Purpose To evaluate the safety and efficacy of topical TOP1630, a novel nonsystemic kinase inhibitor, in dry eye disease (DED). Patients and methods A randomized, double-masked, parallel-group trial of 0.1% TOP1630 ophthalmic solution TID or placebo (vehicle without active drug) was conducted in DED subjects (n=61). Key eligibility criteria consistent with enrolling a moderate to severe DED population included >6 months DED history; OSDI © score ≥18; Schirmer’s test score ≤10 and ≥1 mm/5 minutes; tear film break-up time >1 and <7 seconds; and dry eye exacerbation in corneal staining and ocular discomfort in a Controlled Adverse Environment (CAE ® ). After a 7-day run-in period with placebo TID, eligible subjects were randomized to TOP1630 or placebo for 28 days. No supplemental artificial tears or rescue medication were allowed. Results TOP1630 was safe, well-tolerated, and efficacious in treating DED symptoms and signs. No serious adverse events (AEs) or withdrawals due to treatment emergent AEs occurred. Drop comfort scores showed TOP1630 to be comfortable and comparable with placebo. Significant symptom improvements were seen for TOP1630 vs placebo for ocular discomfort ( P =0.02 post-CAE), grittiness/foreign body sensation (on four independent assessment scales, each P <0.05), worst DED symptom (diary, P =0.06), and ocular pain (VAS, P =0.03). Sign improvements were seen for total ocular surface (all regions), corneal sum, and conjunctival sum staining with TOP1630 compared with placebo (each P <0.05). Conclusion TOP1630 had placebo-like tolerability and produced improvements in multiple symptom and sign endpoints in both environmental and challenge settings. The emergent TOP1630 benefit–risk profile for DED treatment is highly favorable and supports further development.

TOP1362 is a potent inhibitor of kinases upregulated in DED and markedly attenuates proinflammatory cytokine release in vitro and in vivo, highlighting the therapeutic potential of NSKIs for treating ocular inflammation, such as that observed in DED.

Rationale: Musculoskeletal (MS)pain is a known adverse class effect of aromatase inhibitors. Previously we reported high prevalence of Vitamin D deficiency in breast cancer patients complaining of MS pain, and anecdotal improvement of MS pain with weekly supplementation of high dose Vitamin D (HDD) (1). Here we report on a randomized double-blind, placebo-controlled trial of weekly HDD (ergocalciferol 50,000 IU) versus placebo (PBO) in breast cancer patient receiving anastrozole, with new or worsening MS pain since initiation of treatment, and with marginal levels of 25-OH Vitamin D (25OHD). The secondary aim was to determine whether HDD supplementation protects from bone loss.Methods: Inclusion criteria: 1) Postmenopausal women with invasive breast cancer (stage I - IIIB) on Anastrozole for at least 8 weeks; 2) new or worsening MS pain; 3) serum 25OHD level between 10 and 29 ng/ml. Design: 2 strata: 1) if 25OHD levels between 20-29 ng/ml, patients received 8 weeks of HDD then monthly HDD until the end of study (6 months) or PBO; 2) if 25OHD levels between 10-19 ng/ml, patients received 16 weeks HDD followed by monthly HDD until the end of the study or PBO. In addition, all patients received calcium (1000 mg/day) and standard Vitamin D supplementation (400 IU/day). Pain was measured by validated questionnaires (BPI, HAQ, FIQ) at baseline, month 2, month 4 and month 6. Bone Mineral Density was measured at baseline and at 6 months using a Hologic densitometer.Results: Sixty patients were enrolled. Mean age was 61.5 years. HDD and PBO groups did not differ at baseline in pain scores and 25OHD levels.At 2 months the HDD group reported lower scores on pain-related questions on BPI (question #3) at 2 mo, p=0.01 and FIQ (question #15), at 2 mo p=0.02. There was also a trend for better scores for walking and climbing steps on the HAQ [Group x Time Chi-square=3.6; at 2 mo p=0.02; p=0.009 at 4 mo]. Preliminary analysis of bone density data show higher femoral neck values in the HDD group at 6 months [% change 0-6 mo: HDD=0.54±0.71, PBO= -1.43±0.66, p=0.05]. There were no significant toxicities.Conclusions: HDD is well tolerated in this study, improves MS pain in patients receiving anastrozole, and may help functional activity. The effect was limited to the 2 month interval when patients on the active arm were receiving weekly treatment. Improvements decreased at 4 and 6 months once patients switched to monthly supplements. HDD may have also a positive effect on bone health. Limits of this pilot randomized study include the small number of patients, and the difficulty of measuring pain using clinical questionnaires.1) Taylor ME, Rastelli A, et.al. Incidence of 25-OH vitamin D deficiency in patients with a history of breast cancer who have musculoskeletal symptomatology. San Antonio Breast Cancer Symposium, Poster # 3072, December 2004Supported by Astra-Zeneca Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 803.

Background:Patients with inflammatory bowel disease (IBD) are at increased risk to develop malignant melanoma andthis risk may increase with the use of anti-TNF therapy. Impaired survival of immunosuppressed melanoma patients is reported in transplant and rheumatology patients This study aims to 1) identify risk factors for melanoma development in IBD patients, 2) compare clinical characteristics of melanoma in IBD patients to the general population and 3) assess the influence of immunosuppressive medication use on survival. Methods: We retrospectively searched the Dutch Pathology Database to identify all Dutch IBD patients with cutaneous melanoma between January 1991 and December 2011. We then performed two case-control studies. To identify risk factors for melanoma development in IBD, we compared IBD patients with melanoma to the general IBD population. To compare outcome and survival after melanoma diagnosis, we compared cases with non-IBD melanoma patients. Results: We included 304 IBD patients with melanoma, 1800 IBD controls, and 8177 melanoma controls. IBD cases had more extensive IBD (ulcerative colitis: pancolitis: cases 44.5% versus IBD controls without melanoma 28.1%; p<0.01; Crohn's disease: ileal and colonic disease: cases 57.9% versus controls 48.9%; p=0.02). Despite a lower N-stage in IBD patients (N1+ 8.3% versus 18.2%; p<0.01) with comparable T and M stages, survival was similar between groups, regardless of immunosuppressive or anti-TNF therapy. Conclusions: This study showed that IBD extent is a risk factor for melanoma development. Despite the lower N-stage in IBD patients, we could not confirm impaired survival after melanoma in IBD patients, regardless of anti-TNF and/or thiopurine use.

Summary: ADD 94057, a metabolite of fluzinamide, manufactured by the A. H. Robins Company, blocks chemically‐ and electrically‐induced seizures in animals. The primary objective of this open add‐on study was to evaluate patient tolerability of ADD 94057 at ascending target plasma concentrations. Nine subjects with medically refractory seizures were receiving phenytoin (PHT, 3), carbamazepine (CBZ, 3), or both (3). A pharmacokinetic profile after a single oral 400‐mg dose of ADD 94057 was used to calculate ADD 94057 dosages. After a 4‐week baseline period, patients were treated for 4 weeks with weekly ADD 94057 dosage escalations. Two patients completed the study at their assigned highest dosage level; the other patients finished the study at lower dosages. The patients receiving PHT (but not CBZ) tolerated higher plasma concentrations of ADD 94057 than did patients receiving CBZ, alone or in combination with PHT. Adverse experiences included headache, ataxia, blurred vision, diplopia, dizziness, lightheadedness, and mild confusion. Eight of nine patients had reductions in seizure frequency from baseline.