Gastric Side Effects Research Articles

Interaction studies between drugs and a purified natural clinoptilolite

Taking into account the biological properties of the purified natural clinoptilolite, NZ, some studies were conducted to evaluate the physicochemical interaction between this zeolite and two drugs, metronidazole and sulfamethoxazole, which cause considerable gastric side effects. Two modified forms of NZ were also considered. We have studied the drug solutions before and after the contact with the zeolitic materials in a wide range of pH values by UV spectroscopy. The structure of the two drugs remains unaltered after interaction with the zeolitic products. It is demonstrated that metronidazole adsorption by the different materials is small in acidic pH, and that the zeolitic materials studied do not adsorb sulfamethoxazole at the considered pH values. The overall study suggests the possibility of parallel administration of these products. These results are coherent with a complementary investigation by transmission IR spectroscopy about the possible incorporation of drug on NZ and its modified forms.

Peppermint oil reduces gastric spasm during upper endoscopy: a randomized, double-blind, double-dummy controlled trial

GI endoscopy without general anesthesia causes a hyperperistaltic state in the stomach, which frequently necessitates the use of antispasmodic agents, such as hyoscine-N-butylbromide, but these drugs have side effects. Peppermint oil is harmless and acts locally to inhibit GI smooth muscle contraction. A randomized double-blind, double-dummy, controlled trial was conducted in 100 patients to compare the antispasmodic effects of hyoscine-N-butylbromide administered intramuscularly and a placebo solution administered intraluminally by means of the endoscope, and also the effects of a placebo solution administered intramuscularly with those of a peppermint oil solution administered intraluminally. The percent change in diameter of the pyloric ring before and after the administrations was defined as the opening ratio, and the percent change in diameter between the maximally and minimally opened pyloric ring states was defined as the contraction ratio. Time until disappearance of the contraction ring(s) in the gastric antrum and side effects of the drugs were also determined. The opening ratio was significantly higher in the peppermint oil administration group than in the hyoscine-N-butylbromide injection group. The contraction ratio after peppermint oil administration was significantly lower than that after hyoscine-N-butylbromide injection. The time required for disappearance of the antral contraction ring(s) was shorter in the peppermint oil group (97.1 +/- 11.4) than in the hyoscine-N-butylbromide group (185.9 +/- 10.1 s; p < 0.0001). No significant side effects were associated with peppermint oil, whereas hyoscine-N-butylbromide injection produced side effects such as dry mouth, blurred vision, and urinary retention. Peppermint oil solution administered intraluminally can be used as an antispasmodic agent with superior efficacy and fewer side effects than hyoscine-N-butylbromide administered by intramuscular injection during upper endoscopy.

Cyclic AMP-specific PDE4 Phosphodiesterases as Critical Components of Cyclic AMP Signaling

Cyclic AMP-specific PDE4 Phosphodiesterases as Critical Components of Cyclic AMP Signaling

Economic burden of NSAID-induced gastropathy in Sweden.

Gastrointestinal side effects carry a significant cost related to the use of NSAID medications. The economic burden of NSAID-induced gastric side effects is estimated using the cost-of-illness methodology. Costs are calculated using both a prevalence (top-down) approach and an incidence (bottom-up) approach. Using the top-down approach, the total cost in 1998 of NSAID-induced ulcers was MSEK 329-586, direct costs accounting for 76%-83%. The bottom-up approach gives an estimate of MSEK 320, of which MSEK 290 was direct cost. About one-quarter of total costs for ulcer disease can be attributed to the use of NSAIDs. Gastrointestinal side effects carry a significant cost from the use of NSAIDs, costs that are as important as the price of NSAIDs. This should be considered when choice of drug and prophylaxis is being made.

Economic Burden of NSAID-induced Gastropathy in Sweden

Background: Gastrointestinal side effects carry a significant cost related to the use of NSAID medications. Methods: The economic burden of NSAID-induced gastric side effects is estimated using the cost-of-illness methodology. Costs are calculated using both a prevalence (top-down) approach and an incidence (bottom-up) approach. Results: Using the top-down approach, the total cost in 1998 of NSAIDinduced ulcers was MSEK 329-586, direct costs accounting for 76%-83%. The bottom-up approach gives an estimate of MSEK 320, of which MSEK 290 was direct cost. About one-quarter of total costs for ulcer disease can be attributed to the use of NSAIDs. Conclusions: Gastrointestinal side effects carry a significant cost from the use of NSAIDs, costs that are as important as the price of NSAIDs. This should be considered when choice of drug and prophylaxis is being made.

Synthesis and anti-phlogistic potency of some new non-proteinogenic amino acid conjugates of "Diclofenac".

In search for more potent, particularly less ulcerogenic gastritis that hopefully replace the universal NSAID "Diclofenac", (2-[(2,6-dichlorophenyl)amino]-phenylacetic acid, C.A.S. 15307-86-5), twelve new non-proteinogenic amino acid conjugates of the drug, namely that of sarcosine, beta-alanine, D-leucine and D-phenylalanine, were synthesized and biologically screened for their anti-inflammatory, analgesic and ulcerogenic activity in rats. "Diclofenac" amino acid esters (IIa-d), were synthesized via the corresponding HOSu or HOBt active esters. Alkaline hydrolysis (NaOH) followed by acidification (KHSO4) or thioamide formation (Lawsson's Reagent, C.A.S. 19172-47-5), afforded the corresponding free acids IIIa-d or the thioamides IVa-d respectively. Interestingly, in contrary to the parent "Diclofenac", the synthesized candidates (except IIId), were entirely nonulcerogenic in rats. Further, they considerably retained a generalized anti-phlogistic activity. The major "Diclofenac" irritating gastric side effect was thus eliminated. Particularly, the sarcosine conjugate IIa and its thiomimic IVa exhibit promising therapeutic perspectives.

Measurement of differential inhibition of COX-1 and COX-2 and the pharmacology of selective inhibitors.

Since the discovery of a second isoenzyme of cyclooxygenase (COX)-2, it has been hypothesized that the antiinflammatory effects of non-steroidal antiinflammatory drugs (NSAIDs) are dependent on their inhibition of COX-2, whereas inhibition of constitutive COX-1 is responsible for their gastric and renal side effects as well as for inhibition of platelet activation. Consequently, a large number of in vitro assays have been developed to characterize the COX-1 and COX-2 inhibitory activities of NSAIDs in order to look for compounds with preferential inhibition of COX-2. Depending on the test system, however, the experimental conditions may vary greatly, thereby affecting the outcome. These important variables include the source of enzymes COX-1 and COX-2 (human or animal); the cell system used (intact normal cells or transfected cell lines); the method of enzyme preparation (purified enzymes, microsomal or whole cell assays); the COX-2-inducing agent; the source of arachidonic acid and its concentration; the incubation time with drug, inducing agent or arachidonic acid; and the protein concentration in the medium. Depending on the test system employed for defining the IC(50) for COX-1 and COX-2 inhibition, the resultant ratio between these activities may lead to divergent and confusing comparisons. We review the various in vitro test systems available for the measurement of COX-1 and COX-2 inhibition. The use of human recombinant enzymes and the human whole blood assay are examined in detail. The relevance of these test systems to in vivo animal models of inflammation and the side effects of NSAIDs (e.g., gastric mucosal and renal damage) is assessed. Finally, the results of clinical studies on the effect of inhibiting COX-1 and COX-2 activity is summarized.

Stroke in the developing world

Stroke is the third most common cause of death in most western populations after coronary-heart disease and cancer? It is thus the commonest life-threatening neurological disorder, and the resulting disability is the most important single cause of severe disability among western people living in their own homes) The burden of stroke on patients, their families, and society is, correctly, publicised in most developed countries. Stroke in the developing world is less well documented, and some data are not retrievable because of the language barrier or the limited dissemination of data collected. However, more than two-thirds of the world's population live in developing countries, and one of the consensus statements from the Asia-Pacific Consensus Forum on Stroke Management predicts that "In the next 30 years the burden of stroke will grow most in developing countries rather than in developed countries"? Thus stroke in developing countries ought to be examined further--in particular, the similarities and differences in stroke between developed and developing countries.

Constitutive cyclooxygenase-2 expression in healthy human and rabbit gastric mucosa.

Selective cyclooxygenase (COX)-2 inhibitors are expected to cause fewer gastric side effects because of sparing of COX-1-dependent prostaglandin (PG) synthesis in the gastric mucosa. However, the possible contribution of COX-2 to overall gastric PG biosynthesis is not known. This study demonstrates constitutive expression of COX-2 mRNA and protein in apparently healthy human and rabbit gastric mucosa. This basal expression of COX-2 protein in human gastric mucosa was increased by lipopolysaccharide and phorbol ester, indicating its up-regulation in response to appropriate stimuli. The functional significance of COX-2-dependent PG formation was studied in terms of PGE2 generation in the rabbit mucosa and its inhibition by the COX-2-selective inhibitor flosulide. There was concentration-dependent (IC50 = 107 +/- 55 nM) and ultimately complete inhibition of PGE2 generation by flosulide. In addition, gastric mucosa generated 15-hydroxyeicosatetraenoic acid upon treatment with acetylsalicylic acid. The data suggest an important role for COX-2-dependent PG production in apparently healthy gastric mucosa and raise the issue of whether selective COX-2 inhibitors might also interfere with physiological PG formation and actions in the stomach.

Inhibitory effects of JTE-522, a novel prostaglandin H synthase-2 inhibitor, on adjuvant-induced arthritis and bone changes in rats.

To investigate the effect of JTE-522, a novel selective prostaglandin H synthase (PGHS)-2 inhibitor, on adjuvant-induced arthritis and bone changes. Male Lewis rats at 8 weeks old were immunized with heat-killed mycobacteria. JTE-522 (0.1-30 mg/kg) and indomethacin (0.1-3 mg/kg) were administered orally once-daily after immunization. Paw swelling, bone changes in arthritic paws and vertebrae, urinary levels of deoxypyridinoline and pyridinium crosslinks, and the incidence of gastric lesions were determined in arthritic rats. JTE-522 (from 0.3 mg/kg) suppressed the development of paw swelling, and also reduced bone damage (score and bone mineral density) in arthritic paws and the urinary excretion of deoxypyridinoline and pyridinium crosslinks. However, JTE-522 did not cause gastric lesions even at 30 mg/kg in arthritic rats. These results suggest that JTE-522 possesses potent anti-arthritic activities and suppressive activity on inflammatory bone resorption without gastric side effects.

Hydroxypropyl methylcellulose phthalate beads containing a model non-steroid anti-inflammatory drug

When given orally to patients, non-steroid anti-inflammatory drugs (NSAIDs) can provoke mild to severe gastric irritation side effects. Reduction of gastrointestinal irritation caused by NSAIDs can be achieved using enteric beads which are preferable to coated tablets or capsules. The present work reports the studies of formulation of a model NSAID using a recently described method. Drug-loaded hydroxypropyl methylcellulose phthalate (HP 50) beads were prepared using a technique which is based on the variation of HP 50 solubility with pH. Studies carried out to characterise the formulations, such as density, crushing force and encapsulation efficiency, show that the beads are suitable for further pharmaceutical manipulation (e.g. capsule filling). The in vitro release studies confirmed the gastroresistance, and mathematical studies showed that the drug released followed a first order kinetic.

Aspirin for the second hundred years: new uses for an old drug.

The history of aspirin can be traced back to ancient Egypt where extract of willow bark was used to treat inflammation. The active component of the extract was identified as the glucoside of salicylic alcohol. The severe gastric side effects associated with the use of sodium salicylate prompted the synthesis of the o-acetyl-derivative as a possible pro-drug. In fact, acetylsalicylic acid was antiinflammatory, analgesic and antipyretic but also ulcerogenic to the stomach. Acetylsalicylic acid was synthesized one hundred years ago, and was mass-produced under the commercial name of 'Aspirin' (Dreser, 1899) by the German company Bayer for the treatment of fever and rheumatism.

Meloxicam: Selective COX-2 inhibition in clinical practice

Nonsteroidal antiinflammatory drugs (NSAIDs) exert their actions by inhibitingcyclooxygenase (COX). It has recently been postulated that NSAIDs' antiinflammatory efficacy arises from inhibition of the COX-2 isoform of cyclooxygenase, whereas inhibition of the COX-1 isoform produces the troublesome and sometimes serious gastric and renal side effects of NSAIDs. A relatively selective COX-2 inhibitor, such as meloxicam, may combine antiinflammatory efficacy with improved tolerability. In volunteers, indomethacin 75 mg, but not meloxicam 7.5 mg, inhibited renal prostaglandin E 2 excretion and platelet aggregation (COX-1 mediated effects). Double-blind, randomized trials in osteoarthritis and rheumatoid arthritis patients have shown equivalent antiinflammatory efficacy among meloxicam 7.5 mg or 15 mg and diclofenac 100 mg, naproxen 750 mg, and piroxicam 20 mg. In a double-blind, placebo-controlled trial, meloxicam (7.5 or 15 mg) caused less endoscopically detected gastrointestinal (GI) damage (Lanza scale) than piroxicam 20 mg. The Melissa study, a double-blind, randomized, 28-day trial in over 9,000 patients showed that meloxicam 7.5 mg caused statistically less total GI toxicity, dyspepsia, abdominal pain, nausea and vomiting, and diarrhea than diclofenac 100 mg, despite equivalent reductions in pain on movement for each treatment. A global safety analysis of clinical trials, representing over 5,600 patients and comprising 170 and 1,100 patient-years of exposure for meloxicam 7.5 mg and 15 mg, respectively, showed that meloxicam caused less GI toxicity and fewer peptic ulcers and GI bleeds than naproxen, diclofenac, or piroxicam. The renal safety profile and incidence of liver function abnormalities with meloxicam is equivalent to other NSAIDs available for clinical use. In conclusion, relatively selective COX-2 inhibition exemplified by meloxicam may offer effective symptom relief with an improved GI tolerability profile.

Effects of tepoxalin, a dual inhibitor of cyclooxygenase/5-lipoxygenase, on events associated with NSAID-induced gastrointestinal inflammation

Prostaglandins and thromboxanes are products of arachidonic acid metabolism via the cyclooxygenase (CO) enzyme and are responsible for the pain and swelling common to sites of inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the production of these substances and are used in the treatment of inflammatory diseases such as arthritis. However, one of the major side-effects of NSAID therapy is gastric ulceration. It is possible that inhibition of prostaglandin production and a related increase in the formation of leukotrienes via the 5-lipoxygenase (5-LO) enzymatic pathway are responsible for attracting inflammatory cells, causing local sites of inflammation and producing ulceration. To determine the effects of 5-LO inhibition on this hypothesis, studies were performed in rats to evaluate the effects of tepoxalin, a dual CO/LO inhibitor on leukotriene B 4 levels in gastric mucosa and neutrophil adhesion in mesenteric venules. In rats, chronic oral administration of an NSAID, indomethacin (2 mg/kg daily over 4 days), resulted in 40% mortality, accompanied by intestinal adhesions and perforations when evaluated 24 h after the fourth dose of drug. Additionally, neutrophil adhesion was increased in the mesenteric venules and cell infiltration was evident in the mesenteric interstitium. These gastrointestinal side-effects were inhibited in a separate group of rats administered tepoxalin (20 mg/kg, p.o) 30 min prior to each daily indomethacin treatment. Further studies were performed to determine tepoxalin's effects on early events associated with NSAID-induced gastrointestinal inflammation, including neutrophil adhesion, lipid peroxide generation and LTB 4 production. Indomethacin (100 mg/kg, p.o.) produced elevated levels of LTB 4 in rat gastric mucosa 90 min after administration. Additionally, neutrophil adhesion in mesenteric venules was increased at this dose and with the administration of another NSAID, naproxen. No generation of lipid peroxides was evident in the gastric mucosa at this timepoint. Tepoxalin (up to 400 mg/kg, p.o.) did not have an effects on gastric mucosal LTB 4 generation and lipid peroxide levels. A decrease in neutrophil adhesion was observed at the highest dose. In another study, pretreatment with tepoxalin (ED 50=7.5 mg/kg, p.o.) or the selective 5-LO inhibitor zileuton (100 mg/kg, p.o.) prevented the increases in gastric mucosal LTB 4 levels and neutrophil adhesion induced by indomethacin (100 mg/kg, p.o.). These data suggest that LO inhibition may play a vital role in the prevention of NSAID-induced gastric inflammation, providing insight into the lack of ulcerogenicity with tepoxalin and new approaches to anti-inflammatory therapy which may prevent gastric side effects.

A novel approach to reduce the unwanted gastric side-effects of orally administered non-steroidal anti-inflammatory drugs in rats

Among experimental circumstances both cysteine and glutathione, given in the same time as indomethacin or piroxicam, are capable to decrease the unwanted gastric side-effects of the non-steroidal anti-inflammatory drugs. Similar effects were encountered with prostacyclin or D-penicillamine therapy as well but additional prostacyclin therapy is expensive and complicated (its biological half-life is too short;) D-penicillamine has numerous other, non gastrointestinal side-effects, therefore these two latter substances seem to be inferior compared to the previously mentioned ones. Therefore we conclude that in the human non-steroidal anti-inflammatory therapy it would be worthwhile to apply those drugs with a small amount of either cysteine or glutathione to decrease their unwanted side-effects. This assumption is strengthened by the fact that neither cysteine nor glutathione is an unnatural material in the body.

Horizons in Pain Research. San Diego, California, May 19-21, 1995.

Horizons in Pain Research. San Diego, California, May 19-21, 1995.

Effect of zinc on the anti-inflammatory and ulcerogenic activities of indometacin and diclofenac.

In the present study, the potential anti-inflammatory activity of zinc sulfate (zinc) has been examined in rats with acute and chronic inflammation. Additionally, we studied the effect of the concurrent administration of zinc on the anti-inflammatory activity of indometacin and diclofenac and their gastric side effects. Oral or subcutaneous administration of zinc (25 and 15 mg/kg, respectively) significantly reduced carrageenan-induced paw edema. Subcutaneous co-administration of zinc (15 mg/kg) and indometacin (5 mg/kg) or diclofenac (10 mg/kg) resulted in a further reduction in paw edema which was more than either that produced by either agent alone. However, after oral co-administration of zinc and diclofenac the reduction in paw edema was not significantly different from that produced by either zinc or diclofenac alone. In rats with chronic inflammation, the administration of zinc (5 mg/kg s.c. for 7 days) proved as effective as either indometacin (3 mg/kg) or diclofenac (5 mg/kg). Co-administration of zinc with indometacin or diclofenac did not affect the level of activity of either drug. Co-administration of zinc did not affect the ulcerogenic effect of indometacin expressed as the ulcer index. In contrast to indometacin, administration of zinc markedly reduced the ulcerative action of diclofenac. In conclusion, zinc supplementation may contribute significantly to the treatment of inflammation. The combination of zinc with other anti-inflammatory drugs may provide beneficial additive effects and reduce their gastric hazards, particularly with diclofenac.

Treatment of brain metastases from primary lung cancer

A retrospective study of patients treated at the Peter MacCallum Cancer Institute for brain metastases from primary carcinoma of the lung is presented. The medical records of 416 patients with the diagnosis of primary carcinoma of the lung who presented with, or subsequently developed, brain metastases during the period January 1984 to December 1987 were reviewed. Information on a number of factors of potential prognostic significance (sex, age, histology, performance status and interval between diagnosis of the primary and brain metastases) was collected. Details of surgery, radiation and steroid usage were recorded, and any steroid side effects documented. Survival was calculated from the date of diagnosis of brain metastases. Stepwise regression based on Cox's proportional hazards model was used to determine significant prognostic factors affecting survival. Patients with and without steroid side effects were compared using Yates's corrected chi-square test. The overall estimated median survival was only 3.3 months (95% confidence interval 2.9-3.7 months). Only two factors were found to be associated with a significantly improved survival--surgical intervention and good performance status. After taking these two factors into account, the dose of radiation used (< 30 Gy or > or = 30 Gy) did not influence survival. There was a 3% incidence of gastric bleeding or perforation in patients taking steroids, with a 40% fatality rate. Predisposing factors to gastric side effects were a prior history of peptic ulcer and/or aspirin or nonsteroidal anti-inflammatory drug consumption. Radiation of brain metastases from primary lung cancer results in modest survival benefit. Radiation dose (< 30 Gy or > or = 30 Gy) is not a significant determinant of survival. Other treatment modifications, such as concurrent radiation and chemotherapy, should be explored. Steroids should be used with caution as fatal side effects can occur.

Electrical Potential Difference Across the Stomach Wall and Gastric Morphology in Anaesthetized Pigs After Intravenous Administration of Cytotoxic Drugs

Nausea and vomiting are frequent side-effects of cancer chemotherapy. To investigate whether such therapy has an acute toxic effect on the gastric mucosa, cyclophosphamide, epirubicin and fluorouracil were administered intravenously to anaesthetized pigs. Gastric mucosal function was evaluated by continuous measurements of the gastric transmucosal electrical potential difference (PD) and the intragastric pH by using a newly developed microelectrode principle. After sacrifice, gastric histology was examined. During chemotherapy a significant decline in gastric PD was observed two hours after drug infusion, indicating a hampered gastric mucosal function. Apart from a slight hyperemia, gastric histology was normal. In this animal model a change in gastric mucosal function developed at the same time after chemotherapy as the gastric side-effects in humans.

Die klinische Bedeutung der unerwünschten gastrointestinalen Wirkungen nichtsteroidaler Antirheumatika

Present non-steroid antirheumatics (NSAR) have a lower local toxicity at the gastric and duodenal mucosa than the salicylate derivatives. The incidence of gastric or intestinal side effects that are mediated systemically or by enterohepatic recirculation, however, is on the increase. This is ascribed to patientimmanent factors and changed intake habits in elderly patients. The varying average gastrointestinal side-effect potency of individual NSAR is of secondary importance. For each individual patient it will be necessary to find that NSAR that ensures maximum effect and minimum side effects, and this requires trials with probationers. It is only in recent years that we have come to know of NSAR-associated severe gastrointestinal ulcers and haemorrhages of partly lethal outcome, by means of epidemiology studies. Hence, when NSAR are prescribed for the first time or in repeat prescription, risk patients must be identified and, if necessary, treated prophylactically to protect their mucosa, or submitted to additional curative therapy.