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.

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.

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

Endogenous serum testosterone in males after different doses and routes of administration of medroxyprogesterone acetate.

The effects of different doses and routes of administration (oral and IM) of medroxyprogesterone acetate on endogenous testosterone secretion were studied in healthy male volunteers. There were three treatment groups. Serum testosterone levels, measured by radioimmunoassay before, during and after different doses of medroxyprogesterone acetate, were significantly lowered (p < 0.05) in these subjects. A tendency to return toward pretreatment values was noted within three to six weeks after the last dose of medroxyprogesterone acetate. The IM route of administration suppressed the testosterone levels for the longest period of time. No indication of drug-induced toxicity, as judged by vital signs, systemic side effects, standard laboratory evaluations and some special clinical evaluations, was found during treatment or in the period immediately following the course of therapy. No serious or untoward side effects were encountered.

PIP: The effects of different doses and routes of administration (both oral and intramuscular) of medroxyprogesterone acetate on endogenous testosterone secretions were studied in healthy male volunteers. There were 3 treatment groups. Serum testosterone levels, measured by radioimmunoassay before, during, and after different doses of medroxyprogesterone acetate, were significantly lowered (P0.05) in these subjects. A tendency to return toward pretreatment values was noted within 3-6 weeks after the last dose of medroxyprogesterone acetate. Testosterone levels were suppressed for the longest period of time through intramuscular administration. No indication of drug-induced toxicity, as judged by vital signs, systemic side effects, standard laboratory evaluations and some special clinical evaluations, was found during treatment or in the period immediately following therapy. No serious or untoward side effects were encountered.

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.

The clinical pharmacology of methylprednisolone sodium phosphate. I. Intramuscular route of administration.

Intramuscularly administered methylprednisolone sodium phosphate (Medrol Stabisol) in single doses of 40, 80, or 160 mg (methylprednisolone equivalents) had a similar effect as the same doses of methylprednisolone sodium succinate (Solu-Medrol) with regard to eosinophil suppression, elevation of glucose, white blood count differential shifts (lympholytic effect), urinary excretion of sodium and potassium, and localized (pain) and systemic side effects. The average plasma methylprednisolone concentration was approximately 20% higher after the intramuscular administration of methylprednisolone sodium phosphate than after methylprednisolone sodium succinate. The differences in plasma methylprednisolone levels produced by the two esters suggest that either hydrolysis of the succinate ester occurs more slowly or the succinate ester distributes more extensively. This difference in plasma level, however, is not reflected in any other pharmacologic evaluation of the two esters, e.g., both eosinophil depression and hyperglycemic response were identical. No clinically significant changes in the vital signs, standard hematology, and clinical chemistry parameters evaluated were noted after 21 successive doses (q.i.d. for five days with one dose in the morning of day 6) of 80 mg methylprednisolone sodium phosphate. An increase was noted in the systolic blood pressure from a pretreatment mean of 113 mm Hg to a posttreatment mean of 123 mm Hg and an increase in the body weight from a pretreatment mean of 177 pounds to a posttreatment mean of 183 pounds. No signs of adrenal suppression were found as judged by plasma cortisol and ACTH levels. Six (6/12) subjects of the methylprednisolone sodium phosphate group, one (1/12) subject of the vehicle group, and one (1/12) subject of the placebo (sterile saline) group reported the following systemic side effects: gas in stomach, headaches, anorectal itching, and dryness of itching of the skin. No trend was observed for any side effect reported. In these double-blind, randomized studies, single (40, 80, and 160 mg) and multiple (80 mg) intramuscular doses of methylprednisolone sodium phosphate were tolerated in healthy volunteers as well as the same doses of methylprednisolone sodium succinate and similar volumes of vehicle or placebo.

Anorectal pruritus after intravenous hydrocortisone sodium succinate and sodium phosphate.

A double-blind study demonstrated that single intravenous doses of 100, 200, or 400 mg of hydrocortisone sodium succinate and hydrocortisone sodium phosphate were similar in eosinophil suppression, elevation of glucose, white blood count differential shifts (polymorphonuclear cells, lymphocytes, and monocytes), and urinary excretion of sodium and potassium but not in incidence of side effects. More subjects receiving hydrocortisone sodium phosphate experienced systemic or localized adverse effects than those receiving hydrocortisone sodium succinate. The most common side effect was burning or itching in the anorectal area, which occurred in 16 of 18 subjects medicated with hydrocortisone sodium phosphate, in 1 subject of 6 treated with placebo (saline), and in none who received the sodium succinate. The effect is attributed to the phosphate steroid and appears to last as long as it takes to convert to cortisol.

Unfavorable effect of atropine-diphenoxylate (Lomotil) therapy in lincomycin-caused diarrhea.

In this double-blind, randomized study, 200 normal subjects received a three-day course of one of five treatment regimens: lincomycin hydrochloride monohydrate injection (sterile solution, 300 mg/ml) with two tablets of either placebo, a mixture of atropine sulfate and diphenoxylate hydrochloride (Lomotil), an aspirin-phenacetin-caffeine (APC) combination or the latter with codeine, or an injection of saline with two placebo tablets. Gastrointestinal irritation was most prominent in subjects receiving lincomycin with atropine-diphenoxylate and lincomycin with APC plus codeine (P less than .05). Decreased intestinal motility from atropine-diphenoxylate or codeine may increase the contact time between the lincomycin (or its metabolites) or some developing toxic substances and the mucosal epithelium. The use of atropine-diphenoxylate or codeine in treating lincomycin-induced diarrhea may be questionable.