Gastric erosions induced by analgesic drug mixtures in the rat.

Gastric erosions after oral administration of analgesics separately and in admixture have been examined in adult rats. After administration of acetylsalicylic acid (aspirin), phenacetin, paracetamol and caffeine as single drugs, gastric erosions were only observed with aspirin. The combination of aspirin with phenacetin did not change, that of aspirin with caffeine significantly increased, and aspirin with paracetamol significantly decreased the incidence of gastric lesions compared with aspirin alone. The results for aspirin with paracetamol did not differ from those for the vehicle. Addition of caffeine to the combination of aspirin and phenacetin caused a significant increase in erosions, but when given with aspirin and paracetamol no erosions occurred. The mechanisms underlying the effects of these drugs on aspirin-induced erosions are discussed.     

Effects of phenacetin,paracetamol and caffeine on the erosive activity of acetylsalicylic acid in the rat stomach: dose-response relationships,time course of erosion development and effects on acid secretion

Adult male and female Wistar rats were equally susceptible to gastric injury induced with acetylsalicylic acid (aspirin). Both in male and in female rats simultaneous administration of caffeine and aspirin caused significantly more gastric erosions than the same dose of aspirin alone; likewise addition of paracetamol to aspirin decreased the incidence of gastric lesions in either sex, and addition of phenacetin to aspirin had no effect. The potentiation by caffeine and the inhibition by paracetamol were both dose-dependent and only markedly influenced the development of erosions after 3–4 h. Pretreatment with phenacetin or paracetamol 1 h before administration of aspirin did not affect its erosive activity. Administration of benorylate caused no more gastric erosions than the vehicle or than equivalent mixtures of aspirin and paracetamol. The histamine-stimulated acid output of the stomach during gastric perfusion with aspirin was rapidly diminished. Neither paracetamol nor caffeine initially affected this decrease in acid output. However, 30 min after perfusion with aspirin and caffeine, acid secretion increased approximately as strongly as after caffeine alone. Caffeine potentiates aspirin-induced erosions by its stimulatory effect on acid secretion whereas paracetamol inhibits these erosions by preventing their growth.     

Effect of nicotine and caffeine pretreatment on the gastric mucosal damage induced by aspirin, phenylbutazone, and reserpine in rats

The effect of nicotine and caffeine pretreatment by feeding nicotine (2.5 mg %), caffeine (30 mg % base), and their combination (nicotine 2.5 mg % + caffeine 30 mg %) in drinking water ad libitum for 21 days was studied on the gastric mucosal damage induced by aspirin, phenylbutazone, and reserpine in rats. When given alone, neither nicotine nor caffeine produced any visibly discernible gastric lesions. Their concurrent administration too, did not produce any gastric mucosal injury. Pretreatment with nicotine, caffeine, and their combination resulted in significant augmentation of gastric ulcers produced by aspirin, phenylbutazone, and reserpine. However, caffeine administration produced a comparatively less profound augmentation of experimentally induced gastric lesions than that produced by nicotine pretreatment. The enhancement of gastric ulcers in the groups pretreated with the combination of nicotine and caffeine followed by one of the drugs was significantly greater than in the groups treated by either of them alone. The effect of nicotine on the mucus neck cell population of the gastric mucosa and on pancreatic bicarbonate secretion and the gastric secretory effect of caffeine may be responsible for the potentiation of the ulcerogenic effects of aspirin, phenylbutazone, and reserpine.     

Determination of the optimal analgesia-potentiating dose of caffeine and a study of its effect on the pharmacokinetics of aspirin in mice

The addition of caffeine 10 mg/kg to analgin, paracetamol and aspirin increased the potency of the combination compared to that of the analgesic used alone, giving a potency ratio of 1.58, 2.5 and 3.23, respectively as assayed by the writhing method in mice. Increasing the dose of caffeine further reduced the potency of the combination so that with 100 mg/kg caffeine the potency ratio for the combination against the analgesic alone was analgin 1.25, paracetamol 0.94 and aspirin 0.88. The Cmax, Tmax, t1/2 and AUC of plasma salicylate was not significantly different when aspirin 65 mg/kg was given alone or in combination with caffeine 10 mg/kg p.o. in mice. Therefore, caffeine is maximally effective in potentiating the effect of analgesics at a dose of 10 mg/kg and this potentiation is not due to a pharmacokinetic interaction with the analgesic, and also not due to phosphodiesterase (PDE) inhibition.     

Potentiation of gastric toxicity of ibuprofen by paracetamol in the rat.

A fixed dose combination of ibuprofen (400 mg) and paracetamol (325 mg) is by far the most extensively prescribed medicament for a variety of musculoskeletal disorders in India. Following clinical observations that this drug combination induces significant adverse effects, its gastric toxicity was investigated in rats. Ibuprofen (25 mg kg-1 p.o., twice daily x 5 days), paracetamol (20 mg kg-1 p.o, twice daily x 5 days), and a combination of the two, had no significant effect on free and total gastric acidity in pylorus-ligated rats. Ibuprofen induced visible gastric ulceration whereas paracetamol did not. However, the combination of these two drugs had an additive effect inducing severe gastric erosions, ulcerations and bleeding. The augmented toxicity of this drug combination appeared to be a consequence of attenuated gastric mucin activity and reduction in the gastric muco-protective barrier. This investigation indicates the likely hazard of an irrational fixed dose drug combination.     

Zijn combinaties van niet-narcotische analgetica rationeel?

Samenvatting Het dierexperimenteel onderzoek beschreven in dit proefschrift had tot doel de interacties tussen de bestanddelen van niet-narcotische analgeticacombinaties met betrekking tot hun maagbeschadigende, ontstekingsremmende, pijnstillende en koortsremmende werking op te helderen.Coffeïne versterkt de maagbeschadigende werking van acetylsalicyizuur en van de combinatie acetylsalicylzuur met fenacetine; paracetamol daarentegen verzwakt de maagbeschadigende werking van acetylsalicylzuur en van de combinatie acetylsalicylzuur met coffeïne. Mogelijke oorzaken van deze interacties worden besproken.De anti-inflammatoire, analgetische en antipyretische activiteiten van twee-en drievoudige combinaties van acetylsalicylzuur, paracetamol, fenacetine en coffeïne zijn tenminste gelijk aan die welke men op grond van additie kan verwachten.De conclusies uit het experimentele deel van dit proefschrift worden in relatie met de effectiviteit en toxiciteit van de niet-narcotische analgetica bij de mens geëvalueerd. Geconcludeerd wordt dat coffeïnebevattende combinaties met acetylsalicylzuur als irrationeel moeten worden beschouwd, terwijl toevoeging van fenacetine geen voordelen biedt. Open blijft de vraag of bij de mens net zoals bij de rat een gunstige interactie tussen acetylsalicylzuur en paracetamol wat betreff maagbeschadiging kan worden waargenomen.

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Are non-narcotic analgesic drug mixtures rational?

The main purpose of the animal experiments described in this thesis was to elucidate the manner in which interactions between non-narcotic analgesics contribute to the gastric erosive activity of some of their combinations, and to evaluate these interactions in relation to the antiinflammatory, analgesic and antipyretic activities of the drugs concerned.Caffeine potentiates the erosive activity of acetylsalicylic acid and of the combination of acetylsalicylic acid with phenacetin; on the other hand, paracetamol antagonises the erosive activity of acetylsalicylic acid and of the combination of acetylsalicylic acid with caffeine. Possible mechanisms underlying these interactions are discussed.The anti-inflammatory, analgesic and antipyretic activities of dual and triple combinations of acetylsalicylic acid, paracetamol, phenacetin and caffeine at least equal addition of the activities of the individual component drugs.The observed interactions are evaluated in relation to the current status of compound analgesics in clinical medicine; it is concluded that mixtures containing acetylsalicylic acid and caffeine are to be regarded as irrational whereas addition of phenacetin does not appear to offer any advantages. Whether a beneficial interaction between acetylsalicylic acid and paracetamol such as demonstrated on gastric mucosal damage in rats occurs in man remains to be established.

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Autoreferaat van het proefschrift Are non-narcotic analgesic drug mixtures rational? An evaluation of their pharmacological potency and gastric toxicity in rats. Utrecht, 30 januari 1980. (Promotor: Prof. Dr. J. Van Noordwijk.)     

Protection by paracetamol against various gastric irritants in the rat

Four nonsteroid anti-inflammatory drugs (NSAID), indomethacin, phenylbutazone, ibuprofen, and glafenine, caused erosions in the rat stomach in a dose-dependent manner. Paracetamol, which has been shown to protect against the gastric erosive activity of aspirin, reduced the gastric toxicity of indomethacin but was ineffective against the erosive activity of phenylbutazone and glafenine. Only the high erosion score of a large dose of ibuprofen was partly decreased by paracetamol. The gastric damaging effects of necrotizing concentrations of ethanol and sodium hydroxide were strongly reduced by paracetamol, but the erosive activity of hydrochloric acid was only slightly decreased by paracetamol. Thus, although paracetamol protected the gastric mucosa against various noxious agents, this drug was not able to protect against every type of gastric damage. Paracetamol might be protective by stimulating the biosynthesis of prostaglandins in the stomach wall.     

Drugs and gastric damage.

The effects of aspirin, salicylate formulations and substitutes, smoking (nicotine), indomethacin, corticosteroids, phenylbutazone, ethanol, caffeine and reserpine on the gastric mucosa are discussed. The damaging effects of the drugs are considered in terms of the gastric mucosal barrier, gastric erosions, microbleeding and haematemesis and melaena and finally whether they cause peptic ulcer. There is suggestive evidence that unbuffered aspirin is a cause of haematemesis and melaena and of gastric ulcer but the incidence rates for hospital admission are low, being 10 to 15 per 100,000 heavy users per year. Aspirin in solution as acetylsalicylate buffered to maintain a neutral pH protects against gastric damage. Newer aspirin substitutes (mefenamic acid, fenoprofen, naproxen, tolmetin and ibuprofen) appear to cause less faecal blood loss than aspirin but their long-term effects have not been fully evaluated. Smoking is definitely associated with peptic ucler but the mechanism is unknown. Corticosteroids are probably not ulcerogenic despite clinical bias that they are. Indomethacin and phenylbutazone may be ulcerogenic but there is insufficient evidence to make firm judgements. Ethanol, caffeine and reserpine, on available evidence, are probably not ulcerogenic.     

Effect of nicotine, alcohol and caffeine pretreatment on the gastric mucosal damage induced by aspirin, phenylbutazone and reserpine in rats

The effects of nicotine (2.5 mg/100 ml), alcohol (25% v/v) and caffeine (30 mg/100 ml base) and their combination (nicotine, 2.5 mg/100 ml; alcohol, 25% v/v; and caffeine, 30 mg/100 ml base) fed in drinking water ad libitum for 21 days were studied on the gastric mucosal damage induced by aspirin, phenylbutazone and reserpine in rats. When given alone, none of them produced any visibly discernible gastric lesions. Their concurrent administration, however, produced some injury to the gastric mucosa which was far less severe than the lesions induced by any of the ulcerogenic drugs used in this study. Pretreatment with nicotine, alcohol and caffeine and their combination resulted in a significant augmentation of gastric lesions produced by aspirin, phenylbutazone and reserpine. These results establish an association between nicotine, alcohol and caffeine in the pathogenesis of gastric ulcers and also implicate them as modifying factors in the genesis of gastric lesions induced by aspirin, phenylbutazone and reserpine.     

Effect of paracetamol on gastric mucosa

The effect of paracetamol on the gastric mucosa was examined in seven healthy volunteers. The dose used (2 g instilled in 100 ml isotonic saline) was equivalent to about six tablets taken with water. Biopsy specimens were taken before and 10 and 60 minutes after instillation. The mean incidence of damaged surface cells in the control period was 1.7%. Ten minutes after instillation 3.5% of the surface cells were damaged. This increase was not significant. Light microscopy showed focal cell disruption and infiltration of red blood cells. Scanning electronmicroscopy showed minimal loss of normal cell apices. No erosions were seen on microscopy. Biopsy specimens taken 60 minutes after paracetamol showed similar changes. These findings differ appreciably from the extensive cell damage and microscopic erosions caused by therapeutic doses of 600 mg (two tablets) of aspirin. We conclude that large "analgesic" doses of paracetamol cause minimal ultrastructural changes in normal human gastric mucosa. The continued use of paracetamol in place of aspirin appears to be justified when there is a possibility of gastric mucosal injury.     

Comparison of the pharmacokinetic profiles of soluble aspirin and solid paracetamol tablets in fed and fasted volunteers

The aim of this study was to investigate the absorption of popular preparations of two common analgesics--soluble aspirin and solid paracetamol tablets. An open, randomised, crossover study design was used to compare the pharmacokinetic parameters of soluble aspirin and solid paracetamol tablets in 16 healthy, male volunteers from the University of the Witwatersrand, South Africa, in both fed and fasted states. Plasma concentrations of paracetamol, aspirin and salicylic acid were measured. It was found that the rate of absorption was significantly faster for soluble aspirin than for solid paracetamol, regardless of fed or fasting state, considering time to maximum concentration (p < 0.01), time to first quantifiable concentrations (p < 0.05) and absorption rate (p < 0.01). Absorption rate was significantly affected by food for both soluble aspirin (p = 0.028) and for solid paracetamol (p = 0.0003). Time to maximum concentration was not significantly affected by food for soluble aspirin (p = 0.17) but significantly lengthened for solid paracetamol (p = 0.0003). The extent of absorption was affected by food in terms of maximum concentration for both drugs (p = 0.0001), with a reduction of 49% in the fed state for solid paracetamol compared to 18% for soluble aspirin, the difference between the drugs being statistically significant (p = 0.0024). The overall bioavailability of soluble aspirin was unaffected by food and the bioavailability of salicylic acid was increased in the fed state, whereas that of solid paracetamol was lowered in the fed state. Greater inter-individual variation was seen in paracetamol concentrations compared with aspirin or salicylic acid levels. In conclusion, these results show that the absorption of soluble aspirin is largely unaffected by food, whereas, in the same volunteers, the absorption of solid paracetamol tablets is greatly affected. In some volunteers, maximum plasma concentrations of paracetamol following food did not reach levels previously reported to be required for effective analgesia, and this may have implications for pain relief in some individuals. The practice in some individuals of taking aspirin tablets after food to minimise potential gastric disturbance should not affect the level of analgesia.     

Evaluation of a Liver Microfluidic Biochip to Predict In Vivo Clearances of Seven Drugs in Rats

We investigated metabolic clearances of phenacetin, midazolam, propranolol, paracetamol, tolbutamide, caffeine, and dextromethorphan by primary rat hepatocytes cultivated in microfluidic biochips. The levels of mRNA of the HNF4α, PXR, AHR, CYP3A1, and CYP1A2 genes were enhanced in the biochip cultures when compared with postextraction levels. We measured a high and rapid adsorption on the biochip walls and inside the circuit for dextromethorphan and midazolam, a moderate adsorption for phenacetin and propranolol, and a low adsorption for caffeine, tolbutamide, and paracetamol. Drug biotransformations were demonstrated by the formations of specific metabolites such as paraxanthyne (caffeine), paracetamol (phenacetin), 1-OH midazolam (midazolam), paracetamol sulfate (paracetamol and phenacetin), and dextrorphan (dextromethorphan). We used a pharmacokinetic model to estimate the adsorption and in vitro intrinsic drug clearance values. We calculated in vitro intrinsic clearance values of 0.5, 3, 12.5, 83, 100, 160, and 900 μL/min per 10⁶ cells for the tolbutamide, caffeine, paracetamol, dextromethorphan, phenacetin, midazolam, and propranolol, respectively. A second model describing the liver as a well-stirred compartment predicted in vivo hepatic clearances of 0.1, 13.8, 30, 44.1, 61, 72, 85, and 61 mL/min per kg of body mass for the tolbutamide, caffeine, paracetamol, midazolam, dextromethorphan, phenacetin, and propranolol, respectively. These values appeared consistent with previously reported data. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:706–718, 2014     

A synergistic interaction between aspirin, or other non-steroidal anti-inflammatory drugs, and stress which produces severe gastric mucosal damage in rats and pigs.

A synergistic interaction was observed in the development of damage to the gastric mucosa of rats following the administration of a single oral dose of 50 or 200 mg/kg body weight aspirin and exposure to brief periods of cold or restraint stress. Under the experimental conditions employed, the stressed (control) animals did not develop any visible signs of damage while the rats given only aspirin developed typical small erosions. However, the animals given aspirin and simultaneously exposed to stress developed a large number of deep ulcers and massive haemorrhage. Similar results were obtained in rats given a variety of non-steroidal anti-inflammatory drugs, but not with dextropropoxyphene -- an analgesic devoid of ulcerogenic activity. In pigs, the chronic administration of aspirin and exposure to restraint stress resulted in the formation of deep crater-like ulcers. Only small focal lesions were found in the pigs given aspirin alone and no mucosal damage was evident in the pigs exposed only to stress. It appears that the aspirin plus stress synergism may be the basis for the formation of chronic gastric ulcers in humans.     

Formation of reactive metabolites of phenacetin in humans and rats

The metabolism of phenacetin to reactive intermediates in humans was estimated from the excretion of thio adducts in urine. N-Hydroxyphenacetin, a precursor of reactive metabolites, was also quantified. Following an oral dose of phenacetin (10 mg/kg) to humans, these metabolites in 24 h urine were: paracetamol-3-cysteine, 4.4% dose; paracetamol-3-mercapturate, 3.9%; 3-thiomethylparacetamol, 0.4%; N-hydroxyphenacetin, 0.5%. Rats showed a considerable increase in N-hydroxyphenacetin excretion after chronic dosing with phenacetin at high dosage (500 mg/kg) for one month. chronic dosing with a low dose (50 mg/kg) did not increase N-hydroxyphenacetin excretion, but a marked increase occurred on concomitant administration of aspirin and caffeine.     

Comparison of the Pharmacokinetic Profiles of Soluble Aspirin and Solid Paracetamol Tablets in Fed and Fasted Volunteers

Summary

The aim of this study was to investigate the absorption of popular preparations of two common analgesics – soluble aspirin and solid paracetamol tablets. An open, randomised, crossover study design was used to compare the pharmacokinetic parameters of soluble aspirin and solid paracetamol tablets in 16 healthy, male volunteers from the University of the Witwatersrand, South Africa, in both fed and fasted states. Plasma concentrations of paracetamol, aspirin and salicylic acid were measured. It was found that the rate of absorption was significantly faster for soluble aspirin than for solid paracetamol, regardless of fed or fasting state, considering time to maximum concentration (p < 0.01), time to first quantifiable concentrations (p < 0.05) and absorption rate (p < 0.01). Absorption rate was significantly affected by food for both soluble aspirin (p = 0.028) and for solid paracetamol (p = 0.0003). Time to maximum concentration was not significantly affected by food for soluble aspirin (p = 0.17) but significantly lengthened for solid paracetamol (p = 0.0003). The extent of absorption was affected by food in terms of maximum concentration for both drugs (p = 0.0001), with a reduction of 49% in the fed state for solid paracetamol compared to 18% for soluble aspirin, the difference between the drugs being statistically significant (p = 0.0024). The overall bioavailability of soluble aspirin was unaffected by food and the bioavailability of salicylic acid was increased in the fed state, whereas that of solid paracetamol was lowered in the fed state. Greater inter-individual variation was seen in paracetamol concentrations compared with aspirin or salicylic acid levels. In conclusion, these results show that the absorption of soluble aspirin is largely unaffected by food, whereas, in the same volunteers, the absorption of solid paracetamol tablets is greatly affected. In some volunteers, maximum plasma concentrations of paracetamol following food did not reach levels previously reported to be required for effective analgesia, and this may have implications for pain relief in some individuals. The practice in some individuals of taking aspirin tablets after food to minimise potential gastric disturbance should not affect the level of analgesia.     

Paracetamol absorption from Paramax, Panadol and Solpadeine.

Plasma paracetamol concentrations were measured after oral administration of three pharmaceutical preparations to four healthy volunteers. The formulations were Paramax (paracetamol with metoclopramide), Solpadeine (paracetamol with codeine and caffeine) and Panadol (paracetamol alone). After Solpadeine, concentrations at 15 min were significantly higher than after Panadol. Absorption of paracetamol from Paramax tablets did not differ significantly from Solpadeine or Panadol.     

Predictors of gastroduodenal erosions in patients taking low-dose aspirin

Background  Gastroduodenal ulcers are common in patients taking low-dose aspirin. However, the factors predisposing to mucosal erosions, the precursor lesions, are not well known.
Aims  To examine the potential risk factors for the development of erosions in patients chronically taking low-dose aspirin.
Methods  Patients included were taking aspirin 75–325 mg daily for >28 days. Exclusion criteria included use of nonsteroidal anti-inflammatory and ulcer-healing drugs. Demographic data were collected at baseline, prior to endoscopy to determine the frequency and number of erosions and Helicobacter pylori status. In those without ulcer or other exclusions, endoscopy was repeated at 3 months.
Results  Fewer patients had gastric erosions if they were H. pylori +ve (48.5% vs. 66.4% in H. pylori −ve patients at baseline, P  = 0.17; 40.0% vs. 64.1% at 3 months, P  = 0.029). If gastric erosions were present, they were also less numerous in H. pylori +ve patients (3.61 ± 0.83 vs. 4.90 ± 0.53 at baseline, P  = 0.026; 2.17 ± 0.68 vs. 5.68 ± 0.86 at 3 months, P  = 0.029). There was a trend (0.1 >  P  > 0.05) for more gastric erosions in those taking >100 mg/day aspirin. Males had more duodenal erosions at baseline (25.2% vs. 7.5%, P  = 0.016). Patient age did not affect the presence or number of erosions. H. Pylori was not significantly associated with duodenal erosion numbers.
Conclusions  Helicobacter pylori infection may partially protect against low-dose aspirin-induced gastric erosions; damage to the stomach appears weakly dose-related; and older age does not increase the risk of erosions.     

The potentiation of taurocholate-induced rat gastric erosions following parenteral administration of cyclo-oxygenase inhibitors

Subcutaneous administration of anti-inflammatory doses of aspirin, indomethacin, naproxen and flurbiprofen inhibited prostacyclin formation ex vivo in the luminally-perfused gastric mucosa of anaesthetized rats. These doses of anti-inflammatory compounds potentiated the formation of gastric mucosal erosions following 3 h luminal perfusion of the topical irritant, acidified sodium taurocholate (2 mM in 100 mM HCl). The increase in luminal acid-loss during gastric perfusion of acidified taurocholate was not significantly enhanced by these anti-inflammatory agents. A correlation was found between the increase in gastric erosion formation and the inhibition of mucosal prostacyclin formation ex vivo by intravenous injection of aspirin or ketoprofen during acid-taurocholate perfusion. BW755C, which failed to inhibit mucosal prostacyclin formation ex vivo, did not significantly augment acid-taurocholate induced gastric damage. The present findings support the potentiating interactions between topical irritation and inhibition of gastric cyclo-oxygenase in the genesis of the gastric lesions.     

Quantitative NMR assay for aspirin, phenacetin, and caffeine mixtures with 1,3,5-trioxane as internal standard

The method for (1)H NMR determination of aspirin, phenacetin and caffeine (APC) mixtures has been improved by the use of 1,3,5-trioxane as an internal standard. The trioxane absorption occurs in a peak-free region of the spectrum and produces no interferences with any of the analytes. Compared to the original method with caffeine as an external standard, the present method appears to offer better accuracy and precision. Average errors relative to the correct results were: aspirin, 1.0%; phenacetin, 0.8%; and caffeine 1.8%, for known standard mixtures. Coupling constants, (1)J((13)CH), were determined for the methyl groups of aspirin and caffeine and for the trioxane methylene group to clarify potential (13)C satellite interferences.     

Effects of fasting, stress and drugs on gastric glycoprotein synthesis in the rat.

1 The relationship between gastric mucosal damage and synthesis of gastric glycoproteins, as measured by the rate of incorporation of N-acetyl-[3H]glucosamine, was investigated in rats after fasting and restraint stress and a single administration of aspirin (200 mg/kg, orally), phenylbutazone (200 mg/kg, orally), prednisolone (200 mg/kg, orally), or adrenaline (2 mg/kg, i.p.). In one experiment, the effects of aspirin and phenylbutazone on carbohydrate content of the glycoproteins were also determined. 2 Restraint stress, phenylbutazone and aspirin resulted in acute gastric mucosal erosions in some of the rats. Adrenaline produced severe sub-mucosal haemorrhage, but no erosions or ulceration, while prednisolone and fasting gave no gross pathology. 3 The rate of incorporation of N-acetyl-[3H]glucosamine into glycoproteins was decreased after all treatments except adrenaline. In the groups receiving restraint stress, aspirin or phenylbutazone, the decreases were more marked in rats which developed erosions than in those with no gastric pathology. 4 Aspirin and phenylbutazone also produced changes in the carbohydrate content of the glycoproteins, the effects again being greater in the rats which developed erosions. 5 The results are discussed in the context of a possible association between erosion formation and glycoprotein synthesis and it is proposed that inhibition of mucus glycoprotein biosynthesis may be one mode of action of stress and drugs in causing gastric mucosal damage.