The (ProB27, ThrB28) human insulin analogue is more potent and more rapidly absorbed from subcutis than human insulin.

OBJECTIVE: To test the physiological properties of human insulin in which the amino acids Thr (B27) and Pro (B28) are interchanged (PT insulin). This was hypothesised to prevent dimerisation and accelerate the absorption from s.c. tissue without altering the affinity for the insulin receptor. DESIGN: PT insulin was expressed in Pichia pastoris and processed in vitro. The purified compound was used for physiological investigations. METHODS: Receptor binding activity to insulin and IGF receptors was evaluated in a competition assay using iodinated PT insulin and recombinant receptors while growth induction properties were evaluated by thymidine incorporation. Absorption kinetics from pig subcutis was investigated by measuring the disappearance of iodinated PT insulin. The potency was evaluated by measuring the blood glucose lowering activity in mice. RESULTS: The absorption of PT insulin was accelerated compared with human insulin, although still slower than Asp (B28) insulin. Human and PT insulin had similar affinities for the human insulin receptor (K(d)=3.6 x 10(-12) vs 5.2 x 10(-12) mol/l) while the affinity for the IGF receptor was four times higher for PT insulin than for human insulin (K(d)=3.4 x 10(-8) vs 1.3 x 10(-7) mol/l). This resulted in a slightly higher DNA synthesis when assayed in intermediary insulin concentrations. The blood glucose lowering effect in mice exceeded the effect of human insulin (integral 0-60 min: 61.4+/-7 vs 30+/-4, n=6, P=0.046). CONCLUSIONS: PT insulin is absorbed faster and is more potent than human insulin. Although PT insulin stimulates growth more than human insulin, this will not prevent its use in the clinic, but the main interest will probably focus on investigations to clarify the paradox of full biological activity in connection with the recently described lack of structure in the B-chain.

Drug consumption before perforation of peptic ulcer.

In a retrospective study of 195 patients with a perforated peptic ulcer 18 per cent of the patients had taken aspirin, phenylbutazone or corticosteroids during the period before the perforation. In a controlled prospective trial, 18 of 22 patients (82 per cent) had taken drugs known to be potentially harmful to the stomach. Aspirin was the drug mainly used. Thirteen of 22 patients had taken the drugs within 12 hours of the perforation, usually because of symptoms not related to the gastro-intestinal tract. Drug consumption and perforation of pre-pyloric ulcers were most closely associated; the latter applies particularly to female patients, who either had only a short history of upper gastro-intestinal dyspepsia or were asymptomatic.

The influence of acetylsalicylic acid (aspirin) on gastric mucosal content of energy-rich phosphate bond.

The mucosal content of adenosine triphosphate, adenosine diphosphate and adenosine monophosphate in mini-pig corpus gland area and in pyloric gland area was examined after aspirin ingestion in acute experiments and after ingestion for several weeks. Ingestion of aspirin led to a statistically significant decrease of adenine nucleotide content in corpus gland and in pyloric gland area. An inverse correlation between the pH of the aspirin suspensions and the size of the decrease was established in the short-time experiments. In non-affected pyloric gland area mucosa and adenine nucleotide content was significantly lower than in the corpus gland area. Pyloric mucosa was more susceptible to aspirin-induced lowering of adenine nucleotide content than was the corpus mucosa. Prolonged aspirin ingestion led to statistically significant reductions of adenine nucleotide pool. The findings explain the decrease in mucous secretion and in acid secretion demonstrated in several studies. The finding of lower and more susceptible adenine nucleotide pool in the pyloric area might be the explanation for the preponderant occurrence of aspirin ulcerations in this region.

Salicylate- and aspirin-induced uncoupling of oxidative phosphorylation in mitochondria isolated from the mucosal membrane of the stomach.

The hypothesis that the damaging effect on the stomach mucosa of salicylic acid and its derivatives is ascribable to an uncoupling of oxidative phosphorylation has been investigated by testing of mitochondria isolated from the corpus gland area of mini-pig gastric mucosa. Mitochondria, influenced by salicylate or acetylsalicylate (0.7-5.6 mmol/l), demonstrated increased respiration rate, decreased respiratory control ratio, and decreased P/O ratio when tested in vitro. Uncoupling of oxidative phosphorylation occurred at a salicylate concentration between 3.5 and 5.6 mmol/l.

Ulcer formation and histochemical changes in rat-stomach mucosa induced by acetylsalicylic acid.

Numerous papers have emphasized the damaging effect of salicylic acid compounds on the stomach mucosa. The investigations here reported aimed at examining the effect on gastric and duodenal morphology of a moderate dose of aspirin. Oxidative enzymes were evaluated histochemically. To rats in groups of 16, aspirin tablets, placebo tablets, or the same with additional 1 cc of 0.1 N HCl, were administered twice a day for 6 weeks. Approximately 160 mg/kg/24 hrs. were ingested. Microscopy revealed severe hyperaemia along with focal gastritis in the aspirin treated animals. Chronic gactric ulcers were observed in 18 rats in the aspirin treated groups, particularly in the group where HCl was added. Ulcerations in the area of the pyloricgland occurred in the latter group only. A reduction in mucopolysaccharides was demonstrated and involved the acid as well as the neutral ones. NADH-reductase and cytochrome oxidase were inhibited not only in the surface cells but also in those in the deeper layers. The reduction in oxidative enzymes in otherwise undamaged areas suggests an interference with the cellular metabolism, probably processes in the respiratory chain which might lead to reduction in energy-rich phosphate bonds.