Phase 1 dose-escalation study of a siRNA targeting the RTP801 gene in age-related macular degeneration patients.

BACKGROUND: To evaluate the safety, tolerability, pharmacokinetics, and dose-limiting toxicities of a single intravitreal (IVT) injection of PF-04523655, a 19-nucleotide, O-methyl stabilized, double-stranded small interfering ribonucleic acid targeting the RTP801 gene in patients with neovascular age-related macular degeneration (AMD). METHODS: Prospective, phase 1, clinical multicentre trial, enrolled 27 patients with neovascular AMD unresponsive to prior treatment and best corrected visual acuity (BCVA) ≤ 20/200 in the study eye in stratum 1: (dose-escalating, open-label: 50 to 3000 µg of PF-04523655) and 27 patients who had potential to benefit from therapy and BCVA of ≤ 20/100 and ≥ 20/800 in stratum 2 (parallel, masked study of 1000, 1500, 2250, and 3000 µg of PF-04523655). The primary outcome was safety and tolerability assessment as well as pharmacokinetic profiling following a single IVT injection of PF-04523655. RESULTS: Doses of PF-04523655 ≥ 400 µg were generally detectable in the plasma at 1, 4, and 24 h post-injection. And all doses were below the lowest level of quantification by day 14. A single IVT injection of 50 to 3000 µg of PF-045237655 was generally safe and well tolerated over 24 months. There were no dose-limiting toxicities. CONCLUSION: A single IVT injection of PF-0523655 ≤ 3000 µg seems safe and well tolerated in eyes with neovascular AMD.

Benzydamine HCl for prophylaxis of radiation-induced oral mucositis: results from a multicenter, randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Benzydamine was evaluated in patients with head and neck carcinoma for treatment of radiation-induced oral mucositis, a frequent complication of radiation therapy (RT) for which there is no predictable therapy or preventive treatment currently available. METHODS: The safety and efficacy of 0.15% benzydamine oral rinse in preventing or decreasing erythema, ulceration, and pain associated with oral mucositis during RT were evaluated in a randomized, placebo-controlled trial conducted in patients with head and neck carcinoma. Subjects were to rinse with 15 mL for 2 minutes, 4-8 times daily before and during RT, and for 2 weeks after completion of RT; study evaluations were conducted before RT and routinely thereafter up to 3 weeks after RT. RESULTS: During conventional RT, regimens up to cumulative doses of 5000 centigrays (cGy) benzydamine (n = 69) significantly (P = 0.006) reduced erythema and ulceration by approximately 30% compared with the placebo (n = 76); greater than 33% of benzydamine subjects remained ulcer free compared with 18% of placebo subjects (P = 0.037), and benzydamine significantly delayed the use of systemic analgesics compared with placebo (P < 0.05). Benzydamine was not effective in subjects (n = 20) receiving accelerated RT doses (> or = 220 cGy/day). The incidence of adverse events between treatment groups was comparable without significant differences. Early discontinuation because of adverse events occurred in 6% of benzydamine subjects and 5% of placebo subjects, and there was 1 death (related to the primary diagnosis) in a placebo subject. CONCLUSIONS: Benzydamine oral rinse was effective, safe, and well tolerated for prophylactic treatment of radiation-induced oral mucositis.

Dose-response study of dapiprazole HCl in the reversal of mydriasis induced by 2.5% phenylephrine.

Dapiprazole HCL is currently available in the United States for reversal of diagnostic mydriasis. The recommended dosage for this indication is 2 drops followed 5 minutes later by 2 drops. We studied the dose-response profile and tolerance of three different treatment regimens: 1 drop alone, 1 drop followed by 1 additional drop 5 minutes later, and 2 drops followed by 2 additional drops 5 minutes later. Sixty normal male and female volunteers between 18 and 40 years of age were recruited for a double-masked, placebo-controlled, crossover study in which each eye of each subject was dilated with 2.5% phenylephrine. After one hour, one eye was treated with 0.5% dapiprazole, and the contralateral eye was treated with placebo. Each subject was treated with each of the three dapiprazole regimens in three different study sessions separated by at least 5 days (drug half-life in the eye is 5 hours). Analysis of AUC demonstrated no significant difference (P = 0.620) between the 1 drop regimen and the 2 + 2 regimen. A single drop of dapiprazole has a clinical effect equivalent to the 2 + 2 drop regimen in eyes dilated with 2.5% phenylephrine, which should improve the cost-effectiveness of this mydriolytic agent.

A prospective randomized comparison of radiation therapy plus lonidamine versus radiation therapy plus placebo as initial treatment of clinically localized but nonresectable nonsmall cell lung cancer.

PURPOSE: By means of a multicenter, prospective randomized, placebo-controlled study, to assess the impact of adding the radiation-enhancing agent lonidamine to standard "curative-intent" radiation therapy upon overall survival, progression-free survival, and local progression-free survival of patients with clinically localized but nonresectable nonsmall cell lung cancer. METHODS AND MATERIALS: Lonidamine, or the lonidamine-placebo, was administered at a dose of 265 mg/m2 in three divided daily doses. Drug therapy began 2 days prior to the initiation of radiation therapy and continued until progression of disease mandated a change in therapy. The radiation therapy dose was 55-60 Gy, at a daily dose of 1.8 Gy and five treatments per week. Patients with clinical Stage II or III nonsmall cell lung cancer were stratified within the treatment center, and within two histologic strata: epidermoid vs. other nonsmall cell cancers. RESULTS: A total of 310 patients were enlisted on study, 152 on the placebo arm and 158 on the lonidamine arm. The median survival durations were 326 days and 392 days for the placebo and lonidamine-treated groups respectively, p = 0.41 for a comparison of the survival curves. Median progression-free survival and median local progression-free survival durations were 197 days and 341 days for placebo + radiation therapy vs. 230 days and 300 days for lonidamine + radiation therapy; p-values for the respective curves were 0.75 and 0.42. Although there were proportionately more lonidamine-treated patients than placebo-treated patients demonstrating continued local control in excess of 12 months, the numbers of patients still at risk after 24 months were too small for meaningful statistical analysis. CONCLUSION: This multicenter Phase III study failed to demonstrate a significant advantage in the lonidamine-treated population in overally patient survival, in progression-free survival, or in the median duration of local control.

The effects on pupil size and accommodation of sympathetic and parasympatholytic agents.

The time-response effect of two currently used mydriatics, phenylephrine and tropicamide, were evaluated in 524 eyes. Four different types of dilating regimens were used: 2.5% phenylephrine, 10% phenylephrine, 0.5% tropicamide, and the combination of 2.5% phenylephrine and 0.5% tropicamide. The analysis indicated that the recovery from mydriasis occurs between 5.5 and 7.0 hours with 2.5% phenylephrine and at more than 7 hours with 10% phenylephrine. The 0.5% tropicamide induced rapid dilation, whereas the combined treatment, 2.5% phenylephrine plus 0.5% tropicamide, produced the largest maximum pupillary diameter. Tropicamide, alone or in combination, also produced a longer mydriatic effect, lasting more than 7.0 hours. The recovery from the cycloplegic effect of the mydriatics occurred between five and seven hours in the majority of patients, with tropicamide alone or in combination with phenylephrine requiring the most time to revert to normal ranges of accommodation. The findings in this study indicate that, in normal subjects, the recovery from the effect of mydriatic agents is longer than what is generally reported in the literature.

Lonidamine in head and neck cancer: an overview.

Lonidamine (LNM) has been employed in the treatment of advanced head and neck cancer (H & N) primarily with radiotherapy. It has been proposed that LNM potentiates the effects of radiation by inhibiting repair of potentially lethal damage by interfering with the mitochondrial associated repair processes. In addition, LNM appears to be more effective with fractionated doses of radiotherapy, which in light of the current emphasis on hyper/accelerated fractionation schemes may make it more efficacious. Initial H & N studies comparing LNM treated patients to historical controls report a complete response (CR) rate of 65% versus 45% respectively. All major H & N sites were included. Subsequent nonrandomized Phase II studies, although containing small numbers of patients, showed LNM to be ineffective as a single agent in patients previously treated with chemotherapy and not significantly different when radiotherapy was given with conventional dose rates. In a randomized Phase III study in which patients received an accelerated radiotherapy schedule (150 cGy bid) with either lonidamine or placebo, the CR rate was not significantly different, however, the local regional control rate was 48% versus 25% in favor of the LNM group. In addition, the 3 and 5 year duration of resonse (44% and 42% versus 26% and 17%) was improved in the LNM group. However, the 3-year actuarial survival rate was not different (49% v 43%). In summary the role of LNM as a radiopotentiator in advanced head and neck cancer appears to improve the local control rate, although survival was not significantly changed. However, future studies employing hyperfractionation schemes may show that the improved local control rate will translate into improved survival.