Licogliflozin for nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a study.

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease that may advance to fibrosis and lead to mortality; however, no pharmacotherapy is currently available. We tested the hypothesis that inhibition of both the sodium-glucose cotransporters 1 and 2 with licogliflozin would lead to improvement in NASH. A total of 107 patients with phenotypic or histologic NASH were randomized (1:2:2) to receive oral administration of either placebo (n = 21), licogliflozin 30 mg (n = 43) or 150 mg (n = 43) once daily for 12 weeks. Licogliflozin 150 mg showed a significant 32% (80% confidence interval (CI): 21-43%; P = 0.002) placebo-adjusted reduction in serum alanine aminotransferase after 12 weeks of treatment, the primary endpoint of the study. However, the 30 mg dose of licogliflozin did not meet the primary endpoint (placebo-adjusted reduction 21% (80% CI: 7-32%; P = 0.061)). Diarrhea occurred in 77% (33 of 43), 49% (21 of 43) and 43% (9 of 21) of patients treated with licogliflozin 150 mg, 30 mg and placebo, respectively, which was mostly mild in severity. No other major safety concerns were identified. Treatment with 150 mg licogliflozin led to reductions in serum alanine aminotransferase in patients with NASH. Studies of longer duration and in combination with drugs that have different mechanisms of action are needed to validate these findings and to define a role of licogliflozin as a therapeutic option for NASH. ClinicalTrials.gov identifier: NCT03205150.

Investigation and Management of Stool Frequency and Consistency Associated With SGLT1 Inhibition by Reducing Dietary Carbohydrate: A Randomized Trial.

Treatment with licogliflozin, a dual sodium-glucose co-transporter (SGLT)1/2-inhibitor, is associated with increased stool frequency and loose stools, attributed to SGLT1 inhibition. To investigate the effect of carbohydrate content and supplements on licogliflozin-induced stools, a randomized, open-label, two-part (N = 24/part), three-period crossover study was carried out in overweight or obese adults. Significantly higher (P < 0.01) change from baseline in 3-day total number of bowel movements was observed following 3 days of licogliflozin treatment (50 mg q.d.) together with a 50% carbohydrate meal compared with a 25% and 0% carbohydrate meal. The number of stools with Bristol Stool Chart score of 6 or 7 was also significantly lower following a 0% carbohydrate meal. Supplementation with psyllium 6 g or calcium carbonate 1 g had no effect on stool changes following treatment. Licogliflozin was generally safe and well-tolerated. Loose stool associated with licogliflozin treatment and ingestion of meals can be managed by reducing the carbohydrate content of meals taken with licogliflozin.

Licogliflozin, a Novel SGLT1 and 2 Inhibitor: Body Weight Effects in a Randomized Trial in Adults with Overweight or Obesity.

OBJECTIVE: The aim of this study was to explore the dose response of licogliflozin, a dual inhibitor of sodium/glucose cotransporter 1 (SGLT1) and 2 (SGLT2), by evaluating change in body weight in adults with overweight or obesity. METHODS: This dose-response analysis evaluated change in body weight following 24 weeks with four once-daily and twice-daily licogliflozin doses (2.5-150 mg) versus placebo (primary end point). A further 24-week analysis evaluated the efficacy and safety of two once-daily licogliflozin doses in maintaining initial weight reduction. RESULTS: Licogliflozin once daily or twice daily produced a significant dose-response signal for weight loss versus placebo (P < 0.0001). However, mean adjusted percent changes in body weight after 24 weeks were modest, ranging from -0.45% to -3.83% (in the 50 mg twice daily group [95% CI: -5.26% to -2.48%]; n = 75). Responder analysis of ≥ 5% weight loss at week 24 revealed significant differences versus placebo, which were most pronounced with highest doses of 50 mg twice daily (45.3%) and 150 mg once daily (42.9%) (both P < 0.01). While weight loss was greater at higher doses, gastrointestinal adverse events were also more frequent. The 50-mg once-daily dose had perhaps the best balance between efficacy and tolerability. CONCLUSIONS: Licogliflozin produced significant reductions in body weight versus placebo. However, the magnitude of weight reduction was modest.

Multifunctional novel Diallyl disulfide (DADS) derivatives with ß-amyloid-reducing, cholinergic, antioxidant and metal chelating properties for the treatment of Alzheimer's disease.

A series of novel Diallyl disulfide (DADS) derivatives were designed, synthesized and evaluated as chemical agents, which target and modulate multiple facets of Alzheimer's disease (AD). The results showed that the target compounds 5a-l and 7e-m exhibited significant anti-Aß aggregation activity, considerable acetylcholinesterase (AChE) inhibition, high selectivity towards AChE over butyrylcholinesterase (BuChE), potential antioxidant and metal chelating activities. Specifically, compounds 7k and 7l exhibited highest potency towards self-induced Aß aggregation (74% and 71.4%, 25 µM) and metal chelating ability. Furthermore, compounds 7k and 7l disaggregated Aß fibrils generated by Cu(2+)-induced Aß aggregation by 80.9% and 78.5%, later confirmed by transmission electron microscope (TEM) analysis. Besides, 7k and 7l had the strongest AChE inhibitory activity with IC50 values of 0.056 µM and 0.121 µM, respectively. Furthermore, molecular modelling studies showed that these compounds were capable of binding simultaneously to catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. All the target compounds displayed moderate to excellent antioxidant activity with ORAC-FL values in the range 0.546-5.86Trolox equivalents. In addition, absorption, distribution, metabolism and excretion (ADME) profile and toxicity prediction (TOPKAT) of best compounds 7k and 7l revealed that they have drug like properties and possess very low toxic effects. Collectively, the results strongly support our assertion that these compounds could provide good templates for developing new multifunctional agents for AD treatment.

Ingrown nails: a comparison of the nail matrix phenolization method with the elevation of the nail bed-periosteal flap procedure.

Seventy-five procedures were performed on 62 patients with ingrown nails from 1992 to 1996. Those consisted of 51 nail matrix phenolization methods (NMP) and 24 elevation of the nail bed-periosteal flap procedures (ENF). Ingrown nails were classified into type A (normal nail plate) and type B (incurved nail plate). The duration and intensity of postoperative pain were assessed, and the recurrence rate was monitered. The recurrence rate was 3.9% in the NMP group and 4.1% in the ENF group. Concerning the recurrence rate, there was no statistical significance between ENF and NMP in both types. Postoperative pain intensity was less in the NMP group than in the ENF group in both types (P < 0.01). The same tendency was seen in postoperative pain duration. However, the NMP group had longer duration of wound healing compared with the ENF group in type A (P < 0.01). We conclude that NMP is a recommendable treatment for most ingrown nails.

Phase I. evaluation of cyclocytidine (NSC-145668).

Cyclocytidine is a repository form of cytosine arabinoside and has a prolonged plasma half-life (8 hours) compared to cytosine arabinoside (12 minutes). A phase I trail was undertaken to establish the maximum tolerated dose. Nineteen patients were entered into the study (ten children, nine adults) and the dose which achieved consistent myelosuppression was established in five escalation increments as 600 mg/m for 10 days. This dose is consistent with previously reported data on the basic pharmacology of cyclocytidine and with optimum dose data in aminal tumor systems. Limiting toxicity, however, was related to the induction of postural hypotension which is not dose related. Recommendation to proceed with phase II studies of cyclocytidine must await clarification of the mechanism and prevention of the postural hypotension.

Clincal pharmacology of O2,2'-cyclocytidine.

Two metabolites of 2-14C-cyclocytidine (cyclo-C) were found in the plasma and urine and a hydrolytic product, arabinosylcytosine (ara-C), and its deaminated product, arabinosyluracil (ara-U), were found in patients with cancer; 80% of the dose was found in urine in 24 hr, 70% as cyclo-C and 10% as ara-C and ara-U. The plasma disappearance curve of ara-C curvilinear; the half-life of ara-C estimated from the terminal phase is 8 hr. By 6 hr, the ara-C level is 0.35 mug/ml and falls exponentially to 0.006 mug/ml by 24 hr. Plasma concentration ratios of ara-U to ara-C are 0.1 to 0.3, 0.3 to 0.4, and 1.1 to 1.3 at 10 min, 1 hr, and 4 hr following intravenous injection of cyclo-C at 200 mg/m2. Five min after an equal dose of ara-C, this ratio is approximately 2, and by 4 hr, plasma ara-C levels are immeasurable. After intramuscular and subcutaneous administration, cyclo-C is rapidly absorbed. The plasma disappearance curves of the cyclo-C hydrolytic product, ara-C, are similar to those of the intravenous route. Intramuscularly, subcutaneously, and intravenously cyclo-C should be equally effective. Intrathecal injections of cyclo-C (50 mg/m2) result in an effective ara-C level (0.1 mug/ml) in cerebrospinal fluid (CSF) at 24 hr. When cyclo-C is given orally to fasting patients, less than 15% of the dose is excreted in urine in 24 hr and none can be detected in the plasma.