Study on pharmacokinetic interactions between SHR2554 and itraconazole in healthy subjects: A single-center, open-label phase I trial.

BACKGROUND: SHR2554, a novel oral Enhancer of Zeste Homolog 2 inhibitor, shows broad-spectrum anti-tumor efficacy in preclinical studies. As SHR2554 is mainly metabolized by CYP3A4, it is helpful to conduct research on the effects of itraconazole, a strong inhibitor of CYP3A4-metabolizing enzymes, on the pharmacokinetic characteristics and safety of SHR2554. METHODS: We conducted a single-center, open-label pharmacokinetic study of itraconazole on SHR2554 in 18 healthy Chinese subjects. Subjects were orally administrated SHR2554 50 mg on Day 1, itraconazole 200 mg Quaque Die (QD) from Days 4 to 7, SHR2554 50 mg co-administrated with itraconazole 200 mg on Day 8, and itraconazole 200 mg QD from Days 9 to 12. Then, 4 ml of venous blood was collected at predetermined time points. Plasma SHR2554 concentrations were analyzed using a validated high-performance liquid chromatography tandem mass spectrometry method. Pharmacokinetic parameters were calculated using Phoenix WinNonlin v8.1. RESULTS: The Cmax of SHR2554 alone and in combination was 10.197 ± 7.0262 ng·ml-1 versus 70.538 ± 25.0219 ng·ml-1 , AUC0-∞ was 50.99 ± 19.358 h·ng·ml-1 versus 641.53 ± 319.538 h·ng·ml-1 , and AUC0-t was 28.70 ± 18.913 h·ng·ml-1 versus 612.13 ± 315.720 h·ng·ml-1 . Co-administration of SHR2554 and itraconazole caused 7.73-, 12.47-, and 23.75-fold adjusted geometric mean ratios increases in SHR2554 Cmax , AUC0-∞ and AUC0-t respectively. The co-administration regimen was well tolerated and had a good safety profile. CONCLUSIONS: Compared with a single dose of SHR2554 50 mg, the exposure of SHR2554 in vivo was significantly affected by the combined administration of itraconazole.

Long Short-Term Memory Network for Development and Simulation of Warfarin Dosing Model Based on Time Series Anticoagulant Data.

Background: Warfarin is an effective treatment for thromboembolic disease but has a narrow therapeutic index, and dosage can differ tremendously among individuals. The study aimed to develop an individualized international normalized ratio (INR) model based on time series anticoagulant data and simulate individualized warfarin dosing. Methods: We used a long short-term memory (LSTM) network to develop an individualized INR model based on data from 4,578 follow-up visits, including clinical and genetic factors from 624 patients whom we enrolled in our previous randomized controlled trial. The data of 158 patients who underwent valvular surgery and were included in a prospective registry study were used for external validation in the real world. Results: The prediction accuracy of LSTM_INR was 70.0%, which was much higher than that of MAPB_INR (maximum posterior Bayesian, 53.9%). Temporal variables were significant for LSTM_INR performance (51.7 vs. 70.0%, P < 0.05). Genetic factors played an important role in predicting INR at the onset of therapy, while after 15 days of treatment, we found that it might unnecessary to detect genotypes for warfarin dosing. Using LSTM_INR, we successfully simulated individualized warfarin dosing and developed an application (AI-WAR) for individualized warfarin therapy. Conclusion: The results indicate that temporal variables are necessary to be considered in warfarin therapy, except for clinical factors and genetic factors. LSTM network may have great potential for long-term drug individualized therapy. Trial Registration: NCT02211326; www.chictr.org.cn:ChiCTR2100052089.

Carnitine and Depression.

Depression has become one of the most common mental diseases in the world, but the understanding of its pathogenesis, diagnosis and treatments remains insufficient. Carnitine is a natural substance that exists in organisms, which can be synthesized in vivo or supplemented by intake. Relationships of carnitine with depression, bipolar disorder and other mental diseases have been reported in different studies. Several studies show that the level of acylcarnitines (ACs) changes significantly in patients with depression compared with healthy controls while the supplementation of acetyl-L-carnitine is beneficial to the treatment of depression. In this review, we aimed to clarify the effects of ACs in depressive patients and to explore whether ACs might be the biomarkers for the diagnosis of depression and provide new ideas to treat depression.

The role of pro- and mature neurotrophins in the depression.

Neurotrophic factors, which can provide nutritional support to neurons and neuronal cells, also played an important role in their proliferation and survival. As signaling molecules, it also mediated the learning, memory and other activities in the brain. The latest study shows that neurotrophic factors have diametrically opposing effects of the pro- and mature form through distinct receptors. In this review, we summarize the different forms of neurotrophic factors, related receptors, and the corresponding biological effects. More importantly, we expounded the physiology and pathology mechanisms of brain-derived neurotrophic factor(BDNF)in depression. It is hopefully to provide new idea on the relationship of neurotrophic factors and depression.