Fexapotide triflutate: results of long-term safety and efficacy trials of a novel injectable therapy for symptomatic prostate enlargement.

PURPOSE: These studies were undertaken to determine if fexapotide triflutate 2.5 mg transrectal injectable (FT) has significant long-term (LT) safety and efficacy for the treatment of benign prostatic hyperplasia (BPH). METHODS: Two placebo controlled double-blind randomized parallel group trials with 995 BPH patients at 72 sites treated 3:2 FT:placebo, with open-label FT crossover (CO) re-injection in 2 trials n = 344 and long-term follow-up (LF) 2-6.75 years (mean 3.58 years, median 3.67 years; FT re-injection CO mean 4.27 years, median 4.42 years) were evaluated. 12 months post-treatment patients elected no further treatment, approved oral medications, FT, or interventional treatment. Primary endpoint variable was change in Symptom Score (IPSS) at 12 months and at LF. CO primary co-endpoints were 3-year incidence of (1) surgery for BPH in FT treated CO patients versus patients crossed over to oral BPH medications and (2) surgery or acute urinary retention in FT-treated CO placebo patients versus placebo patients crossed over to oral BPH medications. 28 CO secondary endpoints assessed surgical and symptomatic outcomes in FT reinjected patients versus conventional BPH medication CO and control subgroups at 2 and 3 years. RESULTS: FT injection had no significant safety differences from placebo. LF IPSS change from baseline was higher in FT treated patients compared to placebo (median FT group improvement - 5.2 versus placebo - 3.0, p < 0.0001). LF incidence of AUR (1.08% p = 0.0058) and prostate cancer (PCa) (1.1% p = 0.0116) were both reduced in FT treated patients. LF incidence of intervention for BPH was reduced in the FT group versus oral BPH medications (8.08% versus 27.85% at 3 years, p < 0.0001). LF incidence of intervention or AUR in placebo CO group with FT versus placebo CO group with oral medications was reduced (6.07% versus 33.3% at 3 years, p < 0.0001). 28/28 secondary efficacy endpoints were reached in LF CO re-injection studies. CONCLUSIONS: FT 2.5 mg is a safe and effective transrectal injectable for LT treatment of BPH. FT treated patients also had reduced need for BPH intervention, and reduced incidence of PCa and AUR.

Sodium fluoroacetate (1080): assessment of occupational exposures and selection of a provisional biological exposure index.

AIM: Sodium fluoroacetate (1080) is used for control of vertebrate pests in New Zealand. Little is known about chronic effects in humans, but animal studies demonstrate potential for adverse fetal, male fertility, and cardiac effects. We aimed to employ analyses of 1080 to help assess the degree of exposure of bait formulators and distributors, and identify specific tasks where exposure reduction appeared most indicated. We also aimed to utilise the (limited) 1080 toxicity data to assess the significance of the analytical results. METHOD: Exposures during various activities were assessed by monitoring air levels and blood and urine concentrations. To help evaluate the results, a provisional "biological exposure index" (BEI) was later derived, by extrapolating from experimental data. RESULTS: Early monitoring indicated exposures were highest in relation to (cereal) bait manufacturing and aerial carrot baiting procedures. A provisional BEI of 15 microg/L for 1080 in urine was proposed. CONCLUSION: Further protective measures and ongoing workplace monitoring are required, particularly in the above situations. Compliance with the current BEI cannot guarantee complete safety. Any information regarding chronic adverse effects in humans, along with the associated urine levels, would assist risk assessment. Further investigation of the human kinetics of fluoroacetate would be helpful.

Hepatic pathology and skin test reactions to trifluoro-acetylated autologous protein after repeated halothane anaesthesia in the guineapig.

The aetiology of the rare hepatic failure following halothane anaesthesia is not known. In an attempt to develop an experimental model, three groups of guineapigs were exposed to air or oxygen, a single 1% halothane administration, or five exposures of 1% halothane at weekly intervals. In an attempt to identify a hypersensitivity reaction, all animals were skin-tested with the common final metabolite of halothane, fluroxene and isoflurane: trifluoroacetic acid, prepared as a complex with autologous serum protein. Hepatic necrosis was found in all groups and did not correlate with positive skin reactions. There was an increase in fatty changes in the liver in animals anaesthetized with halothane.

Failure to induce hepatic pathology in animals sensitized to a halothane metabolite and subsequently challenged with halothane.

The results of this animal study confirm the induction of delayed hypersensitivity to a halothane metabolite, but the sensitization does not cause hepatic damage on subsequent halothane exposures. Before the hypothesis that hepatic necrosis following halothane has an immunologic basis can be accepted or rejected, more critical studies with different approaches must be made.