Pre-clinical pharmacological profile of QF-036, a potent HIV-1 maturation inhibitor.

QF-036 is an HIV-1 maturation inhibitor in pre-clinical development, and its antiviral activity against a laboratory HIV-1 strain and two drug-resistant strains was determined in the C8166 line. QF-036 was also subjected to absorption, distribution and metabolism (ADM) assessment in vitro, and pharmacokinetic profiles were evaluated in rats and monkeys. The 50% effective concentrations (EC50 ) of QF-036 against the three strains were 20.36 nM, 0.39 µM and 2.11 nM, respectively, demonstrating better antiviral potential than the first-generation antiviral maturation inhibitor bevirimat. QF-036 demonstrated moderate cell permeability, high plasma protein binding ability and good metabolic stability in vitro. After oral QF-036 administration to rats and monkeys, both species exhibited moderate bioavailability, and the plasma drug exposure increased in an approximately dose-proportional manner. When administered orally (30 mg/kg) to monkeys, the QF-036 plasma concentration (Cmax ) peaked at 3671 ng/mL (4.82 µM), 12 to 2410 times higher than the EC50 of laboratory or resistant HIV-1 strains. Moreover, the plasma concentration of QF-036 at 12 hours after administration was 263 ng/mL (0.35 µM), which approximately matched the highest EC50 value of the three test strains. The favourable viral inhibitory activity and pharmacokinetic properties provide critical support for QF-036 as a promising anti-HIV therapeutic candidate.

Single- and repeated-dose toxicity studies on the novel HIV maturation inhibitor QF-036 in Sprague-Dawley rats.

QF-036 is a novel human immunodeficiency virus (HIV) maturation inhibitor that is a lupine triterpenoid derivative. The objective of this study was to evaluate the safety of QF-036. A single oral toxicity and a 4-week repeated oral toxicity were investigated in Sprague-Dawley (SD) rats. The single oral toxicity study of QF-036 in SD rats showed that no mortality or visible pathological changes were noted at doses of 100, 300, and 1000 mg/kg. QF-036 exhibited a non-linear toxicokinetic profile over the dose range of 100-1000 mg/kg in the single dose study, and a saturation trend appeared at doses of 100 and 300 mg/kg. In the 4-week oral toxicity and toxicokinetic study, SD rats were given 0, 50, 100, and 200 mg/kg QF-036 once daily for 4 weeks, followed by a 4-week recovery period. No mortality or significant effects on food consumption, body weight, or behavior were observed. In addition, there were no test article-related changes in hematology, clinical biochemistry and histopathology. The no observed adverse effect level (NOAEL) was 200 mg/kg. The toxicokinetic study demonstrated a dose-dependent increase in the systemic exposure to QF-036 after 4 weeks of oral administration. There were no marked sex differences or drug accumulation observed for repeated doses of QF-036.

Primary Thyroid Extranasal NK/T-Cell Lymphoma Associated With Good Outcome: A Case Report and Literature Review: A Care-Compliant Article.

Most thyroid lymphomas are B-lineage, and T-cell lymphomas are rare. None of primary thyroid extranasal NK/T-cell lymphoma (NKTCL) has been reported in the literature. Here, we report a case of extranasal NKTCL exclusively arising in the thyroid in an 18-year-old Chinese.The patient presented with rapid anterior swelling at the neck and aggravated dyspnea for 2 months. Neck computer tomography scan revealed diffuse thyroid enlargement in the left lobe compressing the trachea. The thyroid function test was indicative of hypothyroidism. Gastroscopy demonstrated chronic nonspecific gastritis. Subtotal thyroidectomy was performed. Histological examination showed a diffuse infiltration of neoplastic lymphoid cells with an angiodestructive behavior. Immunophenotype is positive for CD2, CD56, CD43, and TIA-1, and typically negative for surface CD3. Epstein-Barr virus-encoded small RNAs were detected in tumor cells. A diagnose of primary thyroid extranasal NKTCL-N lymphoma was confirmed by the findings.The patient was treated with CHOP-L combination chemotherapy followed by local radiotherapy, and tolerated the modality well. The patient has been in remission for 28 months so far.To our knowledge, this is the first case report of primary extranasal NKTCL exclusively arising in the thyroid. The case has a relatively good treatment outcome with timely diagnosis and multimodality approach.