A phase I study to evaluate the safety,tolerability, pharmacodynamic and pharmacokinetic profiles of ocular GLH8NDE in healthy male adults

GLH8NDE, a derivative of eupatilin, is currently under development to treat dry eye disease. We conducted a randomized, double‐masked, placebo‐controlled, single‐ and multiple‐day study to evaluate safety, tolerability, pharmacodynamics, and pharmacokinetics of ocular GLH8NDE in healthy male adults. Subjects randomly received topical ocular dosing of GLH8NDE or its matching placebo for a day, then for 7 consecutive days with a 62‐h washout at one of the following daily doses: 9, 18, 36 (Koreans), and 36 mg (Whites). The study drug was administered in divided doses over 10 h with 2‐ or 5‐h intervals. Thirty‐nine (97.5%) out of 40 subjects completed the study. A total of 17 subjects experienced 31 treatment‐emergent adverse events, all of which were mild in severity and recovered without sequelae. Neither pathological changes in eye compartments nor clinically significant systemic effects were observed. GLH8NDE was rapidly absorbed reaching the peak concentration within 0.25–0.75 h postdose. The systemic exposure as measured by area under the concentration‐time curve from time of administration up to the time of the last quantifiable concentration (AUC_last) after single‐day administration of the same dose was 109% higher in Koreans than in Whites. In conclusion, GLH8NDE was safe and well‐tolerated in healthy Korean and White male adults at 9–36 mg/day after single‐ and multiple‐day administrations.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

GLH8NDE (7‐carboxymethyloxy‐3′,4′,5′‐trimethoxy flavone) is a derivative of eupatilin, which is currently under clinical development to treat dry eye disease (DED). GLH8NDE has been effective in various experimentally induced DED animal models. Ocular GLH8NDE has never been studied in humans.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This phase I study evaluated the safety, tolerability, pharmacodynamic, and pharmacokinetic profiles of ocular GLH8NDE in humans. In addition, the ethnic difference in the systemic exposure to GLH8NDE was assessed between Korean and White healthy male adults.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Ocular doses of GLH8NDE from 9 to 36 mg per day after single‐ and multiple‐day administrations were safe and well‐tolerated in Korean and White healthy male adults. GLH8NDE was rapidly absorbed in a dose‐proportional manner. The systemic exposure to GLH8NDE was higher in Koreans than in Whites. GLH8NDE at 9 and 36 mg per day increased tear break‐up time (TBUT) from baseline whereas TBUT was decreased in the placebo group.

• HOW MIGHT THIS CHANGE DRUG DISCOVERY, DEVELOPMENT, AND/OR THERAPEUTICS?

This study shows that GLH8NDE is safe and well‐tolerated in healthy Korean and White male adults over the dose range of 9–36 mg per day. GLH8NDE has a potential to be developed as a useful treatment option for DED. Further research should take account the ethnic differences in the systemic exposure to GLH8NDE.     

A case of cutaneous extranodal natural killer/T-cell lymphoma clinically and histopathologically mimicking interface dermatitis

Extranodal natural killer/T-cell lymphoma (ENKTL) is a rare but aggressive cancer characterised by angiocentric and angiodestructive infiltration by NK-cells, or cytotoxic T-cell types. Histopathologically, ENKTL shows a multinodular or diffuse infiltration localised to vascular structures, resulting in angiodestruction and necrosis. We present a patient with an initially suspected diagnosis of benign interface dermatitis with a differential diagnosis of mycosis fungoides that was later found to be an aggressive extranodal natural killer/T-cell lymphoma of a nasal type and with a dismal prognosis.     

Surgical management of lipomas: Proposal of the Z‐incision design and surgical algorithm based on tumor size

Surgical excision is the treatment of choice for lipomas. However, linear incision methods or minimal extraction techniques often do not provide a sufficient surgical view. Therefore, removing large lipomas is often difficult. To present the Z‐incision and half Z‐incision designs for lipoma extraction, this retrospective study analyzed lipomas surgically excised at our institution between September 2015 and December 2018. The area of surgical field exposed by the Z‐incision versus that exposed by the linear incision was calculated using a schematic model. Cure rate, complications, and surgical field area were investigated. A total of 84 lipomas were included. A Z‐ or half Z‐incision was used to treat 30 lipomas, while a linear incision was used to treat 54 lipomas. The mean diameter of the mass in the Z‐ or half Z‐incision group was 47.7 mm (range, 15–160 mm), larger than that in the linear incision group (25.5 mm; range, 7–59 mm) (p < .001). The Z‐incision involved making rectangular windows by lifting 2 triangular flaps. According to our mathematical model, the Z‐incision provided a larger surgical field area than that provided by the linear incision based on stretched angles (1.81 times larger at 30° and 3.14 times larger at 15°). The Z‐ and half Z‐incisions were successfully performed in all but 1 lipoma (29 lipomas, 96.7%). There was 1 lipoma that resulted in postoperative complications (seroma, 3.3%). The Z‐incision design can be a useful alternative technique for the extirpation of lipomas, especially large lipomas. Here, we proposed a surgical algorithm for lipoma surgery based on tumor size.     

Interval breast cancer risk associations with breast density,family history and breast tissue aging

Interval breast cancers (those diagnosed between recommended mammography screens) generally have poorer outcomes and are more common among women with dense breasts. We aimed to develop a risk model for interval breast cancer. We conducted a nested case–control study within the Melbourne Collaborative Cohort Study involving 168 interval breast cancer patients and 498 matched control subjects. We measured breast density using the CUMULUS software. We recorded first-degree family history by questionnaire, measured body mass index (BMI) and calculated age-adjusted breast tissue aging, a novel measure of exposure to estrogen and progesterone based on the Pike model. We fitted conditional logistic regression to estimate odds ratio (OR) or odds ratio per adjusted standard deviation (OPERA) and calculated the area under the receiver operating characteristic curve (AUC). The stronger risk associations were for unadjusted percent breast density (OPERA = 1.99; AUC = 0.66), more so after adjusting for age and BMI (OPERA = 2.26; AUC = 0.70), and for family history (OR = 2.70; AUC = 0.56). When the latter two factors and their multiplicative interactions with age-adjusted breast tissue aging (p = 0.01 and 0.02, respectively) were fitted, the AUC was 0.73 (95% CI 0.69–0.77), equivalent to a ninefold interquartile risk ratio. In summary, compared with using dense breasts alone, risk discrimination for interval breast cancers could be doubled by instead using breast density, BMI, family history and hormonal exposure. This would also give women with dense breasts, and their physicians, more information about the major consequence of having dense breasts—an increased risk of developing an interval breast cancer.