M&B 28,767: a potent anti-secretory and anti-ulcer PG analogue. A comparative study with 16, 16' dimethyl PGE2 methylester.

M&B 28,767 [(+/-)11-deoxy-16-phenoxy-omega-tetranor PGE1] and 16, 16'-dimethyl PGE2 methylester (DMPG) were compared for their effects on gastric acid secretion (GAS) and gastric ulceration (GU), employing various laboratory models. In anaesthetised rats, GAS was stimulated by a continuous i.v. infusion of pentagastrin (30 micrograms/kg/h), and PG analogues were perfused through the stomach for 1 h. M&B 28,767 (3-15 micrograms/kg/h) and DMPG (3-60 micrograms/kg/h) reduced GAS in a dose-related manner, the ED50 values being 4 and 15 micrograms/kg/h respectively. In conscious rats possessing indwelling gastric cannulae, oral doses of M&B 28,767 (0.025-0.1 microgram/kg) and DMPG (0.50-1.0 microgram/kg) caused a prolonged inhibition of pentagastrin-stimulated GAS. M&B 28,767 was 17 times more potent than DMPG; the respective ED50 values were 0.036 and 0.6 microgram/kg. Indomethacin-induced ulceration in rats, was reduced by both M&B 28,767 and DMPG; the respective ED50 values being 3.0 and 0.8 micrograms/kg. Both compounds given orally increased gastrointestinal motility in mice; M&B 28,767 (1-3 mg/kg) and DMPG (0.1-0.3 mg/kg) caused diarrhoea, the former being about 0.1 times as potent as the latter. In another test, M&B 28,767 (0.5-5.0 mg/kg) and DMPG (10-40 micrograms/kg) overcame morphine-induced constipation in a dose-related manner, the respective ED50s being 0.9-1.4 mg/kg and 20-40 micrograms/kg. Thus, M&B 28,767 had a better profile of activity than DMPG as an antisecretory and antiulcer agent.

Prostaglandins and the side effects of anti-inflammatory drugs--the kidney.

The most important renal side effect of non-steroidal anti-inflammatory therapy in man is analgesic nephropathy. One possible mechanism for this effect is inhibition of renal prostaglandin synthesis. However, an understanding of the regional biosynthesis of renal prostaglandins, of their pharmacological, physiological and pathological properties in the kidney and an understanding of the consequences of their inhibition by drugs is required in order to assess whether such a mechanism is involved. These aspects are reviewed, using much of the early work of the author as a basis for the discussion. The following conclusions can be drawn form a review of published work. "The consequences of the inhbiition of renal prostaglandin synthesis do not seem to bear much relationship to the renal side effects of anti-inflammatory therapy in man". It is further suggested that impaired renomedullary blood flow arising from decreased renomedullary PGE2 synthesis results in increased accumulation of drug in the renal medulla leading to direct toxic damage. Finally, examples of diseases associated with increased or decreased renal PGE2 synthesis are discussed and some examples of drug interactions are presented.

Synthesis and gastrointestinal pharmacology of some 15- and 16- modified (+/-)-11-deoxyprostaglandins.

The synthesis and gastrointestinal pharmacology of some 11-deoxyprostaglandin E1 analogues are described with results analysed for selectivity from side effects. 11-Deoxygenation reduced potency relative to PGE2 but, as has been reported for natural PGs, 15- or 16-methyl analogues were more potent than the unsubstituted parent compound in the order 16-methyl greater than 15-methyl greater than 16,16-dimethyl. The results suggest that a complex interaction between C-15 and C-16 in methyl analogues affects their profile of activity, but that none of the modifications studied conferred a substantial potency or selectivity advantage over PGE2.

Prostaglandin synthesis by bovine mesenteric arteries and veins.

Prostaglandins (PG) were synthesized at similar rates by bovine mesenteric arteries and veins; viz., ca. 200 ng/g wet weight after one hour of incubation. After synthesis, PGE and PGF compounds were released from slices of arteries and veins into the incubating medium; PG were not detected in the walls of these blood vessels. Arachidonic acid, the precursor to PGE-2 and PGF-2-alpha, did not affect PG synthesis, whereas meclofenamate, an aspirin-like agent, decreased synthesis in arteries and veins by 90%. The PG biosynthetic capacity of these blood vessels is high, as indicated by greater than 20% conversion of (1-14C)-arachidonic acid to radiolabeled PG. Under control conditions in both arteries and veins, synthesis of PGE-2 exceeded that of PGF-2-alpha twofold. Bradykinin selectively increased the synthesis of a PGE-like substance in arteries and of a PGE-like substance in veins.

Distribution of prostaglandins in rabbit kidney.

Three prostaglandins (PGE(2), PGF(2alpha) and PGA(2)) are present in rabbit kidney medulla. An acidic lipid extract (0.165g) obtained from 2kg of frozen rabbit kidney cortex was separated by silicic acid chromatography to yield eluates containing fatty acids, possible non-polar prostaglandin metabolites, PGA, PGE and PGF compounds. Ultraviolet spectra of the eluates before and after treatment with sodium hydroxide did not yield chromophores typical of any known prostaglandins or related metabolites. By using more sensitive bioassay procedures (contraction of rabbit duodenum) weak activity equivalent to 60mug of PGE(2) and 10mug of PGF(2alpha) was detected in the PGE and PGF eluates respectively. Extraction and bioassay of fresh kidney cortex revealed no prostaglandin-like activity. Attempts to biosynthesize prostaglandins in fresh homogenates of rabbit kidney cortex from endogenous precursors and from added arachidonic acid were unsuccessful. When freshly prepared homogenates of rabbit kidney cortex were incubated with added PGE(1) no evidence of enzymic breakdown was obtained. It is concluded that rabbit kidney prostaglandins are present predominantly in the medulla and there are no cortical mechanisms for their biosynthesis or inactivation under normal conditions.

The identification of prostaglandins E(2), F(2alpha) and A(2) from rabbit kidney medulla.

Rabbit kidney medulla (10kg.) was homogenized in 5mm-disodium hydrogen phosphate and deproteinized with ethanol, and the concentrated supernatant solution was extracted at pH8 with light petroleum and at pH2 with chloroform. The acidic lipids present in the chloroform phase were separated on silicic acid columns into three biologically active fractions. The first fraction contained only vasodepressor activity; the second fraction contained both vasodepressor and non-vascular-smooth-muscle-stimulating activity; the third fraction contained both vasopressor and non-vascular-smooth-muscle-stimulating activity. Purification of each fraction by reversed-phase partition and thick-layer chromatography yielded three pure acids. Thin-layer chromatographic, spectroscopic and mass-spectral analysis of the acids and their methyl esters established their structures as prostaglandins E(2), F(2alpha) and A(2). Evidence is presented demonstrating that part or all of the prostaglandin A(2) is formed during the isolation procedures from endogenous prostaglandin E(2).

Thin-layer chromatography of 1-dimethylaminonaphthalene-5-sulphonyl derivatives of amino acids present in superfusates of cat cerebral cortex.

1. Five new solvent systems are reported for the separation of 1-dimethylaminonaphthalene-5-sulphonylamino acids by thin-layer chromatography on silica gel. After two-dimensional chromatography with a suitable pair of these solvent systems, most of the 1-dimethylaminonaphthalene-5-sulphonyl derivatives were completely separated and could be located by their intense yellow fluorescence when viewed under u.v. light. 2. These techniques have been used to identify 21 amino acids present in superfusates of cat cerebral cortex, plasma and cerebrospinal fluid. 3. A method for the semiquantitative estimation of amino acids in biological fluids is described in which the fluorescent intensity of their separated 1-dimethylaminonaphthalene-5-sulphonyl derivatives was measured.