NSAID-induced gastric ulceration is dose related by weight: an endoscopic study with flurbiprofen.

Numerous studies have shown that higher doses of nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with increased levels of mucosal injury and ulceration in both normal volunteers and patients. The present dose-ranging study was designed to determine whether escalating doses of a commonly prescribed NSAID, flurbiprofen, when expressed as mg/kg dosages, were associated with increased mucosal injury and ulceration. Subjects received either the recommended dose of 300 mg/day of flurbiprofen (N = 10), or the higher than recommended doses of 400 mg/day (N = 20) and 500 mg/day (N = 10), for a period of 7 days. Endoscopic examination was performed on day 0 and day 7, and the stomach was evaluated on day 7 for mucosal injury on a 0-4 scale, and for the presence or absence of ulcer. One gastric ulcer was seen in each of the 300- and 400-mg groups. However, in the 500 mg/day group, four gastric ulcers were seen (40%) (p = 0.04). Three of the six subjects developing gastric ulcer were of a fairly low body weight (two women, one man), and when the data were analyzed on a mg/kg basis, all six ulcers occurred in 19 of the 40 subjects receiving > 5.95 mg/kg, whereas no gastric ulcers were seen in the 21 subjects receiving dosages below that level (p < 0.01). These data suggest that, at least for this agent, a threshold level may exist above which gastric ulcers are much more likely to occur. This may in part explain why elderly debilitated, low-body-weight female patients are more prone to NSAID-related gastric ulcer.

Cytarabine and neurologic toxicity.

Cytarabine is an effective drug in the treatment of certain hematologic malignancies and its common toxicities are myelosuppression and gastrointestinal disturbance. In the past decade, neurotoxicity has been an increasingly recognized cytarabine effect. Intrathecal (IT) cytarabine may result in myelopathy that is incompletely reversible. Combined IT drug and cranial irradiation may lead to necrotizing leukoencephalopathy. Intravenous (IV) therapy may cause a peripheral neuropathy that varies greatly in its severity. The high IV cytarabine doses now commonly used can cause seizures, cerebral dysfunction, or an acute cerebellar syndrome with an incidence up to 14%. Patient age (greater than 60 years) appears to be the most important risk factor, but drug dose/schedule, cumulative drug dose, renal and hepatic dysfunction, and concomitant use of neurotropic antiemetic agents may also influence the risk of neurotoxicity. A better understanding of the pathophysiology and pharmacology of such cytarabine-induced neuronal injury will allow this drug to be used with greater efficacy and safety.

The effects of flurbiprofen, aspirin, cimetidine, and antacids on the gastric and duodenal mucosa of normal volunteers. An endoscopic and photographic study.

This 7-day, single blind, randomized endoscopic tolerance study compared daily doses of 100, 150 and 200 mg flurbiprofen with 2600 mg aspirin. After seven days the flurbiprofen 100 and 150 mg groups had significantly less gastric irritation than the flurbiprofen 200 mg and aspirin groups. Flurbiprofen showed a linear dose-response relationship with respect to gastric injury and serum drug levels. Four subjects each on aspirin and flurbiprofen with the most severe injuries continued on their medications plus cimetidine and antacids for four more weeks. Both drug groups showed clinical improvement in the gastroduodenal area. In conclusion, flurbiprofen and aspirin therapy can be tolerated in the presence of gastroduodenal irritation by concomitantly administering cimetidine and antacids.

Experimental studies on the response of nude mouse-grown human urothelial cancer to high dose of 1-beta-D-arabinofuranosylcytosine.

The effect of 1-beta-D-arabinofuranosylcytosine (ara-C) on human bladder transitional cell carcinomas (TCC) was evaluated using nude mouse-grown established tumor lines SW-780, SW-1738, TCC-K1, and PR49. In the nude mouse tumors grew subcutaneously and evaluation of response to treatment was based on tumor volume analysis. Ara-C was administered intraperitoneally at a dosage of 250 mg/kg on days 1 to 4. All four tumor lines showed an initial phase of considerable regression during the treatment week. This was followed by a variable period of tumor growth arrest after which a gradual tumor regrowth was observed. The results of the present study suggested that ara-C may alter the growth rate of TCC, its effect becoming apparent during the time of its administration and for a short period thereafter. These observations indicate that more studies are warranted at both the experimental and clinical levels to further evaluate dosage and treatment schedule. The results of such additional studies may determine the importance of ara-C in the management of patients with bladder cancer.

Effect of acetaminophen on human gastric mucosal injury caused by ibuprofen.

Acetaminophen has been proposed as an agent which protects the gastric mucosa against damage induced by aspirin and other non-steroidal anti-inflammatory agents. In order to evaluate this proposal further, 45 normal human volunteers were divided into three groups (n = 15); group one received ibuprofen 2400 mg daily (600 mg qid); group two received acetaminophen 3900 mg daily (975 mg qid) and group three received both drugs at the same dosages. There was no significant difference in the mucosal injury scores noted at endoscopy between the ibuprofen and the ibuprofen-acetaminophen group. The acetaminophen group had virtually no observed mucosal injury and this was statistically significant in comparison with the other groups (p less than 0.01). We conclude that contrary to previously reported studies using single doses of aspirin, acetaminophen failed to decrease the mucosal injury seen with ibuprofen when given for a period of seven days in combination with acetaminophen.

Effects of flurbiprofen and aspirin on the gastric and duodenal mucosa. An endoscopic comparison.

A single-blind, randomized endoscopic tolerance study was conducted to compare daily doses of flurbiprofen (Ansaid, Upjohn) at 100, 150, and 200 mg per day with 2,600 mg of aspirin per day. Ten normal volunteers were enrolled in each of the flurbiprofen groups, and five were enrolled in the aspirin group. Analysis of the mean gastric mucosal injury scores obtained on day eight revealed statistically significant lower mean scores (p = 0.05) in the 100-mg and 150-mg flurbiprofen treatment groups when compared with the 200-mg flurbiprofen group and the aspirin group. No significant differences were found between any of the treatment groups in duodenal mucosal injury scores. Mean scores for gastric mucosal injury in the three groups receiving flurbiprofen showed a definite dose relationship. The aspirin-treated subjects had significantly decreased uric acid levels (p = 0.006) and a significantly higher incidence of tinnitus (p = 0.04) compared with the flurbiprofen treatment groups. There was a poor correlation between subjective symptomatology and endoscopic pathologic findings.

Ethanol, aspirin, ibuprofen, and the gastroduodenal mucosa: an endoscopic assessment.

The effect on the gastroduodenal mucosa of alcohol combined either with aspirin or ibuprofen was studied in 60 normal volunteers. The volunteers were divided into six groups comprised of 10 subjects receiving ibuprofen, placebo, or aspirin with or without alcohol. Medications consisted of 1) three 325-mg aspirin tablets, or three identical placebo tablets, 2) one 600-mg ibuprofen tablet, and 3), three ounces of 100 proof vodka diluted in 6 ounces of orange juice, or alcohol placebo made by diluting 3 ounces of water in orange juice. All subjects received 4 doses over a 24-hr period and underwent endoscopic examination the following morning. The gastroduodenal mucosa was graded according to a 0 to 4 + scale. Aspirin caused considerably greater duodenal and gastric damage than did either ibuprofen or placebo. The addition of alcohol to all drugs increased the damage seen in the stomach but not to a significant degree; this effect was slightly more pronounced with ibuprofen than with placebo or aspirin and approached significance (0.1 greater than p greater than 0.05). These results are compatible with alcohol being a mild damaging agent or a potentiating agent for damage from other drugs.

Safety profile: fifteen years of clinical experience with ibuprofen.

Since its introduction in the United States in 1974, ibuprofen (Motrin, Upjohn) has been shown to be safe and effective for the treatment of pain, dysmenorrhea, inflammation, and fever. A careful review of pre-registration and postmarketing data from both patients and normal subjects clearly indicates ibuprofen's remarkable safety profile compared with that of aspirin and other commonly prescribed nonsteroidal anti-inflammatory agents. Continued safety can be anticipated on the basis of the past 15 years of review experience.

A comparative endoscopic evaluation of the damaging effects of nonsteroidal anti-inflammatory agents on the gastric and duodenal mucosa.

Twenty-five normal volunteers were randomized into five equal parallel groups. Groups I received ibuprofen (2,400 mg./day); group II received tolmetin (2,000 mg./day); group III received indomethacin (150 mg./day); group IV received naproxen (750 mg./day) and group V received placebo (four tablets daily). All drugs were given on a q.i.d. basis except naproxen which was given b.i.d. The doses selected represented the manufacturer's highest recommended dosage for the treatment of arthritic disorders. A single-blind technic was used in which the investigators were unaware of which drug each volunteer was taking. Upper gastrointestinal endoscopy and photography were carried out before and after seven days of administration of each medication. Gastric and duodenal mucosal injury was graded on a 0-4 + scale. Three of the four drugs studied produced essentially equal gastric and duodenal mucosal injury with tolmetin producing the most damage followed by naproxen and indomethacin. Ibuprofen produced gastric mucosal injury equivalent to that seen with naproxen and indomethacin but no duodenal mucosal injury was seen with this drug. Extremely poor correlation was found between subjective symptomatology and endoscopic findings.

Sebum production and plasma testosterone levels in man after high-dose medroxyprogesterone acetate treatment and androgen administration.

PIP: In 47 healthy male volunteers, the administration of 100 mg of oral (MPA) medroxyprogesterone acetate daily for 42 consecutive days caused a modest 16.7% decrease in sebum production from a baseline mean of 2.28 mg to a posttreatment mean of 1.90 mg. This represented a considerably smaller decrement than had been reported in the literature. Immediately following the period of MPA administration, the addition of daily oral doses of either 50 mg of fluoxymesterone, methyltestosterone, or calusterone to the 100 mg daily dose of MPA for 42 additional days resulted in the return of sebum production to essentially presuppression values. A statistically significant decrease in serum testosterone levels from a pretreatment mean of 862 ng/100 ml to a posttreatment mean of 251 ng/100 ml, was seen in all groups treated during the first 42 days with 100 mg of MPA daily (P0.05). The addition of 50 mg of fluoxymesterone, methyltestosterone, or calusterone to the 100 mg of MPA for another 42 day period caused a further decrease in serum testosterone levels (P0.001); the fluoxymesterone-MPA combination produced the greatest decrease of serum testosterone levels, from a pretreatment mean value of 932.8 ng/100 ml (Day 1), to a posttreatment mean value of 70.6 ng/100 ml (Day 85). The daily dose of 20 mg of MPA for 42 consecutive days caused less suppression of serum testosterone levels (from 831 ng/100 ml to a mean of 585 ng/100 ml) than 100 mg of MPA from 831 ng/100 ml to a more than that of placebo (pretreatment mean of 886 ng/100 ml to a posttreatment mean of 871 ng/100 ml). Except for changes in hemoglobin, hematocrit, and haptoglobin values, no other medically significant changes were seen in the routine screening chemistries and urine analyses for any of the drug groups. These changes were not unexpected, as they are known to occur with androgen therapy. Of potentially clinical importance was the absence of any effect of antithrombin-3 levels during the study period. No major side effects were reported other than in 1 patient who developed gynecomastia of his right breast on Day 42 of MPA therapy. After his being removed from the study, the gynecomastia disappeared rapidly.^ieng

Effects of ibuprofen, tolmetin and placebo on the gastric mucosa of aspirin-sensitive volunteers.

Patients who have demonstrated a gastric mucosal sensitivity to aspirin often react to other nonsteroidal, anti-inflammatory drugs to a similar or lesser degree. In a single-blind crossover study, five healthy volunteers who had previously developed erosive gastritis secondary to one week of aspirin therapy were randomly assigned to seven-day courses of treatment with ibuprofen, tolmetin and placebo. Treatment schedules were separated by washout periods to eliminate residual drug effects. Ibuprofen produced less gastric mucosal injury than tolmetin and, over all, appeared to be better tolerated. It was also noted that clinical symptoms often do not reflect the severity of gastroscopic findings, which may explain silent hemorrhaging in patients treated with agents of this type.

The effects of ibuprofen, indomethacin, aspirin, naproxen, and placebo on the gastric mucosa of normal volunteers: a gastroscopic and photographic study.

The effects of various nonsteroidal antiinflammatory drugs on the gastric mucosa were endoscopically evaluated in 40 normal volunteers. Eight groups, each containing five subjects were designed: aspirin (3600 mg/d); placebo; ibuprofen (1600 mg/d); ibuprofen (2400 mg/d); indomethacin (100 mg/d); indomethacin (150 mg/d); naproxen (500 mg/d); and naproxen (750 mg/d). All volunteers took medication for seven days and gastroscopy was carried out on day one and day eight. All findings were documented by photography. Severe gastric mucosal injury occurred with aspirin (P less than 0.05), both doses of indomethacin, and the higher dose of naproxen. Lesser changes were seen with the lower dose of naproxen, both doses of ibuprofen and placebo. The higher doses of ibuprofen, indomethacin, and naproxen caused a greater degree of gastric mucosal injury, but statistical significance was achieved only with naproxen (P less than 0.01). Subjective gastrointestinal complaints generally correlated with endoscopic pathology; however, nine volunteers had evidence of severe injury to the gastric mucosa with no symptomatology. This was confined to the patients on indomethacin, naproxen, and ibuprofen. Aspirin patients all had some degree of symptomatology but to a lesser degree than expected in view of the endoscopic findings.

Ibuprofen versus buffered phenylbutazone in the treatment of osteoarthritis: double-blind trial.

In a double-blind multiclinic trial, a new nonsteroidal anti-inflammatory agent (ibuprofen) was compared with an established therapeutic agent (phenylbutazone-alka) for the treatment of osteoarthritis. Of the 159 patients from the 17 contributing clinics, 144 completed the four weeks of therapy. More than 60 per cent of them reported improvement in exercise-related pain by week 4, and there was no significant difference between treatment groups. The patients' and the physicians' evaluations of the total state of disease, as well as range-of-motion and functional tests, demonstrated similar degrees of improvement in both treatment groups. The incidence of side effects was within acceptable limits, and the frequency distribution was similar in both groups. Of the 70 reported side effects, 29 were considered by the investigator (blind trial) to be drug-related-11 in association with ibuprofen and 18 with phenylbutazone-alka. Hematologic and blood chemical studies, as well as urine and stool examinations, yielded normal results with the exception of a reduced mean value for serum uric acid and a slightly elevated mean value for SGPT in the phenylbutazone-alka group.

A long-term double-blind clinical trial of ibuprofen and indomethacin in rheumatoid arthritis.

Two-hundred and eighteen individuals with rheumatoid arthritis were randomly assigned to six months treatment with ibuprofen (900-1800 mg/day) or indomethacin (75-150 mg/day). The drugs were equally effective in the treatment of rheumatoid arthritis while the incidence of indomethacin side-effects was 1.5 times greater than the incidence of ibuprofen side-effects.