteroids were measured in plasma ultrafiltrates obtained using the Toribara apparatus. Enhancement and quenching of fluorescence by acetylsalicylic acid, phenylbutazone, and indomethacin, and heparin used as an anticoagulant in the blood samples, have been shown to be absent. The results show that acetylsalicylic acid, phenylbutazone and indomethacin given in recommended therapeutic doses for periods of one week have no significant effect on plasma protein-binding of 11-hydroxysteroids.

The metabolism of 16α-ethylprogesterone by rat liver homogenate at different steroid to tissue ratios has been examined. The products, identified by thin-layer chromatography, gas-liquid chromatography and combined gas-liquid chromatography-mass spectrometry were 16α-ethyl-5α-pregnane-3, 20-dione and 16α-ethyl-3α-hydroxy-5α-pregnan-20-one. The yield of these metabolites was 14 and 48% respectively. The results are discussed in relation to the liver in vitrometabolism of progesterone and 16α-hydroxyprogesterone.

(±)-2-Aminomethyl-1, 4-benzodioxan has been resolved into its optically active isomers: (+)- and (-)-guanoxan have been synthesized from these. The pharmacological effects of racemic-guanoxan and of the two optical isomers have been compared on the isolated central ear artery of the rabbit, on the pithed rat in which pressor responses were evoked by stimulation of the thoraco-lumbar sympathetic outflow, and on the pre- and post-ganglionically stimulated nictitating membrane of the cat. The two isomers were equipotent in producing adrenergic neuron blockade. Initial catecholamine release was weak in the cat, but occurred more powerfully in the rabbit ear artery and in the rat. Ability to produce this effect resided mainly with the (+)-isomer. α-Adrenoreceptor blocking activity was detectable in the rat and was produced mainly by the (+)-isomer suggesting that its stereochemical configuration corresponds to that of D-(-)-noradrenaline. Ganglion blockade was an unimportant action of the compounds, but both isomers possessed weak atropine-like activity in the rat.

Aristolochic acid (I) was present in single samples of A. longaand A. indica, in two samples of A. serpentaria, and four samples of A. reticulata.Aristo-red (II) was present only in the samples of A. reticulataand A. serpentaria.Contrary to numerous reports of alkaloids in Aristolochiaspecies, the current investigation has revealed the presence of only negligible amounts in the samples of A. indica, A. longa, A. reticulataand A. serpentariaexamined. A flavone isolated from A. reticulatahas been identified as isorhamnetin.

Conclusion: The chlorohydroxy-triphenylmethane dye III has been shown to possess a low order of antibacterial activity. The results of Fairbrother and Renshaw indicated that the presence of an acidic group in the molecule of a basic triphenylmethane dye, would decrease the activity. The introduction of the phenolic group into the molecule of the dye III has demonstrated this effect and any enhancement of potency due to the presence of the chloro-group was insufficient to compensate for the reduction in activity due to the phenolic group.

Linear bis- and tris-onium ethers (I and II) have weak tubocurarine-like properties. In both series, potency increased with increase in alkyl group size. No evidence was found for a one point receptor attachment in bis-onium ethers

Pyridine-4-sulphinic acid, 4,4′-dipyridyl sulphone and other related 4-pyridyl sulphides and 4-pyridyl sulphones have been prepared.

The tris-onium ethers (XIII, A and B) and the tetra-onium ethers (XV A, B and C), together with the corresponding polymethylene tris-onium (XIV A and B) and polymethylene tetra-onium compounds (XVI, A, B and C), have been synthesised. Replacement of a methylene group in the inter-onium polymethylene chain by an ether link almost always lowers muscle relaxant potency.

A series of 2-iminoselenazolidin-4-ones, selenazolidine-2,4-diones and some 2-alkylidenehydrazones have been synthesised. Wide-range screening for biological activity failed to reveal any compounds of promise.

Dissociation constants have been recorded for ergometrine, ergometrinine and a number of alkanolamides of 3-dimefhylaminopropionic acid, 1-methylhexahydronicotinic acid and arecaidine. The similarity of ΔpK (amide) values for the alkanolamides with that for ergometrine, offers evidence that such values may be taken as an indicator of amino-carboxyl distances.

The ethanolamides of 3-dimethylaminopropionic acid, 1-methyl-1,2,5,6-tetrahydronicotinic acid (arecaidine) and 1-methylhexahydronicotinic acid, and propanolamides of 3-dimethylaminopropionic acid and arecaidine have been synthesised. None of these compounds had demonstrable oxytocic activity on the isolated oestrous rat uterus in concentrations up to 1 mg./ml. Arecaidine propanolamide inhibited acetylcholine-induced contractions in concentrations of 0.075 to 0.3 mg./ml. The 2-styryl derivatives of 3-dimethylaminopropionic and 4-dimethylaminobutyric acids were found to be unstable.

A rapid spectrophotometric method is suggested for the determination of ethisterone and of methyltestosterone in tablets by reaction with Girard-T reagent.

A further series of linear hexamethylene-NNN-trisonium compounds has been synthesised and tested for neuromuscular blocking activity. In the alkyl-substituted derivatives, at least one Et is required for significant potency in mammals. Apart from the Et2Bunand EtBu2ncompounds, larger alkyl substituents lower potency. High potency in mammals requires at least two Et groups on the terminal nitrogens, if the third group is not Me. Only weak activity was shown by the morpholino-deriatives but the fowl was highly sensitive towards the piperidino- and tetrahydro-papaverino-compounds. The results are discussed.

The light petroleum-soluble fraction from a batch of Aristolochia reticulatahas been examined and found to contain the following:A ketonic oil, consisting of at least 2 unidentified components.A crystalline lactone, C15H20O2, m.pt. 110·5° to 111° C, designated aristolactone.A bicyclic monoterpene, which has been tentatively identified as (–)-Δ4-carene.A mixture of esters, which on saponification yields (–)-borneol formic acid and an unidentified cyclic unsaturated acid, C10H16O2.5A bicyclic sesquiterpene, C15H24, designated reticulene.

The tris-quaternary compounds 7-ethyl-7-thioniatridecylenebis(triethylammonium) triiodide (Dihexasulphonium triethiodide; DHSE), 6-ethyl-6-thioniaundecylenebis(triethylammonium) triiodide (Dipentasulphonium triethiodide; DPSE), and 7-methyl-7-thioniatridecylenebis(trimethylammonium) triiodide (Dihexasulphonium trimethiodide; DHSM) have been synthesised. DPSE and DHSE have been shown to be neuromuscular blocking agents, which act by a mechanism resembling that of tubocurarine and gallamine rather than decamethonium. DPSE and DHSE are about equipotent with tubocurarine on the cat gastrocnemius muscle, but less potent on the frog rectus abdominis muscle and rat diaphragm, and the head drop doses are higher. Neuromuscular block can be reversed by neostigmine, eserine, and edrophonium. DHSE and DPSE do not cause ganglion blockade or histamine release, do not increase heart rate and are less potent than tubocurarine in causing respiratory paralysis.

NSN- and NNN-Tris-onium compounds related to dihexasulphonium and dihexazonium in which N-alkyl substituents are varied have been synthesised. All compounds tested qualitatively resembled tubocurarine in their action. Stepwise replacement of Et by Me in dihexasulphonium tri-ethiodide decreases potency and some C 10-like effects appear in compounds Xaand Xb. Potency also falls when Et groups are replaced successively by n-Pr in both dihexasulphonium tri-ethiodide and dihexazonium tri-ethiodide, compounds XIfand XIgbeing the least active of the series and approximately equipotent with dihexasulphonium trimethiodide (Xa). Replacement of one Et group by n-Bu at each quaternary ammonium centre of dihexazonium, as in compound XIcincreases potency.

Preliminary observations upon a series of NNNN-tetra-onium compounds (Iato Ih), an NNSNN-penta-onium compound (II) and an NNNNNN-hexa-onium compound (III) have so far indicated that inter-onium distance is more important in determining the type of activity than the overall length of the molecule or the number of onium centres it contains.

The effect of acetylsalicylic acid, ibufenac, indomethacin, oxyphenbutazone and phenylbutazone on the protein-binding of 11-hydroxysteroids in vitroat concentrations in excess of normal has been examined in human blood bank plasma, in plasma from women in the third trimester of pregnancy, and in plasma from patients after injections of tetracosactide. Phenylbutazone, ibufenac and indomethacin do not significantly affect the protein-binding of 11-hydroxysteroids. Oxyphenbutazone causes a decrease in the proportion of unbound 11-hydroxysteroids and acetylsalicylic acid produces an increase of unbound 11-hydroxysteroids.

The effect of finely divided silica on the antifoaming properties of polydimethylsiloxanes (dimethicone 1000) when formulated in a typical antiflatulent tablet has been examined. A dynamic froth test has been used to show that removal of extractable dimethicone by ether extraction of the tablet powder markedly reduces the antifoaming properties of the powder, despite retention of a small percentage of the polydimethylsiloxane dispersed on the surface of the silica and aluminium hydroxide gel content of the tablet. A series of static froth tests similarly demonstrate that tablet formulations from which silica is omitted also possess significant antifoaming properties.

1. [2-14C]-Methimazole has been synthesized and its absorption, distribution and metabolism studied in male and female rats, after intraperitoneal and oral administration.2. After a single intraperitoneal injection, radioactivity was concentrated in the thyroid rising to a max. at 24 h, whilst the radioactivity was decreasing in other tissues. Thyroid radioactivity appeared to be protein-bound.3. Urinary excretion of 14C accounted for 60% dose at 12 h and 73·4-89·5% within 5 days. On average, 6-7% of methimazole was excreted unchanged in urine after a single intraperitoneal injection. Methimazole was metabolized to a greater extent in rats receiving it by the oral route compared to the intraperitoneal route.4. Thin-layer chromatography suggested the presence of six metabolites, of which the major one was strongly polar. Hydrolysis with β-glucuronidase indicated that only a minor proportion of the activity excreted at 6 h in the urine was present as glucuronide.

1. [5,6-14C]Eicosa-5,8,11,14-tetraynoic acid administered intravenously to the rat was rapidly metabolized probably mainly by the β- and ω-oxidation pathways. Carbon number extrapolation was used to assign probable structures to some of the metabolites observed.2. Two minutes after administration eicosa-5,8,11,14-tetraynoic acid and one metabolite were observed in plasma, and at 15 min after administration three metabolites and the parent compound were observed in liver. The probable structure of the metabolite in plasma and one of those in liver was hexadec-3,6,9,12-tetrayn-1,18-dioic acid.3. In the bile-duct cannulated rat four metabolites, but no eicosa-5,8,11,14-tetraynoic acid, were excreted equally distributed between phosphatidyl ethanolamine and phosphatidyl choline in the phospholipid fraction of bile. Three of the metabolites had the probable structures octadec-3,6,9,12-tetraynoic acid, octadec-3,6,9,12-tetrayn-1,18-dioic acid and hexadec-3,6,9,12-tetrayn-1,16-dioic acid.4. A low level (2.8%) of metabolism of the tetra-acetylenic moiety was indicated from respired 14CO2 measurements.

1. The distribution and excretion of radioactivity from 1 min to 5 days following parental administration of [5, 6-14C]eicosa-5, 8, 11, 14-tetraynoic acid was studied in the rat.2. Following intravenous administration, the compound was rapidly removed from blood with a half-life of less than 1 min. Absorption by liver was extensive (38% at 15 min) and led to major excretion via the bile with 91% of administered activity being removed by this route in 24 h in the bile-duct cannulated rat. Extensive enterohepatic cycling was evident.3. Over a period of 5 days following intraperitoneal administration, 62% of the total recovered activity was excreted in faeces, 12.6% in urine and 2.8% was expired as 14CO2.4. Fat, adrenal glands, intestinal tissue and, to a lesser extent, skin showed significant sp. radioactivity levels throughout the 5 day period.

Cholesterol and cholesterol esters have been identified on the basis of thin-layer and gas—liquid chromatographic data and fluorimetric characteristics as major interfering fluorogens in a simple fluorimetric method for determining plasma corticosteroids.In a small series of normal subjects the average concentration of fluorogen, which was not 11-hydroxysteroid, was 3·4 μg. apparent cortisol/100 ml. plasma, equivalent to 22·4% of the total fluorogen present.