Effect of omeprazole on the bioavailability of unmodified and phospholipid-complexed aspirin in rats.

BACKGROUND: Treatment and prevention of non-steroidal anti-inflammatory drug-induced gastropathy involve the concurrent use of antisecretory drugs. Recently, we have shown that the ability of these drugs to increase the intragastric pH to values > > pKa of NSAIDs compromises their therapeutic activity. In the present study, we evaluated the potential of omeprazole to interfere with the bioavailability of aspirin administered to rats either alone or complexed with the zwitterionic phospholipid, dipalmitoylphosphatidylcholine (DPPC). METHODS: Aspirin or aspirin/DPPC was administered intragastrically to rats pre-dosed with either saline or omeprazole. Concentrations of aspirin and salicylic acid in the blood and the gastric mucosa were assessed by HPLC and the 6-keto-PGF1 alpha gastric mucosal concentration by radioimmunoassay. RESULTS: Gastric absorption of aspirin and its relative bioavailability were reduced by an antisecretory dose of omeprazole; its inhibitory effect on gastric prostaglandin synthesis was consequently attenuated. However, these effects could be partly overcome if aspirin was administered as a complex with DPPC. CONCLUSIONS: These observations suggest that: (i) DPPC increases the lipid solubility and gastric permeability of NSAIDs; and (ii) neutralization of the gastric pH results in a shift of aspirin absorption toward the intestine where it could be degraded to salicylic acid.

Bleomycin induces apoptosis in human alveolar macrophages.

Bleomycin (BLM) is an effective antineoplastic drug; however, cumulative dosage is often associated with inflammation that can progress to pulmonary fibrosis. The mechanisms by which this occurs are not understood, but they have been proposed to involve the alveolar macrophage (AM). In this study, we examined the in vitro effects of BLM on human AM cytotoxicity and the role of heat shock proteins (HSP or stress proteins) in this process. Although BLM did not cause marked necrosis, it caused significant DNA fragmentation detected by in situ DNA labeling and confirmed by BLM-induced DNA ladder formation after 24 h. The DNA fragmentation was significantly blocked by 10 and 50 microM ZnCl2, suggesting that BLM was inducing apoptosis. BLM did not alter intracellular protooncogene bcl-2 or glutathione levels. However, BLM significantly (50%) blocked HSP-72 expression by 4 h during a mild heat stress (39.8 degrees C). This inhibition occurs without affecting mRNA levels (in situ hybridization) for HSP-72 or overall protein synthesis ([35S]methionine incorporation), suggesting that BLM is blocking the stress response relatively specifically and post-transcriptionally. In summary, these results suggest that BLM causes apoptosis in human AM in vitro that is preceded by the inhibition of HSP-72 induction that appears to be caused by a posttranscriptional mechanism.

Phase I clinical investigation of benzisoquinolinedione (amonafide) in adults with refractory or relapsed acute leukemia.

After Phase I studies of benzisoquinolinedione (amonafide) in solid tumors identified myelosuppression as the dose-limiting toxicity, we conducted a Phase I study in patients with relapsed or refractory acute leukemia to define the optimal dose. Amonafide was given i.v. over 2-4 h daily for 5 days. The starting dose was 600 mg/m2/day with subsequent escalation to 750, 900, 1100, 1400, and 1800 mg/m2/day. Thirty-eight courses were administered to 24 patients, of whom 12 participated in concomitant pharmacological studies. Nausea and vomiting, transient orange discoloration of the skin, and tinnitus occurred at all dose levels. The latter symptom, along with lightheadedness and flushing, was related to infusion duration; this was increased to 4 h with doses greater than or equal to 900 mg/m2. The dose-limiting toxicities were mucositis and painful skin erythema which occurred in all 4 patients treated with 1800 mg/m2. No remissions occurred. Clearing of peripheral blood blasts occurred in 67% of patients treated with 1100 mg/m2 and in all patients treated with greater than or equal to 1100 mg/m2/day. A decrease in marrow leukemic infiltrate (% blasts x % cellularity) to less than 10% occurred in 15 and 50% of patients treated at these levels, respectively. There were 10 deaths (42%), which were unrelated to dosage. The harmonic mean terminal plasma half-life was 4.6 h (range, 2.5-35.5 h). Three patients had long drug half-lives of 9.7, 16.4, and 35.5 h and each had initial bilirubin levels greater than 1.0 mg/dl. The average urinary excretion of amonafide over 5 days was 3.5% of the total dose. This establishes 1100-1400 mg/m2/day for 5 days as the maximally tolerated dose of amonafide for studies in acute leukemia.

Phase II study of 4-demethoxydaunorubicin in previously untreated extensive disease non-small cell lung cancer.

Fifteen patients with previously untreated extensive non-small cell lung cancer (E-NSCLC) were treated with oral 4-demethoxydaunorubicin (4-DMDR) at the dose of 10 mg/m2/day x 5 days every 3 weeks with routine administration of antiemetic drugs. They received a median of two courses of treatment with the cumulative dose range from 50-712.5 mg/m2. One patient achieved partial remission with a duration of 14 weeks. Two patients had minor responses with durations of 14 and 24 weeks. Stable disease occurred in three patients (21, 22, and 27 weeks). Median survival was 33 weeks (range 3-73+ weeks). Toxicities were tolerable. Neutropenia (less than 1,000 mm3) occurred in only 16% of all treatment courses. Three patients developed correctable arrhythmias (two with atrial fibrillation and one with accelerated junctional rhythm). The cause of arrhythmia was unclear. No clinical evidence of congestive heart failure or decreased cardiac ejection fraction was observed. Nausea and vomiting were common but tolerable. Alopecia and mucositis were uncommon. Clinical pharmacokinetic studies were done in nine patients. However, plasma 4-DMDR levels were below the limit of detection (3 ng/ml). Because 4-DMDR has shown some activity in previously untreated E-NSCLC and the toxicities at this dose schedule are mild, we suggest that further studies of this drug at a higher dose in this schedule are indicated.

Prospective randomized trial of high-dose cisplatin and fluorouracil infusion with or without sodium diethyldithiocarbamate in recurrent and/or metastatic squamous cell carcinoma of the head and neck.

Previous studies have indicated that sodium diethyldithiocarbamate (DDTC) can reduce cisplatin's (CP) toxic effects without altering the antitumor activity. DDTC has also been shown to have immunostimulative properties. Sixty patients with objectively measurable recurrent and/or metastatic squamous cell carcinoma (SCC) of the head and neck were randomized to receive either (A) CP at 120 mg/m2 over one hour on day 1, plus fluorouracil (5-FU) at 1,000 mg/m2 over 24 hours as a continuous infusion on days 1 through 5, or (B) CP/5-FU as in A, plus DDTC at 600 mg/m2 over 30 minutes administered intravenously (IV) exactly 30 minutes after CP infusion. Group B also received DDTC at 200 mg/m2 administered IV over 30 minutes on days 8 and 15. Each cycle was repeated at 3-week intervals. Objective responses were achieved in 41% of the CP/5-FU group and in 29% of the CP/5-FU with DDTC group (P = .26). Median survival was 9 months in group A and 10 months in group B. CP-related toxicity between the groups was equivalent with respect to nausea and vomiting, renal impairment, neurotoxicity, ototoxicity, and hematologic toxicity. The pharmacokinetics of reactive platinum species in plasma ultrafiltrate and urine samples obtained from both groups were comparable. The immune status of 48 patients was evaluated before and after completion of therapy. There were no significant differences in mean pretreatment and posttreatment values within or between groups A or B, except for absolute pretreatment OKT4 values (P = .02). We conclude that (1) the present dose and infusion schedule of DDTC did not significantly reduce CP-mediated toxic effects, (2) DDTC did not alter the disposition of ultrafilterable platinum species, (3) DDTC did not affect immune responses, and (4) the addition of DDTC improved neither the clinical response nor the survival of patients with recurrent SCC of the head and neck.

Phase I clinical investigation of benzisoquinolinedione.

A phase I study of benzisoquinolinedione (amonafide) was conducted in 30 patients with advanced solid tumors refractory to conventional therapy. The starting dose was 10 mg/m2/day X 5 days and the highest tolerated dose was 625 mg/m2/day X 5. The daily dose was mixed in 100 ml of normal saline and infused over 30-60 minutes. The dose-limiting toxicity was myelosuppression with nadirs of blood counts reached on Day 15 and recovery by Day 21-28. Other side effects included mild nausea and vomiting, mild phlebitis, skin rashes, and alopecia in some patients. A majority of the patients experienced dizziness, tinnitus, and hot flushes occurring predominantly at the higher dose levels. These were related to the rate of drug infusion and resolved on prolonging the infusion to 60 minutes. Pharmacokinetic studies of amonafide revealed a monoexponential plasma disappearance curve with a mean half-life of 3.5 +/- 1.9 hours. The recommended dose of amonafide for phase II studies in solid tumors is 400 mg/m2/day X 5 for good-risk and 300-320 mg/m2/day X 5 days for poor-risk patients with courses repeated at 21-28-day intervals.

Pharmacokinetics and metabolism of the antitumor drug amonafide (NSC-308847) in humans.

Pharmacokinetics and urinary excretion of Amonafide (5-amino-2-[2-(dimethylamine)ethyl]-1H-benz[de]isoquinoline-1,3-(2H)- dione) were examined in seven patients who were administered 400 mg/m2 of drug as a 30-min infusion on a daily schedule for 5 consecutive days. Amonafide concentrations in plasma and urine were determined using reversed phase HPLC. Amonafide was eliminated from plasma with a terminal half-life of 3.5 hr. Renal excretion accounted for 23% of the administered dose. Amonafide pharmacokinetic parameters after the initial dose (day 1) were similar to those calculated after the fifth daily dose. Amonafide undergoes a significant amount of metabolism and eight urinary metabolites have been identified using a thermospray liquid chromatography-mass spectrometry (LC/MS) technique. Various N-acetylated species appear to be the major metabolites, although no evidence of N-acetylation was found in urine obtained from two patients. Two of the primary metabolites, the N(N5)-acetyl and N'(N1)-oxide metabolites of Amonafide, were tested in vitro for cytotoxicity against P388 murine leukemia cells. In this test system, the N-acetyl metabolite was observed to be only slightly less cytotoxic than the parent compound. The N'-oxide of Amonafide, however, proved to be inactive. These results are discussed together with the pharmacokinetic and metabolism data of this new investigational antitumor drug.

Pulmonary disposition and pharmacodynamics of verapamil.

Verapamil, a calcium channel blocker, has received recent attention as a potential therapeutic agent in pulmonary hypertension. Accordingly, the pulmonary disposition and pharmacodynamics of verapamil were evaluated in isolated rat lungs perfused at a constant rate with a physiological salt solution. Isolated rat lungs sequestered but did not metabolize verapamil. The efflux of verapamil into drug-free perfusate occurred from two kinetically distinct pools with half-lives of 1.3 and 14.1 min. The theoretical amount of verapamil effluxed at infinite time was less than the amount taken up during the infusion, thereby suggesting that verapamil was also bound in a third "noneffluxable" pool. The time course for decline of verapamil inhibition of pulmonary vasoconstriction was compared with the rate of verapamil efflux. Inhibition of pulmonary vasoconstriction was related to the amount of verapamil in a pool exhibiting mono-exponential efflux of drug with a half-life of 12.6 min. This half-life suggests association of the inhibitory response with the efflux component having a half-life of 14.1 min. These findings indicate that the verapamil persists in the lungs in the form of a noneffluxable pool and that verapamil in the pool with half-life of 14.1 min is responsible for some of the vasoactivity in the pulmonary circulation.