Oral liarozole in the treatment of patients with moderate/severe lamellar ichthyosis: results of a randomized, double-blind, multinational, placebo-controlled phase II/III trial.

BACKGROUND: Oral liarozole, a retinoic acid metabolism-blocking agent, may be an alternative to systemic retinoid therapy in patients with lamellar ichthyosis. OBJECTIVE: To demonstrate the efficacy and safety of once-daily oral liarozole in the treatment of moderate/severe lamellar ichthyosis. METHODS: This was a double-blind, multinational, parallel phase II/III trial (NCT00282724). Patients aged ≥ 14 years with moderate/severe lamellar ichthyosis [Investigator's Global Assessment (IGA) score ≥ 3] were randomized 3 : 3 : 1 to receive oral liarozole (75 or 150 mg) or placebo once daily for 12 weeks. Assessments included: IGA; a five-point scale for erythema, scaling and pruritus severity; Short Form-36 health survey; Dermatology Life Quality Index (DLQI); and safety parameters. The primary efficacy variable was response rate at week 12 (responder: ≥ 2-point decrease in IGA from baseline). RESULTS: Sixty-four patients were enrolled. At week 12, 11/27 (41%; liarozole 75 mg), 14/28 (50%; liarozole 150 mg) and one out of nine (11%; placebo) patients were responders; the difference between groups (liarozole 150 mg vs. placebo) was not significant (P = 0.056). Mean IGA and scaling scores decreased from baseline in both liarozole groups at weeks 8 and 12 vs. placebo; erythema and pruritus scores were similar between treatment groups. Improvement in DLQI score was observed in both liarozole groups. Treatment with liarozole for 12 weeks was well tolerated. CONCLUSIONS: The primary efficacy variable did not reach statistical significance, possibly owing to the small sample size following premature termination. However, once-daily oral liarozole, 75 and 150 mg, improved scaling and DLQI and was well tolerated in patients with moderate/severe lamellar ichthyosis.

Development of in vitro models for investigating spatially fractionated irradiation: physics and biological results.

We present different in vitro experimental models which allow us to evaluate the effect of spatially fractionated dose distributions on metabolic activity. We irradiated a monolayer of MCF-7/6 human breast cancer cells with a steep and a smooth 6 MV x-ray dose gradient. In the steep gradient model, we irradiated the cells with three separate small fields. We also developed two smooth gradient models. In the first model, the cells are cultured in a T25 flask and irradiated with a smooth dose gradient over the length of the flask, while in the second one, the cells are cultured in a 96-well plate and also irradiated over the length of the plate. In an attempt to correlate the spatially fractionated dose distributions with metabolic activity, the effect of irradiation was evaluated by means of the MTT assay. This assay is used to determine the metabolic activity by measuring the amount of formazan formed after the conversion of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) by cellular dehydrogenases. The results obtained with our different models suggest a dose-specific effect on metabolic activity, characterized by an increased formazan optical density occurring in the dose range 1.0-4.0 Gy in the steep dose gradient model and in the dose ranges 4.2-6.5 Gy and 2.3-5.1 Gy in the two smooth dose gradient models. The corresponding times for maximal formazan accumulation were 5-7 days in the steep dose gradient model and day 9-13 and day 9-11 in the smooth dose gradient models. Altogether, our results suggest that the MTT assay may be used as a biological dose-response meter to monitor the radiotherapeutic effectiveness.

Defining the human copper proteome and analysis of its expression variation in cancers.

Copper (Cu) is essential for living organisms, and acts as a cofactor in many metabolic enzymes. To avoid the toxicity of free Cu, organisms have specific transport systems that 'chaperone' the metal to targets. Cancer progression is associated with increased cellular Cu concentrations, whereby proliferative immortality, angiogenesis and metastasis are cancer hallmarks with defined requirements for Cu. The aim of this study is to gather all known Cu-binding proteins and reveal their putative involvement in cancers using the available database resources of RNA transcript levels. Using the database along with manual curation, we identified a total of 54 Cu-binding proteins (named the human Cu proteome). Next, we retrieved RNA expression levels in cancer versus normal tissues from the TCGA database for the human Cu proteome in 18 cancer types, and noted an intricate pattern of up- and downregulation of the genes in different cancers. Hierarchical clustering in combination with bioinformatics and functional genomics analyses allowed for the prediction of cancer-related Cu-binding proteins; these were specifically inspected for the breast cancer data. Finally, for the Cu chaperone ATOX1, which is the only Cu-binding protein proposed to have transcription factor activities, we validated its predicted over-expression in patient breast cancer tissue at the protein level. This collection of Cu-binding proteins, with RNA expression patterns in different cancers, will serve as an excellent resource for mechanistic-molecular studies of Cu-dependent processes in cancer.

Tolerability of levocabastine eye drops.

Levocabastine is a very potent histamine H1 antagonist, available for ocular use as eye drops containing 0.5 mg/ml of levocabastine with benzalkonium chloride as a preservative. Local tolerability of the eye drops was evaluated by objective measurements including slit lamp, tonometry, fluorescein and rose Bengal staining, ophthalmoscopy, visual acuity and visual field determinations, as well as subjectively by questioning for adverse experiences. Seven ocular tolerability studies were performed in a total of 71 volunteers and 103 patients with allergic conjunctivitis. Levocabasine was given from twice to four times daily for 1-8 weeks. Two studies were open, three were placebo controlled and in two, levocabastine was compared with terfenadine. No changes of either clinical or statistical significance were observed in the ocular or peri-ocular tissues. Subjectively, local irritation, pain and tearing were virtually absent. Detailed ophthalmological tolerance studies therefore showed levocabastine eye drops to be very well tolerated.

Levocabastine eye drops in the treatment of vernal conjunctivitis.

The efficacy and tolerability of levocabastine eye drops in vernal conjunctivitis (VC) were evaluated in a double-blind, placebo-controlled trial involving 46 patients over a period of 4 weeks. After 1 week of treatment, therapeutic efficacy was considered to be excellent or good for 70% of the levocabastine-treated patients compared with only 33% of patients in the placebo group (p < 0.009). Levocabastine patients experienced significantly greater relief of their individually severest symptom than placebo-treated patients both after 1 week and at the end of the trial (p < 0.04). The reduction in symptom severity was significantly greater in the levocabastine group than in the control group for photophobia (p < 0.003) after 1 week, and for photophobia (p < 0.008), irritation (p = 0.05) and itchy eyes (p = 0.05) at the end of the trial. The percentage of days on which patients were completely symptom-free was significantly higher in the levocabastine group than in the placebo group (28% versus 4%; p < 0.02). Eight placebo-treated patients withdrew from the trial due to treatment inefficacy compared with only four levocabastine-treated patients (p = 0.013). Two of the three levocabastine, and all five placebo patients who elected to continue on open-label levocabastine had an excellent or good overall response after 1 to 3 weeks of treatment. All reported adverse reactions were mild and their incidence was equal in the two treatment groups. Levocabastine eye drops are effective and well tolerated in the treatment of VC.

New trends in the treatment of allergic conjunctivitis.

Histamine is the key mediator producing itching, redness and chemosis in allergic conjunctivitis. Histamine levels in tears are increased ten-fold in patients with this allergic condition. Levocabastine is a newly synthesized histamine H1 antagonist which has been formulated as both eye drops and nasal spray. In well established assays of antihistamine activity, levocabastine was found to be the most potent antihistamine compound available, being 15,000 times more potent than chlorpheniramine. Ocular provocation studies in man have shown that levocabastine protects against the symptoms of allergen-induced conjunctivitis. Ophthalmological examinations, including slit lamp and ophthalmoscopy showed no adverse effects. Data from therapeutic studies are available for more than 1700 patients with allergic conjunctivitis treated for 2-16 weeks. One drop of levocabastine (0.5 mg/ml) per eye given two to four times daily provided significantly better symptom control than placebo, with good to excellent results in 71% of patients on levocabastine compared to 55% on placebo (p < 0.001). Levocabastine has a fast onset of action. In one study 94% of patients experienced symptom relief within 15 minutes after the first instillation. The effects observed with levocabastine were at least as good as those with ocular cromoglycate or oral terfenadine. The incidence of adverse experiences was not different from placebo. Levocabastine promises to be a valuable treatment for patients with allergic conjunctivitis.