Phase I chemoprevention study of difluoromethylornithine in subjects with organ transplants.

Individuals who receive life-saving organ transplants and the required immunosuppression often develop secondary cancers. One of the most common secondary cancers is nonmelanoma skin cancer in sun-exposed areas. Attempts to prevent these cancers have not been successful. Difluoromethylornithine (DFMO), a suicide inhibitor of ornithine decarboxylase (ODC), is a known experimental cancer prevention agent that is being evaluated in a number of human cancer prevention trials. This report describes a Phase I trial in 18 organ transplant recipients, randomized to 1.0 and 0.5 g of DFMO or a placebo, designed to look at short-term toxicities over 28 days as well as the impact of DFMO on two biological parameters, skin polyamines and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ODC activity. Blood levels of DFMO were also measured. The results indicate that DFMO was well tolerated over the 28-day period. The TPA-induced ODC activity in 3-mm skin biopsies was significantly lowered by 80 and 67% at the two dose levels. Polyamine levels were not affected significantly except for putrescine at the 0.5-g level. Blood levels of DFMO were about two times higher than expected, based on our prior pharmacokinetic studies. Our studies indicate that DFMO is a reasonable agent that should be tested further in larger Phase 2b trials in this population as a chemopreventive agent. TPA-induced ODC activity appears to be a relevant intermediate biological assay.

Bioavailability study of oral liquid and tablet forms of alpha-difluoromethylornithine.

The purpose of this study was to assess the bioavailability of two oral preparations of difluoromethylornithine (DFMO). The current preparation of DFMO is a liquid with a concentration of 0.2 gram/ml that must be drawn up into a syringe and dispensed into a small medicine glass. This form of DFMO causes wastage of the medication. The liquid form also makes compliance and blinding difficult. Recently, a new coated tablet preparation has become available from Ilex Oncology Services (San Antonio, TX). The coated tablets are 0.25 gram and are scored. The tablet form should increase compliance by making it much easier for the subject to take the medication. This report compares the bioavailability of both preparations with the goal of demonstrating equivalence of the preparations. Ten normal subjects entered the cross-over study in which the order in which they would receive the liquid or tablet preparation of DFMO was randomized. The study was designed with the objective of establishing the bioequivalence of a tablet preparation of DFMO at daily dose 0.5 gram/m2 and a liquid preparation of DFMO at the same daily dose. The mean area under the time-by-concentration curves (microM x hours) for the liquid and tablet preparations was 368.2 and 370.4, respectively. The peak concentrations for the liquid and tablet preparations were 47.3 and 48.2 microM, respectively. No statistically significant differences were seen in these parameters, in time to peak concentration, or in serum half-life.

Associations among cystoscopic findings and symptoms and physical examination findings in women enrolled in the Interstitial Cystitis Data Base (ICDB) Study.

OBJECTIVES: To determine if specific symptoms or physical findings were associated with findings on cystoscopic examination under anesthesia in patients participating in the Interstitial Cystitis Data Base (ICDB) Study. METHODS: Subjects entering the ICDB Study completed symptom questionnaires and underwent physical examinations. Additionally, at the discretion of study investigators, 150 women underwent cystoscopy under anesthesia following a specific protocol of bladder distension at 70 to 80 cm irrigating fluid height and reinspection after capacity was reached and the irrigant drained. RESULTS: Statistically significant (p < 0.01) associations between bodily pain and urinary urgency with the presence of a Hunner's patch, and urinary frequency and urgency with a reduced bladder capacity under anesthesia were seen. Neither the findings of bloody irrigating fluid nor glomerulations were strongly associated with any symptom, and except for an association of urethral tenderness with Hunner's patch, no physical examination finding was associated with any cystoscopic findings. CONCLUSIONS: The strong associations of Hunner's patch and reduced bladder capacity under anesthesia with severe pain and urinary urgency, and urgency and frequency, respectively, indicate not only the importance of these findings in diagnosing interstitial cystitis, but also their potential utility in subclassifying this disease.